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Dulaglutide.nxml | Dulaglutide | 2019-04-10 | Dulaglutide is a recombinant DNA produced polypeptide analogue of human glucagon-like peptide-1 (GLP-1) which is used in combination with diet and exercise in the therapy of type 2 diabetes, either alone or in combination with other antidiabetic agents. There have been no published reports of hepatotoxicity attributed to dulaglutide therapy. | Dulaglutide (doo" la gloo' tide) is a glucagon-like peptide-1 (GLP-1) analogue that acts like the native gastrointestinal hormone (incretin) to increase insulin secretion. Dulaglutide reproduces the activity of GLP-1, binding to specific receptors on pancreatic beta cells and increasing insulin secretion, which can lead to improvement of glycemic control in patients with type 2 diabetes. Dulaglutide, like other GLP-1 analogues, also causes weight loss which may contribute to its clinical effects. Dulaglutide is a recombinant DNA produced polypeptide that shares 97% homology to endogenous human GLP-1(7-37), but has an amino acid substitution which makes it resistant to DPP-4 degradation and thus extends its half-life in serum. In addition, the GLP-1 like polypeptide is linked to an Fc fragment of human IgG4 which further prolongs its serum half-life and duration of activity. Dulaglutide, like other GLP-1 analogues, must be given parenterally. Dulaglutide was approved for use in the United States in 2014 and current indications are for management of glycemic control in adults with type 2 diabetes in combination with diet and exercise, with or without other oral hypoglycemic agents. Dulaglutide is available under the brand name Trulicity in solution for subcutaneous injection in prefilled, single dose pens or syringes (0.75 and 1.5 mg/0.5 mL). The typical initial dose is 0.75 mg once weekly, which can be increased to 1.5 mg weekly. Dulaglutide is generally well tolerated, but side effects can be dose limiting and include nausea [~20%], vomiting [~5%], diarrhea [~12%], abdominal pain, decreased appetite, dyspepsia and fatigue. Rare side effects include pancreatitis [0.1-0.3%], hypoglycemia and hypersensitivity reactions. | In large clinical trials, serum enzyme elevations were no more common with dulaglutide therapy than with placebo or comparator agents, and no instances of clinically apparent liver injury were reported. Since licensure, there have been no published case reports of hepatotoxicity due to dulaglutide and the product label does not list liver injury as an adverse event. Thus, liver injury due to dulaglutide must be rare, if it occurs at all. | Dulaglutide is a polypeptide and is metabolized to amino acids by serum and tissue proteases, and is unlikely to have any direct hepatotoxic potential. Dulaglutide acts through the incretin pathway to affect glucose metabolism and, thus, is often grouped with other incretin-based antidiabetic mediations such as the DPP-4 inhibitors, sitagliptin, saxagliptin and linagliptin, and other GLP-1 analogues such as exenatide, liraglutide and albiglutide which are also discussed in LiverTox.\n\nReferences regarding the hepatotoxicity and safety of dulaglutide are given with the Overview section of the GLP-1 Analogues.\n\nDrug Class: Antidiabetic Agents\n\nOther Drugs in the Subclass, Incretin-Based Drugs, Glucagon-Like Peptide-1 (GLP-1) Analogues: Albiglutide, Exenatide, Liraglutide, Lixisenatide, Semaglutide | null | Dulaglutide – Trulicity® | Antidiabetic Agents | null |
Piroxicam.nxml | Piroxicam | 2020-03-20 | Piroxicam is a commonly used nonsteroidal antiinflammatory drug (NSAID) that is available by prescription only and is used in therapy of chronic arthritis. Piroxicam can cause mild serum aminotransferase elevations and, in rare instances, leads to clinically apparent acute liver injury that can be severe and even fatal. | Piroxicam (pir ox' i kam) belongs to the oxicam family, which is a class of enolic acids structurally unrelated to other NSAIDs. Piroxicam, like other NSAIDs, acts through inhibition of tissue cyclooxygenases (Cox-1 and -2) leading to a decrease in synthesis of pro-inflammatory prostaglandins, which are potent mediators of pain and inflammation. Piroxicam has analgesic as well as antipyretic and antiinflammatory activities. Piroxicam was approved for use in the United States in 1982 and is still widely used, with several million prescriptions filled yearly. Current indications include rheumatoid arthritis and osteoarthritis. Piroxicam is available as capsules of 10 and 20 mg in several generic forms as well as under brand names such as Feldene, Novo-Pirocam and Nu-Pirox. The recommended dose is 10 to 20 mg orally once daily. Piroxicam is available by prescription only. Other oxicam NSAIDs include meloxicam, tenoxicam, and droxicam, the latter two being available in other countries, but not the United States. As with other NSAIDs, piroxicam is generally well tolerated, but side effects can include headache, dizziness, somnolence, dyspepsia, abdominal discomfort, diarrhea, peripheral edema and hypersensitivity reactions. Rare but serious adverse events from NSAIDs include gastrointestinal ulceration and bleeding, increased risk for cardiovascular disease, renal dysfunction and hypersensitivity reactions including anaphylaxis, exfoliative dermatitis and Stevens Johnson syndrome. | Elevated serum aminotransferase levels have been reported in 3% to 18% of patients taking piroxicam, but symptomatic liver disease with jaundice is rare (estimated at 1 to 5 cases per 100,000 prescriptions). The latency to onset of symptoms of clinically apparent liver injury due to piroxicam is variable from a few days to several months, but is generally within the first 1 to 6 weeks of treatment. The pattern of injury is predominantly cholestatic, although cases presenting with mixed or hepatocellular patterns have been reported (Case 1). Eosinophilia, rash and fever can occur, but are not always present and are usually not prominent. Autoantibodies are rarely found. The injury is usually self-limited and recovery occurs within 1 to 2 months. Rare cases of acute liver failure have been reported.\n\nLikelihood score: B (rare but likely cause of clinically apparent liver injury). | The mechanism of piroxicam induced liver injury is not known, but may be due to a toxic metabolic intermediate of piroxicam metabolism, which occurs largely in the liver. Cases with allergic manifestations (fever, rash, eosinophilia) may also have a component of hypersensitivity. | Severity of the liver injury from piroxicam ranges from asymptomatic elevations in serum aminotransferase levels to severe hepatitis with acute liver failure. Several instances of chronic vanishing bile duct syndrome have been attributed to other oxicam NSAIDs, but not specifically to piroxicam. In most instances, however, complete recovery is expected after stopping the drug and usually takes one to two months. Cross sensitivity to liver injury among the various NSAIDs has not been well studied or described. Due to the wide availability of alternative medications, rechallenge with piroxicam and other oxicam forms of NSAIDs (meloxicam, droxicam, tenoxicam) should be avoided.\n\nDrug Class: Nonsteroidal Antiinflammatory Drugs, see also Meloxicam | Piroxicam – Generic, Feldene® | Nonsteroidal Antiinflammatory Drugs | null |
Ertapenem.nxml | Ertapenem | 2017-01-17 | Ertapenem is a broad spectrum carbapenem antibiotic used primarily for the treatment of aerobic gram-negative bacterial infections. Ertapenem, like other carbapenems, is associated with transient and asymptomatic elevations in serum enzymes. The carbapenems have also been linked to rare instances of clinically apparent, acute cholestatic liver injury. | Ertapenem (er" ta pen' em) is a broad spectrum beta-lactam antibiotic used predominantly for treatment of severe aerobic gram-negative infections. Ertapenem, like other carbapenems, binds to bacterial penicillin binding proteins and interferes with bacterial cell wall integrity and synthesis. It is a broad spectrum antibiotic with activity against many aerobic and anaerobic gram-positive and gram-negative organisms, including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis, Escherichia coli, Proteus mirabilis, Bacteroides fragilis and Peptostreptococcus species. Ertapenem was approved for use in the United States in 2001, and its use is largely restricted to serious infections in hospitalized patients. Ertapenem is indicated for the treatment of severe or complicated skin, tissue, joint, respiratory tract, intraabdominal, urinary tract and urogenital infections as well as endocarditis and sepsis due to susceptible organisms. The recommended dosage is 1 gram given intramuscularly once daily for 5 to 28 days. It is currently available as Invanz. The most common side effects of ertapenem are infusion site pain and phlebitis, diarrhea, nausea, rash, pruritus and headache. | Mild, transient, asymptomatic elevations in serum aminotransferase levels occur in about 5% of patients receiving parenteral ertapenem for 5 to 14 days. These abnormalities are usually self-limited and asymptomatic. In the limited period that it has been available, no cases of hepatitis with jaundice have been reported. Nevertheless, several instances of cholestatic jaundice arising during or shortly after therapy have been reported with other carbapenems. The latency to onset has been within 1 to 3 weeks and the pattern of enzyme elevations is usually cholestatic. Immunoallergic features can occur but autoantibodies are rare. The course is usually self-limiting, but at least one case of vanishing bile duct syndrome related to a carbapenem has been reported. Ertapenem and other carbapenems have not been linked to cases of acute liver failure.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury). | null | The liver injury due to the carbapenems is usually mild, asymptomatic and self-limited. Rarely, the carbapenems can cause a clinically apparent acute cholestatic hepatitis that is usually self-limiting and not requiring therapy or intervention. There is little information on possible cross sensitivity to liver injury among the different beta-lactam antibiotics, but patients with clinically apparent liver injury due to ertapenem should probably avoid the other carbapenems.\n\nReferences to the safety and potential hepatotoxicity of ertapenem are given in the Overview section on Carbapenems.\n\nDrug Class: Antiinfective Agents, Carbapenems\n\nOther Drugs in the Subclass, Carbapenems: Doripenem, Imipenem, Meropenem | Ertapenem – Invanz® | Antiinfective Agents | null |
Captopril.nxml | Captopril | 2018-02-11 | Captopril is an angiotensin-converting enzyme (ACE) inhibitor used in the therapy of hypertension and heart failure. Captopril is associated with a low rate of transient serum aminotransferase elevations and has been linked to rare instances of acute liver injury. | Captopril (kap' toe pril) was the first ACE inhibitor to be approved for use in the United States and is still widely used for therapy of hypertension and heart failure. Like other ACE inhibitors, captopril inhibits the conversion of angiotensin I, a relatively inactive molecule, to angiotensin II which is the major mediator of vasoconstriction and volume expansion induced by the renin-angiotensin system. Other enzymes besides that which converts angiotensin I to II may also be inhibited, which may account for some of the side effects of the ACE inhibitors. Captopril was approved for use in the United States in 1981 and current indications are for hypertension, congestive heart failure, left ventricular dysfunction after myocardial infarction, and treatment and prevention of diabetic nephropathy. Captopril is available in 12.5, 25, 50 and 100 mg tablets in many generic forms and formerly under the trade name Capoten. The typical dose of captopril in adults in 25 to 50 mg two or three times daily, and it is administered long term. Captopril is also available in several fixed combinations with hydrochlorothiazide (Capozide and others). Common side effects of captopril and ACE inhibitors in general include dizziness, fatigue, headache, cough, gastrointestinal upset and skin rash. | Captopril, like other ACE inhibitors, has been associated with a low rate of serum aminotransferase elevations (<2%) that, in controlled trials, was no higher than with placebo therapy. These elevations were transient and rarely required dose modification. While rare, several dozen cases of clinically apparent liver injury have been reported with captopril therapy. The onset is usually within 2 to 12 weeks of starting therapy and the serum enzyme pattern is typically cholestatic (Case 1). In some instances, cholestasis has been prolonged and relapsing and associated with persistent elevations in serum alkaline phosphatase, suggestive of vanishing bile duct syndrome. Immunoallergic manifestations (rash, fever, eosinophilia) are infrequent and most patients do not develop autoantibodies. Rare instances of captopril injury with a hepatocellular pattern and cases with a long latency (one or more years) have been described as well, a distinctly unusual pattern of drug induced liver injury.\n\nLikelihood score: B (likely but rare cause of clinically apparent liver injury). | The cause of the minor serum aminotransferase associated with captopril is not known. The clinically apparent acute liver injury from captopril is likely an idiosyncratic reaction to a metabolite. Captopril is hydrolyzed by the liver to its active metabolite captoprilat and has little further hepatic metabolism. | Most instances of acute liver injury reported with captopril use have been self limited, but there have been rare reports of acute liver failure due to captopril and several reports of cholestatic hepatitis leading to prolonged jaundice. Patients with severe captopril induced acute liver injury and hypersensitivity reactions should avoid use of other ACE inhibitors, although cross sensitivity to liver injury among the members of this class of agents has not always been shown.\n\nReferences to the safety and potential hepatotoxicity of captopril are given in the Overview section on the Angiotensin-Converting Enzyme (ACE) Inhibitors.\n\nDrug Class: Antihypertensive Agents, Angiotensin-Converting Enzyme Inhibitors | Captopril – Generic, Capoten® | Angiotensin-Converting Enzyme Inhibitors | null |
SawPalmetto.nxml | Saw Palmetto | 2020-04-02 | Saw palmetto is a popular herbal medication and extract derived from the fruit of the low growing, small palm, Serenoa repens, which has fan shaped leaves and is native to Florida and the Southeast United States. Currently, saw palmetto is used mostly for symptoms of benign prostatic hypertrophy. Saw palmetto has been implicated in rare cases of clinically apparent liver injury, but its specific role in causing liver injury remains uncertain. | Saw palmetto (saw pal met’ toe) is a widely used herbal derived from the fruit of the low growing bushy palm of the same name (Serenoa repens). Native Americans used saw palmetto fruit both as a food as well as an herbal remedy with multiple uses, including as a sedative, diuretic, sleeping aid, expectorant and cough suppressant, aid to lactation, infertility, indigestion and urinary problems. Currently, saw palmetto is one of the most widely used herbal medications and is used largely for symptomatic benign prostatic hypertrophy. Saw palmetto is available in multiple formulations including liquid extracts, tablets, capsules, and as an herbal tea. The active components of palmetto extracts are believed to be the volatile oils and free fatty acids which have activity in inhibiting 5-alpha-reductase and the conversion of testosterone to dihydrotesterone, which has been demonstrated in vitro, but not in human studies. In short term clinical trials, saw palmetto appeared to be beneficial in improving symptoms of prostatic hypertrophy, but it had no effects on prostate size or serum prostatic specific antigen (PSA) levels. In longer term studies, the benefit of saw palmetto in improving urinary symptoms of benign prostatic hypertrophy was less clear. Saw palmetto is available in multiple over-the-counter preparations often in combination with other herbals or dietary supplements, and most commonly for symptoms of urinary hesitancy, urgency or burning. Side effects of saw palmetto are uncommon and mild and may include dizziness, headache, nausea, vomiting, constipation and diarrhea. In most randomized controlled clinical trials, side effects were no more frequent with saw palmetto than with placebo therapy. | Chronic therapy with saw palmetto has not been linked to serum enzyme elevations and prospective trials found little or no evidence of liver injury from its administration. However, there have been rare case reports of clinically apparent liver injury attributed to saw palmetto, although in some instances, other possible causes of liver disease were present. In the reported cases, the latency to onset was within 1 to 2 weeks of starting therapy, and clinical features resembled acute viral hepatitis with a hepatocellular pattern of serum enzyme elevations and resolution within 1 to 3 months. Immunoallergic and autoimmune features were not present.\n\nLikelihood score: D (possible, rare cause of clinically apparent liver injury). | Saw palmetto extracts have many components, but none of them has been shown to be particularly hepatotoxic. The rare cases of liver injury reported with saw palmetto use have had idiosyncratic features. Saw palmetto has few herb-drug interactions and is not affected by inducers or inhibitors of the cytochrome P450 enzyme system. | Hepatotoxicity from saw palmetto is very rare and cases have been self-limiting upon stopping the herbal. There have been no instances leading to fatalities, liver transplantation, chronic hepatitis, or vanishing bile duct syndrome. Studies of rechallenge have not been reported.\n\nOther Names: Cabbage palm, Sabal\n\nDrug Class: Herbal and Dietary Supplements | Saw Palmetto – Generic | Herbal and Dietary Supplements | null |
Histrelin.nxml | Histrelin | 2023-05-28 | Histrelin is a gonadotropin releasing hormone (GnRH) agonist that is a potent inhibitor of production of testosterone (in men) and estrogen (in women) and is used predominantly to treat advanced prostate cancer. Histrelin is associated with a low rate of transient serum enzyme elevations during therapy, but has not been linked convincingly to cases of clinically apparent acute liver injury. | Histrelin (his trel' in) is a nonapeptide analogue of gonadotropin releasing hormone that acts on the pituitary to cause the synthesis and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH), two gonadotropins that act on the male testes to stimulate the production of testosterone and on the female ovaries to induce synthesis of estrogen. Histrelin and other GnRH agonists cause an initial surge of gonadotropin release, but then lead to down-regulation of their synthesis and secretion which results in a decline in testosterone and estrogen production. Histrelin, alone or in combination with other antiandrogens, has been found to be palliative in advanced prostate cancer and as effective as surgical castration. Histrelin was approved for use in the United States in 1991 and as a once-yearly implant formulation in 2004. The major indications for histrelin are advanced prostate cancer and precocious puberty. The GnRH agonists have also been used off label for precocious puberty, infertility, and as a part of gender affirming therapy. Histrelin is available under the brand names Supprelin (for precocious puberty) and Vantas (for prostate cancer; discontinued September 2021) in solution as implants of 50 mg, which are inserted subcutaneously in the inner aspect of the upper arm at 12 month intervals. Histrelin and the other GnRH analogues cause a profound hypogonadism ("chemical castration") and its common side effects are typical of androgen deprivation, including hot flashes, loss of libido, erectile dysfunction, depression, nausea, diarrhea, weight gain and fluid retention. Rare, but potentially severe adverse events include hypersensitivity reactions and transient tumor flare with the first injection. | Histrelin has been associated with serum enzyme elevations during therapy in rates similar to those of other GnRH analogues. The serum enzyme elevations are generally mild, asymptomatic and resolve even without dose adjustment or drug discontinuation. ALT elevations above 3 times the upper limit of normal occur in less than 1% of recipients. Histrelin has been linked to a single case of acute liver injury, but it was unclear from the report whether the episode was associated with jaundice or symptoms and other diagnoses remained possible. Thus, clinically apparent liver injury from histrelin may occur, but it is extremely rare and usually self-limited in course. There have been no episodes of acute liver failure, chronic hepatitis or vanishing bile duct syndrome associated with histrelin or other GnRH analogue therapy.\n\nLikelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury). | The cause of the minor serum enzyme elevations that can occur during histrelin therapy is unknown. Histrelin is a short peptide similar to GnRH and is metabolized locally in tissue and not by the hepatic cytochrome P450 system. Some serum enzyme elevations may be caused by nonalcoholic fatty liver arising because of weight gain or metabolic changes caused by the androgen deprivation state induced by the GnRH agonist. | The serum enzyme elevations during histrelin therapy rarely require dose modification or drug discontinuation and should instead lead to investigation of other possible causes of liver injury. There is no evidence for cross sensitivity to liver injury among the various GnRH analogues, despite their similarity in chemical structure.\n\nDrug Class: Antineoplastic Agents, GnRH Analogues\n\nOther Drugs in the Subclass, GnRH Analogues: Degarelix, Goserelin, Leuprolide, Relugolix, Triptorelin | Histrelin – Supprelin® | Antineoplastic Agents | null |
Apoaequorin.nxml | Apoaequorin | 2019-12-11 | Apoaequorin is a recombinant protein used as a dietary supplement that is purported to improve memory and verbal learning. Apoaequorin has not been associated with serum enzyme elevations during therapy nor with clinically apparent liver injury. | Apoaequorin is a calcium binding protein found in luminescent jellyfish (Aequorea victoria). When the natural (apo) form of the protein is conjugated with coelenterazine, the resulting protein aequorin has natural bioluminescence when exposed to calcium. For this reason, it has been used as a research molecule to study intracellular physiology and regulation of calcium flux. Recombinant apoaequorin, developed for use in research studies, was subsequently evaluated for its potential to improve memory. The basis for this use of aequorin was its calcium binding characteristics which resembled those of calmodulin, an intracellular protein complex which appears to play a central role in memory. A single trial of oral apoaequorin in patients with memory problems found no overall differences in changes in measures of verbal learning in comparison to placebo, but slightly greater improvements were reported in a subset of patients with normal cognitive test values at baseline. These findings were questioned later because of the lack of evidence that apoaequorin is absorbed orally or can cross the blood-brain barrier. Nevertheless, apoaequorin is marketed as a dietary supplement that supports brain health and helps with aging-related memory loss. It has been used off label in patients with amyotrophic lateral sclerosis and multiple sclerosis. Apoaequorin is available in tablets of 10, 20 and 40 mg under the brand name Prevagen. It has not been approved by the FDA as therapy of memory loss or neurologic illnesses. Side effects were not reported in the few prospective studies that have been published. Adverse events reported to the sponsor have been rare but have included headache, nausea, constipation, edema and hypertension. There have been anecdotal reports of serious adverse events in persons with multiple sclerosis taking apoaequorin including hypotension and depression with suicidal ideation. | Apoaequorin is considered generally safe and without major adverse effects. In the human studies that have been published there were no reports of serum enzyme elevations occurring during therapy and no mention of serious adverse events or hepatotoxicity.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).\n\nMechanism of Injury\n\nThe mechanism by which apoaequorin might cause hepatotoxicity is unclear. Indeed, there is little evidence that apoaequorin is absorbed orally, most proteins being broken down in the stomach and intestines to individual amino acids or short polypeptides. Allergic reactions can occur with proteins taken orally but have not been reported with apoaequorin. The possibility of mislabeling or adulteration with hepatotoxic natural products is always an issue in commercial supplements.\n\nDrug Class: Herbal and Dietary Supplements | null | null | Apoaequorin – Prevagen® | Herbal and Dietary Supplements | null |
Givosiran.nxml | Givosiran | 2020-02-27 | Givosiran is synthetic small interfering RNA (siRNA) molecule directed against 5-aminolevulinic acid synthase that is used to treat acute hepatic porphyria. Givosiran has been linked to mild-to-moderate ALT elevations during therapy, but has not been linked to instances of idiosyncratic acute liver injury with symptoms and jaundice. | Givosiran (giv” oh sir’ an) is a synthetic double stranded, small interfering RNA (siRNA) directed against 5-aminolevulinic acid synthase 1, which results in decreases in serum delta aminolevulinic acid (ALA) and porphobilinogen (PBG), intermediates in porphyrin metabolism which accumulate in patients with acute hepatic porphyrias and are believed to cause the neurologic and visceral symptoms of acute attacks. The siRNA molecule is covalently linked to three N-acetylgalactosamine residues which directs it to specific receptors found largely on hepatocytes. Once taken up by the hepatocyte, the siRNA is cleaved into smaller fragments and separated into single strands that bind and silence the mRNA of ALA synthase. In animal models, givosiran reduced ALA synthase mRNA levels in liver that was accompanied by a corresponding decline in urine and plasma ALA and PBG. In placebo controlled trials of givosiran in patients with recurring acute attacks, single infusions of givosiran resulted in dose related reductions in urinary ALA and PBG levels and, with monthly injections, annualized rates of attacks were reduced by 75% to 90%. Givosiran was approved for use in the United States for adults with acute hepatic porphyria in 2019. Current indications are limited to adults. Givosiran is available in solution in single dose vials of 189 mg/mL under the brand name Givlaari. The recommended regimen is 2.5 mg per kg body weight once monthly by subcutaneous injection. Givosiran is generally well tolerated but side effects can include nausea, injection site reactions, rash, fatigue and creatinine and serum aminotransferase elevations. Less common, but more severe side effects include severe injection reactions, anaphylaxis and recall reactions. In registration studies, immunogenicity was uncommon; only 1% of givosiran treated patients developed anti-drug antibodies. | The acute hepatic porphyrias are rare, and the pivotal trials of givosiran were conducted in rather small numbers of patients, so the full spectrum of hepatotoxicity may not be fully known. Nevertheless, in the registration controlled trials, serum aminotransferase elevations arose in 13% of givosiran- versus 2% of placebo-recipients, but rose to levels above 5 times the upper limit of normal only rarely. One patient was reported as discontinuing givosiran therapy because of aminotransferase elevations, but no patient developed concurrent elevations in serum bilirubin or symptoms suggestive of hepatitis. Thus, givosiran has not been linked to instances of acute hepatitis or jaundice, but it has had limited clinical use.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury). | The cause of hepatic injury from the givosiran and other siRNA therapeutics is unknown. One possibility is that suppression of 5-aminolevulinic acid synthase may cause cell damage in some hepatocytes. The mRNA suppression appears to lower but not completely eliminate enzyme activity, but individual hepatocytes may vary in the sensitivity to the enzyme inhibition and effects of its loss. Givosiran is metabolized intracellularly by nucleases and is not a substrate of cytochrome P450 enzymes. On the other hand, the chronic inhibition of ALA synthase can result in decreases in CYP 1A2 and 2D6 synthesis and lead to supra-therapeutic or toxic levels of drugs that are metabolized by these enzymes. | The liver injury associated with givosiran therapy has invariably been mild, not associated with jaundice and rapidly resolving often without discontinuation or even dose adjustment. In prelicensure clinical trials, subjects received hemin therapy for acute attacks without evidence of liver injury, and there is no reason to suspect cross reactivity of hepatic injury with other therapies of acute porphyria. Monitoring of liver tests during therapy is recommended during givosiran therapy as well as interruption or discontinuation for significant elevations in serum aminotransferases.\n\nDrug Class: Genetic Disorder Agents\n\nOther Therapeutic siRNA and Antisense Agents: Eteplirsen, Golodirsen, Patisiran | Givosiran – Givlaari® | Genetic Disorder Agents | null |
Anagrelide.nxml | Anagrelide | 2017-07-05 | Anagrelide is an antithrombotic and platelet reducing agent that is used to treat the thrombocythemia associated with myeloproliferative diseases. Anagrelide has had limited clinical use, but has not been linked to significant serum enzyme elevations during therapy or to instances of clinically apparent acute liver injury. | Anagrelide (an ag' re lide) is platelet reducing agent that is used to treat thrombocytosis due to myeloproliferative diseases. Its mechanism of action is not well defined, but it appears to inhibit the maturation and differentiation of megakaryocytes, and both synthesis and release of platelets as well as subsequent platelet aggregation. In addition, anagrelide inhibits phosphodiesterase-3 which causes vasodilation and may account for many of its side effects. In several open label trials, anagrelide was shown to reduce platelet counts in patients with thrombocythemia due to essential thrombocytosis and other myeloproliferative diseases. Severe thrombocythemia is associated with an increased risk of arterial and venous thromboses including transient ischemic attacks, stroke, myocardial infarction and other thrombotic ischemic conditions. Less commonly, thrombocytosis is associated with venous thromboses including deep vein thrombosis, pulmonary embolus and portal or splanchnic vein thrombosis. Anagrelide was approved for use in thrombocythemia due to myeloproliferative diseases in 1997, but is considered a second line agent, appearing to be less effective and less well tolerated than hydroxyurea. Anagrelide is available in capsules of 0.5 mg generically and under the brand name Agrylin. The typical initial dose is 0.5 mg daily, with subsequent gradual and monitored dose escalation based upon platelet counts and tolerance, not to exceed 10 mg daily or 2.5 mg in a single dose. It is often given in combination with aspirin. Side effects can include headache, dizziness, palpitations, fatigue, nausea, abdominal pain, dyspnea, cough, fever, edema, rash, chest pain and tachycardia. Rare, but potentially severe adverse reactions include arrhythmias, prolongation of the QTc interval, excessive bleeding and interstitial nephritis. | In preregistration studies, anagrelide was not associated with serum enzyme elevations or with episodes of clinically apparent liver injury. Since its approval, there has been a single published abstract reporting progressive, ultimately fatal cholestasis after liver transplantation and use of anagrelide, but there have been no other published reports of anagrelide hepatotoxicity in the literature. In large, long term follow up studies there have been occasional instances of transient serum enzyme elevations without jaundice or symptoms. The product label for anagrelide mentions abnormal enzymes as an adverse event but not clinically apparent liver injury, hepatitis or jaundice. However, the general clinical experience with anagrelide has been limited.\n\nLikelihood score: E* (unlikely, but suspected rare cause of clinically apparent liver injury). | The mechanism by which anagrelide might cause serum aminotransferase elevations or liver injury is not known. The typical daily dose is low (1 to 10 mg), which may account for its relative lack of hepatotoxicity.\n\nDrug Class: Antithrombotic Agents\n\nOther Drugs in the Subclass (Primary Thrombocythemia): Hydroxyurea, Interferon alfa, Aspirin | null | Anagrelide – Generic, Agrylin® | Antithrombotic Agents | null |
ThrombopoietinRecept.nxml | Thrombopoietin Receptor Agonists | 2018-12-30 | The thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts. Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins were used clinically, they were found to cause rebound thrombocytopenia, probably due to induction of anti-thrombopoietin antibodies. For this reason, direct administration of thrombopoietin was abandoned as an approach to treating thrombocytopenia and other approaches to activating the thrombopoietin receptor were sought.\n\nSeveral thrombopoietin receptor agonists were subsequently developed and are now in clinical use for chronic idiopathic thrombocytopenic purpura (ITP) and for raising platelet counts in persons with thrombocytopenia undergoing surgical procedures or other thrombocytopenic conditions. Eltrombopag, lusutrombopag and avatrombopag are peptide-like, small molecular weight agonists of the thrombopoietin receptor. These agents are given by mouth and result in significant increases in platelet counts in normal persons as well as patients with thrombocytopenia due to hematologic and liver diseases. Romiplostim, in contrast, is a recombinant polypeptide that binds to and activates the thrombopoietin receptor despite having no amino acid homology to native thrombopoietin. It also increases platelet counts in normal subjects as well as patients with chronic ITP but has not been associated with induction of anti-thrombopoietin antibodies. | null | null | null | null | Avatrombopag – Doptelet® | Hematologic Growth Factors | [
{
"cas_registry_number": "570406-98-3",
"molecular_formula": "C29-H34-Cl2-N6-O3-S2",
"name": "Avatrombopag"
},
{
"cas_registry_number": "496775-61-2",
"molecular_formula": "C25-H22-N4-O4",
"name": "Eltrombopag"
},
{
"cas_registry_number": "1110766-97-6",
"molecular_formula": ... |
Romidepsin.nxml | Romidepsin | 2020-09-25 | Romidepsin is an intravenously administered histone deacetylase inhibitor and antineoplastic agent that is approved for use in refractory or relapsed cutaneous and peripheral T cell lymphomas. Romidepsin is associated with modest rate of minor serum enzyme elevations during therapy but has not been linked to cases of clinically apparent liver injury, although it has been reported to cause reactivation of hepatitis B. | Romidepsin (roe" mi dep' sin) is an intravenously administered antineoplastic agent which acts by inhibition of histone deacetylases, thereby preventing removal of acetyl groups from histones. The accrual of acetyl groups on histones causes cell cycle arrest and apoptotic cell death. Malignant cells and particularly malignant T cells are particularly sensitive to the effects of inhibition of histone deacetylases. Romidepsin was initially isolated from a bacterium Chromobacterium violaceum and found to have antineoplastic activity. Elucidation of its molecular structure and analysis of its in vitro effects demonstrated that it was a histone deacetylase. Romidepsin has been evaluated as therapy of several malignancies and found to have greatest activity in T cell lymphomas. Romidepsin was approved for use in the United States in 2009 as monotherapy for refractory or relapsing cutaneous T cell lymphoma (CTCL) and indications were expanded in 2011 to include refractory or relapsing peripheral T cell lymphoma (PTCL). Romidepsin is available as a powder for reconstitution in 10 mg vials under the commercial name Istodax. The recommended dose is 14 mg/m2 given intravenously on days 1, 8 and 15 of a 28 day cycle. Side effects are common, but usually mild-to-moderate in severity, and include nausea, fatigue, fever, anemia, neutropenia, thrombocytopenia, constipation and rash. Side effects lead to early discontinuation in up to 15% of patients. Severe adverse events can include marked neutropenia, thrombocytopenia, serious infections, sepsis, tumor lysis syndrome and cardiac arrhythmias. | In clinical trials of romidepsin in patients with CTLC and PTLC, the rates of serum enzyme elevations during therapy ranged from 7% to 20%, but the abnormalities were usually transient and mild and did not require dose modifications. Serum ALT elevations above 5 times ULN occurred in 6% of patients. In the preregistration clinical trials of romidepsin, there were no reports of hepatitis, jaundice or clinically apparent liver injury among the treated subjects. Romidepsin has had limited clinical use, but there is no evidence that it is associated with significant liver injury.\n\nRomidepsin also has immunomodulatory activities and has been reported to cause reactivation of latent DNA viruses including Epstein-Barr, varicella zoster and hepatitis B virus. Reactivation of hepatitis B occurred in a patient who was initially negative for HBsAg, but reactive for anti-HBc and anti-HBs. Nevertheless, the clinical features of hepatitis B reactivation were mild and responded to oral antiviral therapy. In patients with EBV associated lymphoma, romidepsin has been associated with severe reactivation of EBV infection and acute hepatitis that can be severe and even fatal.\n\nLikelihood score: C (probable cause of clinically apparent liver injury, which can be due to reactivation of hepatitis B or EBV infection). | The reason why romidepsin might cause serum enzyme elevations is not known, but may be a direct toxicity to hepatocytes caused by inhibition of histone deacetylase or other enzyme activities. Romidepsin is metabolized in the liver by cytochrome P450 system, predominantly CYP 3A4 and is susceptible to drug-drug interactions. Reactivation of hepatitis B and EBV is likely due to the immunomodulatory actions of romidepsin. | Serum enzyme elevations during romidepsin therapy are usually mild and rarely dose limiting. Romidepsin should be held if ALT or AST values rise above 5 times the ULN and should be permanently discontinued if elevations exceed 20 times the ULN, or with the appearance of jaundice or symptoms of liver injury. There is no known cross sensitivity to hepatic injury among the different histone deacetylase inhibitors. Patients who are to receive romidepsin should be screened for evidence of hepatitis B and monitored carefully or given prophylaxis against HBV reactivation if they have evidence on ongoing or previous infection. Patients with active EBV infection should be treated with caution and with prophylaxis against reactivation.\n\nDrug Class: Antineoplastic Agents, Histone Deacetylase Inhibitors | Romidepsin – Istodax® | Antineoplastic Agents | null |
Zolpidem.nxml | Zolpidem | 2018-02-20 | Zolpidem is a benzodiazepine receptor agonist that is used for the treatment of insomnia. Zolpidem has rarely been implicated in causing serum enzyme elevations and has not been reported to cause clinically apparent liver injury. | Zolpidem (zol' pi dem) is a non-benzodiazepine, benzodiazepine receptor agonist of the imidazopyridine class that acts by binding to the benzodiazepine (BZ) site on the GABA receptor complex, causing neural inhibition and helping to induce sleep. Zolpidem has selectivity for certain BZ receptor subtypes and does not have the neuromuscular relaxation or anticonvulsant effects of the standard benzodiazepines. Zolpidem has a short half life and rapid onset of action. In multiple placebo controlled trials, zolpidem was shown to decrease the latency to onset of sleep and improve perceived sleep quality with minimal next day residual somnolence or rebound insomnia after withdrawal. Zolpidem was approved for use in the United States in 1992 for the short term treatment of insomnia and is the most commonly prescribed medication for insomnia with more than 10 million prescriptions filled yearly. Zolpidem is available in 5 and 10 mg tablets generically and under the brand name Ambien. The recommended dose is 5 mg taken orally immediately before bedtime. Higher doses should be used with caution as they may result in next-morning impairment in motor activity that may affect driving. Zolpidem is also available in an extended release and in a low dose sublingual form (3.5 mg) for middle-of-the-night awakening. Like the other benzodiazepine receptor agonists, zolpidem is classified as a Schedule IV controlled substance (low potential for abuse and limited physical or psychological dependence). Side effects are uncommon, usually mild and may include headache, nausea, dizziness and drowsiness. | In multiple premarketing randomized controlled trials, zolpidem was not associated with an increased rate of serum enzyme elevations in comparison to placebo therapy. A single instance of clinically apparent liver injury has been reported. The onset of injury was 2 days after a single dose of zolpidem and was accompanied by abdominal pain, but no jaundice. The pattern of liver enzyme elevations was hepatocellular and the abnormalities were self-limited, although they seemed to recur on reexposure. Zolpidem is metabolized in the liver by the cytochrome P450 system (predominantly CYP 3A4) and can cause drug-drug interactions, although such interactions are rare. Thus, zolpidem has not been linked to cases of liver injury with jaundice, but rarely may cause transient, mild-to-moderate serum enzyme elevations with or without symptoms.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).\n\nDrug Class: Sedatives and Hypnotics\n\nOther Drugs in the Subclass, Benzodiazepine Receptor Agonists: Eszopiclone, Zaleplon | null | null | Zolpidem – Generic, Ambien® | Sedatives and Hypnotics | null |
Tofacitinib.nxml | Tofacitinib | 2022-08-30 | Tofacitinib is an oral, small molecule inhibitor of Janus kinases that is used to treat moderate-to-severe rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Tofacitinib is associated with transient and usually mild elevations in serum aminotransferase levels during therapy, but has yet to be linked to cases of clinically apparent acute liver injury. | Tofacitinib (tow" fa sye' ti nib) is an orally available, specific inhibitor of Janus-associated kinases (mainly JAK1 and JAK3) that is used to treat moderate-to-severe rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. The Janus kinases are critical steps in immune activation as well as in hematopoiesis. The immunomodulatory effects of tofacitinib led to its evaluation in several autoimmune conditions including rheumatoid arthritis and psoriasis. In multiple, randomized controlled trials, tofacitinib was found to improve symptoms and signs of severe rheumatoid arthritis and psoriatic arthritis when used alone or in combination with other disease modifying antirheumatologic drugs (DMARDs). Tofacitinib was approved for use in rheumatoid arthritis in the United States in 2012. Subsequently, indications were expanded to psoriatic arthritis and inflammatory bowel disease. The Janus kinase inhibitors including tofacitinib are also being evaluated as therapy of the COVID-19, focusing upon alleviating the hyperinflammatory stages of advanced COVID-19 infection. At present, indications for tofacitinib are limited to moderate-to-severe rheumatoid arthritis and active psoriatic arthritis after failure or intolerance to methotrexate or other non-biological DMARDs, juvenile idiopathic arthritis with a polyarticular course, and moderately to severely active ulcerative colitis after failure of tumor necrosis factor (TNF) inhibitors. Tofacitinib is available in tablets of 5 and 10 mg under the brand name Xeljanz. The recommended dose is rheumatoid arthritis and psoriatic arthritis is 5 mg twice daily. For patients with active ulcerative colitis, an induction dose of 10 mg twice daily is recommended for the first three months. More recently, an extended release formulation of tofacitinib (Xeljanz XR, 11 and 22 mg tablets) that allows for once daily dosing has been made available. Common side effects of tofacitinib are neutropenia, headaches, diarrhea, fatigue, hypertension and symptoms of upper respiratory tract infection. Severe adverse events may include severe infections, reactivation of latent tuberculosis or herpes zoster, gastrointestinal perforation, venous and arterial thromboses, and de novo malignancies including Epstein-Barr virus related lymphoproliferative disorder. | In large registration clinical trials, serum aminotransferase elevations occurred in 28% to 34% of tofacitinib treated subjects compared to 25% in comparator arms and 10% in placebo recipients. These elevations were typically mild and transient, but values above 3 times the upper limit of normal (ULN) occurred in 1% to 2% of patients on tofacitinib compared to less than 1% on placebo. The elevations occasionally led to early discontinuations, but more often resolved even without dose adjustment. In prelicensure studies, there were no instances of clinically apparent liver injury attributed to tofacitinib. Since approval and more wide scale availability of tofacitinib, there have been no published reports of hepatotoxicity associated with its use but a proportion of patients do develop serum aminotransferase elevations which in some cases leads to drug discontinuation. While other Janus kinase inhibitors such as ruxolitinib have been associated with episodes of reactivation of hepatitis B, spontaneous reports of clinically apparent reactivation of hepatitis during tofacitinib therapy have not been reported. On the other hand, retrospective studies on patients with HBsAg and inactive liver disease who were treated with tofacitinib have been reported to develop rising levels of HBV DNA and modest elevations in serum aminotransferase levels without symptoms. In contrast, studies of patients with anti-HBc without HBsAg in serum have shown no evidence of HBV DNA rises and appearance of HBsAg. Thus, reactivation of hepatitis B during therapy can occur, although it is generally mild and self-limited in course. Whether reactivation of hepatitis B can arise after therapy of susceptible patients with tofacitinib for severe COVID-19 pneumonia is unknown, but there have been no such reports to date.\n\nLikelihood score: E* (suspected but unproven rare cause of clinically apparent liver injury with the potential to cause reactivation of hepatitis B). | The causes of serum enzyme elevations during tofacitinib therapy are not known. Tofacitinib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic or immunogenic intermediate. Because it is a substrate for CYP 3A4, tofacitinib is susceptible to drug-drug interactions with agents that inhibit or induce this specific hepatic microsomal activity. Tofacitinib is a potent immunomodulatory agent and appears to be capable of causing reactivation of hepatitis B. | Monitoring of serum aminotransferase levels is recommended for patients starting tofacitinib. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to dose reduction or temporary cessation. There are no data to suggest a cross reactivity in risk for hepatic injury between tofacitinib and other kinase inhibitors or biologic or nonbiologic DMARDs. Because tofacitinib is capable of inducing reactivation of hepatitis B, patients starting long term therapy with tofacitinib should be screened for HBsAg and anti-HBc. Patients with preexisting HBsAg in serum should undergo evaluation and prophylaxis against reactivation of HBV using potent oral antiviral agents, such as tenofovir or entecavir. Those with anti-HBc without HBsAg or HBV DNA should be monitored for evidence of infection and treated if there is de novo appearance of HBsAg or HBV DNA.\n\nDrug Class: Antirheumatic Agents, Protein Kinase Inhibitors, COVID-19 Drugs | Tofacitinib – Xeljanz® | Antirheumatic Agents | [
{
"cas_registry_number": "941678-49-5",
"molecular_formula": "C17-H18-N6",
"name": "Ruxolitinib"
},
{
"cas_registry_number": "477600-75-2",
"molecular_formula": "C16-H20-N6-O",
"name": "Tofacitinib"
}
] |
Acalabrutinib.nxml | Acalabrutinib | 2021-03-21 | Acalabrutinib is an oral inhibitor of Bruton’s tyrosine kinase that is used in the therapy of B cell malignancies including refractory mantle cell lymphoma and chronic lymphocytic leukemia. Acalabrutinib has been associated with mild-to-moderate serum enzyme elevations during therapy but has not been linked to instances of idiosyncratic acute liver injury, although it has been associated with cases of reactivation of hepatitis B which can be severe and even fatal. | Acalabrutinib (a kal" a broo' ti nib) is an orally available, small molecule inhibitor of Bruton’s tyrosine kinase (BTK), which is an essential component in the B cell receptor signaling pathway. Inhibition of this pathway prevents B cell activation, differentiation and proliferation. Deficiency of BTK is the cause of X linked (Bruton’s) agammaglobulinemia, and B cell receptor signaling through BTK has been shown to be critical for proliferation and survival of malignant B lymphocytes in mantle cell lymphoma and chronic lymphocytic leukemia (CLL). Unlike ibrutinib, another BTK inhibitor, acalabrutinib has a high degree of specificity for BTK and has little or no activity against other tyrosine kinases. Acalabrutinib was approved for use in the United States as therapy for refractory mantle cell lymphoma in 2017 and for CLL and small lymphocytic lymphoma in 2019. It is under evaluation in other malignancies such as Waldenstrӧm’s macroglobulinemia, pancreatic and non-small cell lung cancer. Acalabrutinib is available in capsules of 100 mg under the brand name Calquence. The recommended dose is 100 mg twice daily. Side effects are common, but usually mild-to-moderate in severity; they include myelosuppression, fatigue, diarrhea, nausea, headache, arthralgia, myalgia, bruising and rash. Uncommon, but potentially serious side effects include severe bone marrow suppression, severe or opportunistic infections, bleeding episodes, hypertension, cardiac arrhythmias and secondary malignancies. | In open label clinical trials of acalabrutinib in patients with CLL and mantle cell lymphoma, serum aminotransferase elevations occurred in 19% to 23% of patients during therapy and rose to above 5 times ULN in 2% to 3%. These elevations were transient and resolved spontaneously but occasionally led to early drug discontinuation. Among the 610 patients treated with acalabrutinib in pre-registration trials, there were no instances of clinically apparent liver injury attributed to its use, but there was a single instance of acute liver failure and death due to reactivation of hepatitis B. Similar cases of reactivation have been reported with ibrutinib, another small molecule inhibitor of Bruton's tyrosine kinase. Experience with acalabrutinib has been limited and the frequency of clinically apparent liver injury and reactivation of hepatitis B are not known. The majority of cases have occurred in patients taking multiple immunosuppressive agents and not just acalabrutinib alone.\n\nLikelihood score: D (possible rare cause of reactivation of hepatitis B). | The mechanism by which acalabrutinib might cause liver injury is unknown but may be due to off-target inhibition of tyrosine kinases. Acalabrutinib is metabolized in the liver largely by the CYP 3A4 and is susceptible to drug-drug interactions with inhibitors or inducers of this enzyme reactivity. Reactivation of hepatitis B from acalabrutinib is probably the result of profound B cell suppression, which can lead to increases in viral replication, which can result in severe hepatitis upon immune reconstitution. | Liver injury due to acalabrutinib is generally mild and asymptomatic. Reactivation of hepatitis B, however, can result in severe hepatitis and even acute hepatic failure. Patients who are to receive B cell inhibitors such as acalabrutinib, ibrutinib, rituximab and usteokinumab should be screened for serologic markers of hepatitis B infection, including HBsAg and anti-HBc before starting chemotherapy, and those who are positive given prophylaxis against reactivation using oral antiviral agent with activity against HBV such as tenofovir or entecavir. Alternatively, patients can be monitored carefully for changes in HBV DNA levels during therapy. If HBV DNA levels appear de novo or increase significantly (by 10-fold or greater; at least one log increase in HBV DNA), initiation of antiviral therapy is appropriate. Therapy should be continued for at least six months after immunosuppressive therapy has been completed.\n\nDrug Class: Antineoplastic Agents, Protein Kinase Inhibitors | Acalabrutinib – Calquence® | Antineoplastic Agents | [
{
"cas_registry_number": "1420477-60-6",
"molecular_formula": "C26-H23-N7-O2",
"name": "Acalabrutinib"
},
{
"cas_registry_number": "936563-96-1",
"molecular_formula": "C25-H24-N6-O2",
"name": "Ibrutinib"
}
] |
Selegiline.nxml | Selegiline | 2017-07-21 | Selegiline is an inhibitor of monamine oxidase used in the treatment of depression and as adjunctive therapy in combination with levodopa and carbidopa in the therapy of Parkinson disease. Selegiline has been associated with a low rate of serum enzyme elevations during treatment, but has not been linked to instances of clinically apparent acute liver injury. | Selegiline (se le' ji leen) is a specific inhibitor of monamine oxidase (MAO) type B, which is a major enzyme in the pathway of dopamine and levodopa metabolism. As a result, selegiline results in an increase in the bioavailability of levodopa, enhancing and increasing the duration of its effects in Parkinson disease. Selegiline is also an antidepressant, its mechanism of action being inhibition of dopamine reuptake from the synaptic cleft. Selegiline was approved for use in the United States in 2006, the first MAO-B inhibitor approved for use in the therapy of Parkinson disease as an adjunct to levodopa therapy. Selegiline is available in capsules and tablets of 5 mg generically and under the brand name Eldepryl, the typical dose being 10 mg daily in two divided doses. It is also available in oral disintegrating tablets of 1.25 mg under the brand name Zelapar, which is given once or twice daily. Transdermal patches of selegiline in amounts of 6, 9 and 12 mg/24 hours are available under the brand name Emsam for treatment of depresssion, the usual dose being 6 to 12 mg daily. Common side effects include headache, nausea, dizziness, agitation, delusions, insomnia, orthostatic hypotension, dry mouth, headache and gastrointestinal upset – most of which are attributable to enhanced dopaminergic effects. In higher doses, selegiline can also inhibit MAO-A and, similar to the nonspecific MAO inhibitors, cause increased susceptibility to dietary tyramine inducing hypertensive crises (“cheese effect”). | Selegiline has been reported to cause serum enzyme elevations in up to 40% of patients treated long term. Although the abnormalities were usually mild and self-limiting, they were persistent with continuation of treatment in some patients, ultimately requiring drug discointuation. Selegiline has not been implicated in cases of clinically apparent acute liver injury, but such instances have been reported with other less specific MAO inhibitors.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | Selegiline is extensively removed from the blood by the liver (first pass metabolism) and undergoes hepatic conjugation and elimination. The pathways of selegiline metabolism have not been well defined. | The only liver abnormalities that have attributed to selegiline have been mild and self-limiting elevations in serum enzymes. No instances of acute hepatitis, acute liver failure, chronic hepatitis or vanishing bile duct syndrome have been linked to selegiline use.\n\nDrug Class: Antiparkinson Agents\n\nOther Drugs in the Subclass, Selective MAO-B Inhibitors: Rasagiline, Safinamide | Selegiline – Generic, Atapryl®, Eldepryl® | Antiparkinson Agents | null |
Chlorzoxazone.nxml | Chlorzoxazone | 2017-01-30 | Chlorzoxazone is a centrally acting muscle relaxant commonly used for low back pain. Chlorzoxazone has been linked to rare instances of acute liver injury, a few of which have been fatal. | Chlorzoxazone (klor zox' a zone) acts centrally rather than directly on muscles to relieve muscle spasms, either through its sedative effects or other unknown mechanisms. Chlorzoxazone is indicated for therapy of low back pain and muscle spasms, although its overall efficacy is considered only fair. Chlorzoxazone was approved for use in the United States in 1958 and is still widely used. It is available in various generic forms as well as under the brand names of Parafon Forte and Remular in tablets of 250 or 500 mg. The usual recommended dose in adults is 250 to 750 mg orally three to four times daily, reducing the dose to lowest effective level once a response occurs. Chlorzoxazone is typically given for 1 to 4 weeks only. Common side effects of chlorzoxazone include dizziness, drowsiness, headache, fatigue and tremor. | There have been no adequate prospective studies demonstrating the rates of ALT or AST elevations on chlorzoxazone therapy. Rare instances of clinical apparent liver disease possibly attributable to chlorzoxazone have appeared, including fatal cases. Such cases must be very rare, as this agent is widely used. While case reports have been few, in many instances chlorzoxazone was clearly implicated; furthermore, a related muscle relaxant with similar structure (zoxazolamine) was withdrawn from use in 1961, largely because of hepatotoxicity. The usual latency period is 1 to 4 weeks and the pattern of disease typically hepatocellular with marked elevations in ALT levels and jaundice, with minimal increases in alkaline phosphatase. Cholestatic enzyme elevations after exposure to chlorzoxazone have also been described. Allergic manifestations (rash and fever) are common, particularly in cases with a short latency (Case 1); autoantibodies are rare. Recovery is rapid once chlorzoxazone is stopped, but fatal cases have been reported, with disease progression despite early discontinuation of the agent (Case 2). There is rapid recurrence of injury with reexposure, often accompanied by fever.\n\nLikelihood score: B (Highly likely cause of clinically apparent liver injury). | The cause of acute hepatic injury from chlorzoxazone is unknown, but is clearly idiosyncratic and likely due to hypersensitivity. | The idiosyncratic liver injury due to chlorzoxazone ranges from mild, self-limited hepatitis to severe, protracted liver injury leading to death or need for liver transplantation. Rechallenge leads to rapid return of hepatic injury and should be avoided. No cross reactivity with other muscle relaxants has been identified.\n\nDrug Class: Muscle Relaxants | Chlorzoxazone – Generic, Parafon Forte® | Autonomic Agents: Muscle Relaxants, Central | null |
SerotoninRcptAgonist.nxml | Serotonin Receptor Agonists (Triptans) | 2018-02-10 | The triptans are a group of serotonin receptor agonists that are useful in the therapy of vascular headaches and migraine. The triptans are generally used in low doses for a limited period of time and have not been associated with serum enzyme elevations, but some have been implicated in rare instances of clinically apparent, acute cholestatic hepatitis. | The triptans (trip' tans) are synthetic serotonin receptor agonists that are used in the therapy of migraine and vascular headache. Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine that has multiple actions, acting as a neurotransmitter and bioactive amine. The diversity of actions of serotonin is partially due to the multitude of different serotonin receptors and their tissue location. There are at least 15 classes of serotonin receptors which have overlapping actions, but variable distribution and intracellular pathways of response to stimulation and inhibition. The triptans are serotonin agonists with high affinity for the 5-HT1B and 5-HT1D receptors which are found on smooth-muscle cells of blood vessels. Simulation of the 5-HT1D receptor results in constriction of intracranial blood vessels. The triptans may also block the release of vasoactive peptides from perivascular trigeminal neurons through their action at presynaptic 5-HT1D receptors on nerve terminals. Regardless, the triptans have been found to be effective in preventing or aborting migraine headaches with shortening of the period of pain and symptoms. The triptans are considered “first line” agents for patients whose vascular headaches do not reliably respond to conventional analgesics. They generally have a more rapid onset of action and fewer side effects than the ergot alkaloids. Seven triptans are approved for use in the United States including almotriptan (al" moe trip' tan), eletriptan (el" e), forvatriptan (froe" va), naratriptan (nar"' a), rizatriptan (rye" za, sumatriptan (soo" ma) and zolmitriptan (zole" ma). Generic formulations are available for most agents. The short acting triptans include sumatriptan, almotriptan, eletriptan, rizatriptan and rolmitriptan and generally provide relief within 30 to 60 minutes. The longer activing oral triptans include naratriptan and frovatriptan which have a slower onset of action but may be better tolerated. Intranasal formulations may have a more rapid onset of action as do subcutaneous administered forms. Brand names, year approved, tablet or wafer size, usual dose and maximum daily recommended doses are shown in the Table.\n\n* Also available as nasal spray, transdermal patch and solution for injection.\n\n** Also available in orally disintegrating tablets and as nasal spray.\n\nEarly therapy is recommended in patients with recurrent migraine, and typically the dose is repeated in 2 to 4 hours if relief has not occurred. However, the total dosage should be limited to 2 to 3 doses per 24 hour period. Parenteral and intranasal administration is helpful in patients with nausea and vomiting. Chronic, long term use of triptans to prevent migraines has been studied, but is not currently approved. The seven triptans have similar side effect profiles which include “triptan sensations” characterized by tightening of the throat, chest, neck and limbs with paresthesias and hot or cold sensations. Triptans may also cause flushing, headache, somnolence and fatigue. Rare but potentially severe adverse events include medication overuse syndrome, cerebrovascular and cardiovascular events such as myocardial infarction and stroke, serotonin syndrome and anaphylaxis. | In large prospective controlled trials, the different triptans have not been associated with serum enzyme elevations or hepatotoxicity; however, the frequency of monitoring in most studies was limited and rates of ALT elevations not reported. There have been rare individual reports of cholestatic hepatitis after the use of triptans, largely associated with zolmitriptan. Typically, the onset of injury was within 1 to 2 weeks of taking several doses of the zolmitriptan for a protracted and severe migraine attack. Recurrent jaundice with intermittent therapy has also been reported (Case 1). The pattern of serum enzyme elevations was mixed or cholestatic, and recovery was complete within 1 to 2 months. Allergic manifestations (rash, fever, eosinophilia) were not present and autoantibodies did not develop.\n\nLikelihood score, zolmitriptan: D (probable rare cause of clinically apparent liver injury).\n\nLikelihood score, rizatriptan: E* (suspected but unproven cause of liver injury).\n\nLikelihood score, other triptans: E (unlikely cause of clinically apparent liver injury). | The cause of idiosyncratic liver injury after triptan use is not known, but is likely due to a toxic metabolite causing an acute, cholestatic hepatitis-like injury. An intriguing hypothesis is that the serotonin agonist activity causes biliary dyskinesis and functional obstruction. | null | Almotriptan – Generic, Almogran®, Axert® | Migraine Headache Agents | [
{
"cas_registry_number": "154323-57-6",
"molecular_formula": "C17-H25-N3-O2-S",
"name": "Almotriptan"
},
{
"cas_registry_number": "177834-92-3",
"molecular_formula": "C22-H26-N2-O2-S.Br-H",
"name": "Eletriptan"
},
{
"cas_registry_number": "158930-17-7",
"molecular_formula": "... |
Thioguanine.nxml | Thioguanine | 2017-08-17 | Thioguanine (also referred to as 6-thioguanine and as tioguanine) is a purine analogue that is used in the therapy of acute and chronic myelogenous leukemias. Thioguanine therapy is associated with minor, usually transient and asymptomatic elevations in serum aminotransferase levels and has also been linked to rare instances of cholestatic acute liver injury and to chronic liver injury, resulting in portal hypertension due to nodular regenerative hyperplasia. | Thioguanine (thye" oh gwa' neen) is a thiopurine, a purine analogue and antimetabolite. It is a derivative of mercaptopurine (2-amino-6-mercaptopurine) and, like its parent molecule, inhibits purine metabolism, thus blocking DNA, RNA and subsequent protein synthesis. Thioguanine also has antiinflammatory activity. Thioguanine was approved for use in the United States in 1966 and is commonly used in the therapy of acute and chronic myelogenous (nonlymphocytic) leukemias. Thioguanine has also been used off-label to treat autoimmune diseases as a steroid sparing agent. Thioguanine is available generically and under the brand name of Tabloid as tablets of 40 mg. The usual dose is 1 to 3 mg per kilogram or 40 to 120 mg daily and it is typically given long term. Common side effects include nausea, abdominal upset, rash, aphthous ulcers and dose related bone marrow suppression. | As with other thiopurines, thioguanine has been associated with several forms of hepatotoxicity, including mild, transient and asymptomatic rises in serum aminotransferase levels, an acute hepatic injury developing during the first year of starting therapy, and a chronic hepatic injury marked by variable degrees of peliosis hepatis, veno-occlusive disease and/or nodular regenerative hyperplasia. Chronic injury typically arises 1 to 5 years after starting thioguanine and can present insidiously with signs and symptoms of portal hypertension.\n\nMild serum aminotransferase elevations can occur during thioguanine therapy, particularly with high doses during the first 12 weeks of therapy. These elevations are generally asymptomatic, benign and self-limited, resolving rapidly either with stopping therapy, decreasing the dose and often even with continuing treatment without modifications. ALT elevations during thioguanine therapy may be due to a direct toxic effect of the drug; ALT elevations as well as myelotoxicity have been linked to higher levels of methyl-mercaptopurine, a product of one of the metabolic pathways of thioguanine metabolism.\n\nThe acute hepatic injury due to thioguanine usually presents with fatigue and jaundice and with a mixed hepatocellular-cholestatic pattern of serum enzyme elevations after 2 to 12 months of starting therapy. Rash, fever and eosinophilia are uncommon and autoantibodies are generally not found. Liver biopsy typically shows intrahepatic cholestasis with focal hepatocellular necrosis and scant inflammation. The liver injury usually resolves rapidly on stopping, but prolonged cholestasis has been reported and some cases have been fatal. This form of hepatotoxicity appears to be idiosyncratic and a class effect of the thiopurines, although more typical of azathioprine than thioguanine or mercaptopurine.\n\nThe chronic thioguanine hepatotoxicity typically presents with fatigue and signs and symptoms of portal hypertension with mild liver enzyme abnormalities and minimal jaundice arising 6 months to many years after starting thioguanine. Liver biopsy shows nodular regenerative hyperplasia and varying amounts of sinusoidal dilation and central vein injury. This syndrome can progress to hepatic failure, particularly if thioguanine is continued, but improvement on stopping therapy is typical. The onset of this syndrome may be acute with abdominal pain and ascites, in which situation liver biopsy usually shows sinusoidal dilation, central congestion and injury to sinusoidal endothelial cells suggestive of veno-occlusive disease, which is currently referred to as sinusoidal obstructive syndrome. Typically, serum aminotransferase levels and alkaline phosphatase levels are minimally elevated, even in the presence of hyperbilirubinemia and other manifestations of hepatic dysfunction and portal hypertension. Many cases of nodular regenerative hyperplasia due to the thiopurines present initially with thrombocytopenia of unknown cause, and a gradual decrease in platelet count is probably the most reliable marker for the development of non-cirrhotic portal hypertension. Among the thiopurines, this syndrome is more frequent with thioguanine than azathioprine, and appears to be least frequent with mercaptopurine.\n\nFinally, long term therapy with thiopurines has been implicated in leading to the development of malignancies, including hepatocellular carcinoma (HCC) and hepatosplenic T cell lymphoma (HSTCL). Both of these complications are rare, but have been reported in several dozen case reports and small case series, most frequently with azathioprine. In neither instance, has the role of thiopurine therapy in causing the malignacies been proven, and similar cases have been described in patients with autoimmune conditions or after solid organ transplantation who have not received thiopurines. Hepatocellular carcinoma typically arises after years of thiopurine therapy and in the absence of accompanying liver disease (although sometimes with focal hepatic glycogenosis). The HCC is most frequently found on an imaging study done of an unrelated condition. The prognosis is more favorable than that of HCC associated with cirrhosis. Hepatosplenic T cell lymphoma has been reported largely among young men with inflammatory bowel disease and long term immunosuppression with a thiopurine with or without anti-tumor necrosis factor therapy. The typical presentation is with fatigue, fever, hepatosplenomegaly and pancytopenia. The diagnosis is made by bone marrow or liver biopsy showing marked infiltration with malignant T cells. HSTCL is poorly responsive to antineoplastic therapy and has a high mortality rate.\n\nLikelihood score: A (well known cause of clinically apparent liver injury). | The mechanism by which thioguanine causes idiosyncratic acute liver injury is not known, but is likely due to an immunological response to a metabolic byproduct of its metabolism. Thioguanine undergoes extensive hepatic metabolism to 6-mercaptopurine and thereafter to other thiopurines via three different pathways. Patients with deficiency in thiopurine methyltransferase which mediates one of these metabolic pathways have a higher rate of complications of thioguanine use, particularly bone marrow suppression. but do not appear to be at higher rise of acute cholestasis or nodular regeneration. The cause of the nodular regenerative hyperplasia that develops after long term thioguanine therapy is not well defined, but it appears to be due to injury to endothelial cells that causes variable degrees of venous outflow obstruction or vascular damage that promotes the nodular transformation. This form of injury is more likely to be a direct toxic effect of the antimetabolite. | The serum aminotransferase elevations that occur during thioguanine therapy may improve spontaneously or with dose reduction and generally resolve rapidly with discontinuation. In patients who have aberrant metabolism of thiopurines to 6-methylmercaptopurine (6-MMP) as shown by elevated plasma levels, lowering the dose of thiopurine and adding allopurinol (100 mg daily) may lower 6-MMP levels, reverse aminotransferase elevations while maintaining 6-thioguanine (6-TGN) levels and clinical response. Both the acute cholestasis and the chronic nodular regeneration caused by thioguanine improve upon stopping the medication, but instances of progression to hepatic failure despite discontinuation of thioguanine have been reported with both syndromes. Rechallenge with thioguanine usually results in recurrence of the injury (within days to weeks) and should be avoided. Some patients have tolerated switching therapy to mercaptopurine or azathioprine, but substitution with a structurally unrelated antimetabolite may be more appropriate.\n\nDrug Class: Antineoplastic Agents, Antimetabolites\n\nOther Drugs in the Subclass, Purine Analogues: Azathioprine, Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Nelarabine, Pentostatin\n\nSee also: Transplant Drugs\n\nOther Drugs in the Subclass, Purine Analogues/Thiopurines: Azathioprine, Mercaptopurine | Thioguanine – Generic, Tabloid® | Antineoplastic Agents | null |
disclaimer.nxml | Disclaimer | 2019-09-03 | null | null | null | null | null | null | null | null |
Famotidine.nxml | Famotidine | 2018-01-25 | Famotidine is a histamine type 2 receptor antagonist (H2 blocker) which is commonly used for treatment of acid-peptic disease and heartburn. Famotidine has been linked to rare instances of clinically apparent acute liver injury. | Famotidine (fam oh' ti deen) was the third H2 blocker introduced into clinical practice in the United States and is a commonly used agent for treatment of duodenal and gastric ulcer and gastroesophageal reflux disease. The H2 blockers are specific antagonists of the histamine type 2 receptor, which is found on the basolateral (antiluminal) membrane of gastric parietal cells. The binding of famotidine to the H2 receptor results in inhibition of acid production and secretion, and improvement in symptoms and signs of acid-peptic disease. The H2 blockers inhibit an early, “upstream” step in gastric acid production and are less potent that the proton pump inhibitors, which inhibit the final common step in acid secretion. Nevertheless, the H2 blockers inhibit 24 hour gastric acid production by about 70% and are most effective in blocking basal and nocturnal acid production. Famotidine was first approved for use in the United States in 1986 and more than 3 million prescriptions for it are filled yearly. Famotidine is now available both by prescription and over-the-counter. The listed indications for famotidine are duodenal and gastric ulcer disease, gastroesophageal reflux and prevention of stress ulcers. Famotidine is available in tablets of 20 and 40 mg in several generic forms and in parenteral forms under the brand name Pepcid. Over-the-counter formulations are typically gelcaps or tablets of 10 or 20 mg. Liquid solutions are also available for intravenous use. The typical recommended dose for therapy of peptic ulcer disease in adults is 40 mg once daily for 4 to 8 weeks and maintenance therapy of 20 mg daily. Lower, chronic and intermittent doses of famotidine are used for therapy of heartburn and indigestion. Side effects are uncommon, usually minor, and include diarrhea, constipation, fatigue, drowsiness, headache and muscle aches. Famotidine is metabolized by the hepatic cytochrome P450 system, but has minimal inhibitory effects on the metabolism of other drugs, making it less likely to cause drug-drug interactions than cimetidine. | Chronic therapy with famotidine has been associated with minor elevations in serum aminotransferase levels in 1% to 4% of patients, but similar rates were reported in placebo recipients. The ALT elevations are usually asymptomatic and transient, and may resolve without dose modification. Rare instances of clinically apparent liver injury have been reported in patients receiving famotidine, but few cases have been reported and clinical characteristics in published cases have varied in the time to onset and pattern of injury. Onset has ranged from 1 to 14 weeks and serum enzyme pattern has typically been hepatocellular. The injury resolves within 4 to 12 weeks of stopping famotidine. Immunoallergic features (rash, fever, eosinophilia) are uncommon, as is autoantibody formation.\n\nLikelihood score: C (probable rare cause of clinically apparent liver injury). | Famotidine is metabolized by the microsomal P450 drug metabolizing enzymes and injury may be the result of its activation to a toxic intermediate. | The hepatic injury caused by famotidine is usually rapidly reversible with stopping the medication (Case 1). Famotidine has not been definitively linked to cases of acute liver failure, chronic hepatitis, prolonged cholestasis or vanishing bile duct syndrome. The results of rechallenge have not been reported. There appears to be cross reactivity in hepatic injury with cimetidine (Case 2). If acid suppression is required, use of an unrelated proton pump inhibitor is probably prudent for patients with clinically apparent famotidine induced liver injury.\n\nThe H2 receptor blockers include cimetidine, famotidine, nizatidine, and ranitidine. Combined general references on the H2 receptor blockers are given together after this overview section, while specific references are provided in the separate section on each drug. See also the Proton Pump Inhibitors.\n\nDrug Class: Antiulcer Agents\n\nOther Drugs in the Subclass, Histamine Type 2 Receptor Antagonists: Cimetidine, Nizatidine, Ranitidine | Famotidine – Generic, Pepcid® | Antiulcer Agents | null |
Oliceridine.nxml | Oliceridine | 2024-07-05 | Oliceridine is an intravenously administered, synthetic opioid that is used to treat moderate-to-severe pain not responsive to nonsteroidal antiinflammatory agents. Oliceridine is associated with a low rate of serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent liver injury. | Oliceridine (oh” li ser’ i deen) is an intravenously administered, synthetic opioid approved for use in moderate-to-severe acute pain in adults after surgery or painful procedures. Oliceridine is an agonist of the μ-opioid receptor with a potency similar to that of morphine, but with post-receptor actions that are biased to G protein signaling and with less β-arrestin2 recruitment and receptor internalization. This bias in μ-opioid receptor agonism was associated with fewer adverse effects in animal models, but this selectivity has been less well shown in humans. In several controlled trials, intravenous oliceridine was shown to be superior to placebo in controlling postoperative pain, but responses were numerically less than with morphine. Oliceridine was approved in the United States in 2020 for management of adults with acute pain severe enough to require intravenous opioid analgesia. Oliceridine is available in 1 and 2 mg single dose vials (1 mg/mL) and as a 30 mg single patient use vial of 30 mL (1 mg/mL) for patient-controlled analgesia. The common adverse events of oliceridine are similar to other opiates and include nausea, vomiting, headache, dizziness, constipations, pruritus, and respiratory depression with hypoxia. The gastrointestinal adverse events appear to be less frequent and milder with oliceridine than with morphine. Severe adverse events include serious, life threatening or fatal respiratory depression particularly in patients with chronic pulmonary disease, the elderly, debilitated patients, and those on other CNS depressants. High doses of oliceridine may cause prolongation of the QTc interval and dosing should be limited to less than 27 mg daily. Oliceridine, like other opioid drugs, has a boxed warning for addiction, abuse, and misuse. Use of oliceridine during pregnancy may cause fetal harm and can result in neonatal opioid withdrawal syndrome. | Serum ALT elevations developed in 1% to 3% of patients receiving oliceridine and in a similar proportion (2.4%) receiving morphine after abdominal surgery. However, the aminotransferase elevations were not associated with jaundice and were usually considered unrelated to therapy. Since approval of oliceridine, there have been no published reports of clinically apparent liver injury attributed to its use.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | Oliceridine like other opioid analgesics has not been associated with significant liver injury. The reasons for its lack of hepatotoxicity may relate to the short duration of therapy and the low doses used. Oliceridine is metabolized in the liver predominantly by cytochrome P450 enzymes (CYP 2D6 and 3A4). | The product label for oliceridine does not recommend screening or monitoring for routine liver tests before or during therapy.\n\nDrug Class: Opioids, Opioid Antagonists\n\nOther Drugs in this Class: Alfentanil, Fentanyl, Morphine, Remifentanil, Sufentanil | Oliceridine – Olinvyk® | Opioids | null |
Eplerenone.nxml | Eplerenone | 2021-10-13 | Eplerenone is an aldosterone receptor antagonist and potassium-sparing diuretic used in the therapy of hypertension. Eplerenone therapy has been associated with transient elevations in serum aminotransferase levels, but has yet to be linked to cases of clinically apparent drug induced liver disease. | Eplerenone (e pler' e none) is a competitive antagonist of aldosterone at the mineralocorticoid receptor. The aldosterone receptor in the late distal tubules and collecting ducts of the kidneys induces sodium reabsorption and potassium excretion in the distal tubule. Inhibition of this receptor promotes a sodium diuresis, but maintains body potassium levels. Eplerenone has a higher affinity for the aldosterone receptor than spironolactone and is claimed to have fewer anti-androgenic effects (gynecomastia, hair loss). However, the two molecules are structurally quite similar. Eplerenone was approved for use in the United States in 2002 for treatment of hypertension and later for improving survival of stable patients with heart failure after myocardial infarction. Eplerenone is available in 25 and 50 mg tablets generically and under the brand name of Inspra. The typical dose of eplerenone is 25 or 50 mg once daily initially, with modification of the dose based upon blood pressure response and tolerance, maintenance doses ranging from 25 to 100 mg daily in one or two divided doses. Eplerenone is well tolerated and the most common side effects are hyperkalemia and increases in serum creatinine. | Eplerenone therapy has been associated with a low rate of serum aminotransferase elevations which are typically mild and transient. ALT elevations of greater than 3 times the ULN occurred in 0.7% and greater than 5 times in 0.2% of eplerenone treated compared to 0.3% and 0.3% of placebo treated subjects. Idiosyncratic, clinically apparent liver injury from eplerenone has yet to be reported. The similarity in structure to spironolactone suggests that it may share susceptibility to the acute liver injury reported rarely with that agent.\n\nLikelihood score: E* (unproven but suspect rare cause of clinically apparent liver injury). | Eplerenone is metabolized in the liver by the cytochrome P450 system (CYP 3A4) and hepatic reactions may be generated by intermediates in its metabolism. | The mild serum aminotransferase elevations that have been reported with eplerenone resolved rapidly on discontinuation and in some instances resolved even with drug continuation. While yet unproven, cross reactivity to the liver injury that can occur with spironolactone should be assumed.\n\nDrug Class: Diuretics, Potassium-Sparing Diuretics\n\nOther Drugs in the Subclass: Amiloride, Spironolactone, Triamterene | Eplerenone – Generic, Inspra® | Diuretics | null |
LoopDiuretics.nxml | Loop Diuretics | 2021-10-13 | The loop diuretics are potent and widely used agents in the therapy of edematous states and congestive heart failure and less commonly for hypertension. Clinically apparent acute liver injury due to the loop diuretics is exceeding rare, if it occurs at all. | The loop diuretics act by inhibition of the sodium-potassium-chloride symporter present in the thick ascending limb of the loop of Henle causing an inhibition of sodium reuptake. The increase in delivery of sodium to the distal convoluted loop overwhelms its capacity for sodium reabsorption and a brisk sodium diuresis ensues. The loop diuretics are grouped together because of shared mechanism of action, but they have distinct chemical structures. The loop diuretics are more potent than the typical thiazide diuretics and usually have a shorter duration of action. As a result, the loop diuretics are used more for the therapy of edema than long term therapy of hypertension. Common and shared side effects of the loop diuretics include dizziness, headache, gastrointestinal upset, hyponatremia, hypokalemia and dehydration. Uncommon but potentially severe adverse events include profound electrolyte and water loss, dehydration leading to hypotension and syncope, electrolyte depletion with hypokalemia, hypomagnesemia, and hyponatremia, increases in serum creatinine and uric acid with worsening of renal failure and precipitation of hepatic encephalopathy in patients with cirrhosis, hyperuricemia, gout, ototoxicity, thrombocytopenia and hypersensitivity reactions.\n\nFurosemide (fure oh' se mide) was the first loop diuretic to be approved in the United States (1966) and is still widely used with more than 37 million prescriptions filled yearly. Furosemide is available in tablets of 20, 40 and 80 mg in generic forms and under the brand name Lasix. Furosemide is also available as an oral solution and as a liquid solution for injection. The usual adult dose of furosemide is 20 to 320 mg daily, given in one to three divided doses.\n\nEthacrynic (eth a krin' ik) acid was the second loop diuretic to be approved for use in the United States (1967), but is now rarely used; it remains available in 25 mg tablets and a solution for intravenous use generically and under the brand name Edecrin. The usual oral adult dose is 25 to 100 mg in one to three divided doses daily.\n\nBumetanide (bue met' a nide) is a potent loop diuretic that was approved for use in the United States in 1983 and continues to be used for the treatment of edema. Bumetanide is available as tablets of 0.5, 1 and 2 mg in generic forms and under the trade name of Bumex as well as a solution for parenteral administration. The usual oral adult dose is 0.5 to 2 mg once daily.\n\nTorsemide (tor' se mide) was approved for use in edema in the United States in 1993 and is still in common use used for both edema and hypertension. Torsemide is available in tablets of 5, 10, 20 and 100 mg in generic forms and under the brand name of Demadex. Solutions are available for intravenous use as well. The usual oral adult dose is 5 to 20 mg once daily. | Use of the loop diuretics has not been associated with an increased rate of serum aminotransferase elevations. There have been only rare, reported cases of clinically apparent liver injury associated with loop diuretics and most of these reports were not very convincing. Interestingly, furosemide causes a direct hepatotoxicity in mice and has been used as an animal model of drug induced liver injury. This injury does not appear to occur in humans. Instances of liver injury in patients on furosemide usually present with ischemic hepatitis (shock liver) caused by heart failure with diuretic induced dehydration and hypotension. Thus, idiosyncratic, clinically apparent liver injury from the loop diuretics must be exceeding rare, if it occurs at all.\n\nLikelihood score, all loop diuretics: E (unlikely causes of clinically apparent liver injury). | The cause of the rare occurrence of clinically apparent liver injury associated with the loop diuretics is not known. These agents are metabolized minimally by the liver and generally have rapid renal excretion. | Cases of clinically apparent liver injury due to the loop diuretics have been too few to characterize their severity and course. There have been no published instances of acute liver failure or chronic liver injury attributed to any of the loop diuretics. Cross reactivity among the four agents is unlikely because of the variability of their chemical structure.\n\nDrug Class: Diuretics | Bumetanide – Generic, Bumex® | Diuretics | [
{
"cas_registry_number": "28395-03-1",
"molecular_formula": "C17-H20-N2-O5-S",
"name": "Bumetanide"
},
{
"cas_registry_number": "58-54-8",
"molecular_formula": "C13-H12-Cl2-O4",
"name": "Ethacrynic Acid"
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{
"cas_registry_number": "54-31-9",
"molecular_formula": "C12-H11-Cl-... |
Apalutamide.nxml | Apalutamide | 2023-03-15 | Apalutamide is a third generation, oral nonsteroidal antiandrogen used to treat nonmetastatic castration-resistant prostate cancer. Apalutamide is associated with a low rate of serum enzyme elevation during therapy but has not been linked to cases of clinically apparent liver injury with jaundice. | Apalutamide (a pa lut' a mide) is a small molecule androgen receptor antagonist which binds to the intracellular receptor and prevents its translocation to the nucleus and subsequent DNA binding, thereby blocking its activity. Therapy with apalutamide lowers residual testosterone levels after surgical castration in men with prostate cancer and has been shown to prolong metastasis free survival in men with castration-resistant prostate cancer with rising levels of prostate-associated antigen (PSA) without measurable metastatic disease. Apalutamide was approved for use in the United States in 2018 and current indications include metastatic, castration-sensitive prostate cancer and non-metastatic castration-resistant prostate cancer. Apalutamide is available as tablets of 60 and 240 mg under brand name Erleada. The recommended initial dose is 240 mg daily with subsequent dose reduction for intolerance. It should be administered with a gonadotropin-releasing hormone (GnRH) analog or after bilateral orchiectomy to insure optimal androgen suppression. Common side effects include symptoms of androgen deficiency including fatigue, diarrhea, nausea, anorexia, weight loss, constipation, joint and muscle pain, hot flushes, headaches, dizziness, and edema. Rare, but potentially serious side effects associated with long term therapy include seizures, osteoporosis, falls, bone fractures, severe cutaneous adverse events, embryo-fetal toxicity, and cardiovascular events. | In prelicensure controlled trials of apalutamide, serum aminotransferase elevations were uncommon and generally transient and mild, not requiring dose modification. Clinically apparent liver injury with jaundice attributable to apalutamide was not reported in the preregistration trials and is not mentioned as an adverse event in the product label. Since the approval and general clinical use of apalutamide, there have been no publications or descriptions of the clinical features of hepatotoxicity with jaundice associated with its use. The first and second generation androgen receptor blockers, flutamide, nilutamide, and bicalutamide, have all been linked to instances of hepatitis-like liver injury with jaundice that can be severe and even fatal. However, such cases have not been described with apalutamide and other third generation androgen receptor antagonists. Thus, clinically apparent liver injury due to apalutamide must be rare, if it occurs at all.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | The possible cause of liver injury due to apalutamide therapy is unknown. While first and second generation antiandrogens have been implicated in causing liver injury, the more potent third general factors have not. Apalutamide is extensively metabolized in the liver predominantly by CYP 2C8 and 3A and is an inducer of CYP 3A4. While coadministration of apalutamide with substrates of CYP 3A4 and with modulators of CYP 2C8 and 3A4 may result in drug-drug interactions, the effects are relatively modest. | The liver injury linked to apalutamide therapy has been generally mild, consisting of transient and asymptomatic elevations in serum aminotransferase levels and rarely requiring dose modification or discontinuation. Apalutamide has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There is no information on cross sensitivity to hepatic injury between apalutamide and other antiandrogens, such as flutamide, bicalutamide, or abiraterone.\n\nDrug Class: Antineoplastic Agents, Antiandrogens | Apalutamide – Erleada® | Antineoplastic Agents | null |
Temozolomide.nxml | Temozolomide | 2020-09-02 | Temozolomide is an orally administered alkylating agent used largely in the therapy of malignant brain tumors including glioblastoma and astrocytoma. Temozolomide has been associated with a low rate of serum enzyme elevations during treatment and with rare instances of clinically apparent cholestatic liver injury. | Temozolomide (tem" oh zol' oh mide) is an imidazotetrazine derivative similar to dacarbazine (DTIC), which acts as an alkylating agent disrupting DNA replication, causing modification and cross linking of DNA, thus inhibiting DNA, RNA and protein synthesis and causing programmed cell death (apoptosis) in rapidly dividing cells. Temozolomide rapidly crosses the blood-brain barrier and has been evaluated largely in the therapy of malignant brain tumors. Temozolomide has been shown to induce tumor regression and remissions in patients with malignant astrocytoma and glioblastoma multiforme. It may also have activity in melanoma. Temozolomide was approved for use in the United States in 1999 and is now commonly used in treating patients with malignant brain tumors. Temozolomide is available in capsules of 5, 20, 100, 140, 180 and 250 mg and as a solution for injection generically and under the brand name of Temodar. The recommended dose regimen is calculated based on phase (initial cycles, maintenance), body weight, bone marrow toxicity and tolerance. It is typically given in a dose of 150 mg/m2 once a day during concurrent radiation therapy for 42 days followed by 75 mg/m2 on days 1 to 5 of each 28 day cycle. Temozolomide is considered somewhat less toxic and better tolerated than many other alkylating agents, but does have the common side effects of fatigue, nausea and vomiting, gastrointestinal upset, alopecia and bone marrow suppression. Less common but potentially severe adverse events included severe myelosuppression, myelodysplastic syndromes, pneumocystis pneumonia, hepatotoxicity and embryo-fetal toxicity. | Serum aminotransferase elevations occur during temozolomide therapy in up to 12% of patients, but these elevations are usually mild and self-limited, not requiring dose adjustment or drug discontinuation. An instance of serum aminotransferase elevation with jaundice was reported in the registration trials of temozolomide and subsequent to its approval. More strikingly, multiple single case reports and several case series of temozolomide hepatotoxicity have been reported in the literature. The onset of injury was typically within 2 to 8 weeks of starting temozolomide but several patients had received multiple courses before the onset of liver injury. The pattern of serum enzyme elevations was usually mixed initially, but the disease tended to be cholestatic. In several instances, jaundice was deep and prolonged. Features of hypersensitivity (rash, fever, eosinophilia) and autoantibody formation were not present. Liver histology demonstrated cholestasis and bile duct injury and a striking decrease in bile ducts (bile duct loss or paucity). Jaundice and pruritus tended to be prolonged and some patients developed vanishing bile duct syndrome, while others recovered clinically but had persistent serum alkaline phosphatase elevations during follow up and to the time of death from the brain tumor. Rechallenge was not done, but several patients subsequently received other antineoplastic agents, some of which were alkylating agents without recurrence of liver injury.\n\nIn addition, temozolomide has been associated with several cases of reactivation of chronic hepatitis B in patients who were hepatitis B surface antigen (HBsAg) positive at the start of chemotherapy. Clinical symptoms and signs of a flare of hepatitis B arose 6 to 12 weeks after starting temozolomide frequently in a cyclic pattern. Most patients had not received corticosteroids or other immunosuppressive agents that are more traditionally associated with reactivation. The episodes are marked by rises in HBV DNA levels and mild jaundice and responded to prompt antiviral therapy for hepatitis B which allowed for restarting of temozolomide in some cases. Fatal cases of reactivation have not been reported, but in general hepatitis B reactivation with jaundice has a mortality rate in excess of 10%.\n\nLikelihood score: B (highly likely but uncommon cause of clinically apparent liver injury and reactivation of hepatitis B). | Temozolomide is hydrolyzed to the active intermediate at physiological pH and does not require hepatic metabolism or affect the cytochrome P450 (CYP) system to a major degree, perhaps accounting for its relative lack of direct hepatotoxicity. The cases of acute cholestatic liver injury have resembled idiosyncratic drug induced liver injury. | The severity of liver injury caused by temozolomide ranges from minor transient elevations in serum enzymes to severe cholestatic hepatitis that can be prolonged. Temozolomide has not been reported to cause acute liver failure but has been linked to instances of chronic liver injury and paucity of bile ducts on liver biopsy suggestive of mild vanishing bile duct syndrome. Because temozolomide is used as therapy of highly malignant brain tumors, long term follow up of liver injury from its use is rarely available. Most patients recover clinically, but may persist in having mild and asymptomatic alkaline phosphatase elevations. There is no evidence for cross sensitivity to hepatic injury between temozolomide and other alkylating agents. Because temozolomide has been linked to instances of reactivation of hepatitis B, it is appropriate to screen all patients scheduled to receive temozolomide for HBsAg and anti-HBc. Patients with serologic evidence of ongoing or previous hepatitis B should be monitored for evidence of reactivation (rise in HBV DNA). If evidence of reactivation arises, prompt therapy with an antiviral with potent activity against HBV is appropriate (such as entecavir or tenofovir). An alternative approach is to use the antiviral agent prophylactically in such patients. The antiviral therapy (either as prophylaxis or treatment) should be continued as long as the chemotherapy is planned and for 3 to 6 months thereafter.\n\nDrug Class: Antineoplastic Agents, Alkylating Agents | Temozolomide – Generic, Temodar® | Antineoplastic Agents, Alkylating Agents | null |
Teplizumab.nxml | Teplizumab | 2023-01-15 | Teplizumab is a humanized monoclonal antibody to CD3 which is used to delay the onset of clinically significant type 1 diabetes (stage 3 diabetes) in a patient at high risk as shown by the presence of anti-pancreatic islet cell autoantibodies and dysglycemia (stage2 diabetes). Teplizumab is given intravenously once daily for 14 days, is generally well tolerated, and is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent liver injury with jaundice. | Teplizumab (tep liz’ ue mab) is a humanized monoclonal IgG1 antibody directed against CD3, which results in inhibition of cytotoxic T cell activation and proliferation. Because type 1 diabetes is thought to be caused by cytotoxic T cell destruction of pancreatic islet beta cells that produce insulin, teplizumab was evaluated as a means of therapy and prevention of type 1 diabetes. While a limited course of teplizumab appeared to have little effect on established type 1 diabetes, it did appear to delay the onset of clinically apparent type 1 diabetes. In preregistration trials, stage 2 diabetes was defined by the presence of at least two anti-pancreatic islet cell autoantibodies and dysglycemia without frank hyperglycemia (stage 3 diabetes). Patients with stage 2 diabetes were generally identified among relatives of patients with type 1 diabetes by screening for anti-pancreatic islet cell autoantibodies. Natural history studies demonstrated that almost all subjects with stage 2 diabetes develop stage 3 diabetes, generally within 1 to 5 years. In a single, randomized controlled trial of teplizumab given as daily intravenous infusions daily for 14 days, therapy was associated with a subsequent median delay in onset of stage 3 diabetes of 24 months. On the basis of this trial, teplizumab was approved in 2022 the United States for use in preventing stage 3 diabetes in adults and children (8 years of age or older) with stage 2 diabetes. Teplizumab is available in single use vials of 2 mg per 2 mL (1 mg/mL). The recommended regimen is a daily infusion in escalating doses for the first 5 days from 65 to 1,030 µg/m2, which is then continued for another 9 days. Premedication is recommended at least during the first 5 days using an oral analgesic (acetaminophen or a nonsteroid antiinflammatory agent), antihistamine, and antiemetic. Monitoring of symptoms, blood counts and liver enzymes is also recommended during the 14 days. Common side effects during and for the several weeks after treatment include mild local injection reactions, nasopharyngitis, fatigue, headache, nausea, diarrhea, arthralgia and skin rash. Uncommon, potentially severe adverse reactions include cytokine release syndrome, severe hypersensitivity reactions, lymphopenia, and reactivation of latent viral infections or tuberculosis. | Mild-to-moderate serum aminotransferase elevations arise in up to 25% of patients treated with teplizumab, usually during the 14 days of therapy and often associated with evidence of mild-to-moderate cytokine release syndrome. The ALT and AST elevations are usually mild, transient and asymptomatic, rising to above 3 times the upper limit of normal (ULN) in 5% of patients and rarely necessitating drug discontinuation. Serum bilirubin levels also rise, particularly in patients with cytokine release syndrome, but clinically apparent liver injury with jaundice has not been reported, and liver test abnormalities resolve in almost all patients within days or a few weeks of ending the 14 day course. There has been limited clinical experience with use of teplizumab and scant information on the safety and efficacy of repeated courses of treatment. Development of antibodies to teplizumab is not uncommon (up to 50%), but the clinical significance of drug antibodies has not been defined.\n\nLikelihood score: E (unlikely cause of clinically apparent acute liver injury). | The possible mechanisms of liver injury due to teplizumab are unclear, but probably relate to cytokine release induced by the binding of the monoclonal antibody to activated T cells that then release cytokines into the circulation that can cause transient liver injury. There is no evidence that the cytokine release induced by teplizumab can result in prolonged or chronic liver injury. | Drug Class: Monoclonal Antibodies, Antidiabetic Agents | Teplizumab – Tzield® | Antidiabetic Agents | null |
Acetaminophen.nxml | Acetaminophen | 2016-01-28 | Acetaminophen is a widely used nonprescription analgesic and antipyretic medication for mild-to-moderate pain and fever. Harmless at low doses, acetaminophen has direct hepatotoxic potential when taken as an overdose and can cause acute liver injury and death from acute liver failure. Even in therapeutic doses, acetaminophen can cause transient serum aminotransferase elevations. | Acetaminophen (a seet" a min' oh fen), which is known as paracetamol in Europe, is an aminophenol that is believed to act centrally as an analgesic and antipyretic agent. While technically a nonsteroidal antiinflammatory drug (NSAID), acetaminophen unlike typical NSAIDs (ibuprofen, naproxen, indomethacin) has only minor effects on tissue cyclooxygenase activity (Cox-1 and Cox-2) and appears to produce analgesia by increasing pain thresholds, perhaps through inhibition of the nitric oxide pathway which is activated by many pain neurotransmitter receptors. Acetaminophen has lower antiinflammatory activity than aspirin or typical NSAIDs. Acetaminophen is typically recommended for management of minor aches and pains from the common cold, viral and bacterial infections, sinusitis, headache, toothache, back ache, muscle strain, tendonitis, osteoarthritis, trauma or menstrual cramps. Acetaminophen has been available as an over-the-counter preparation in the United States since 1960. In 2011, an intravenous formulation of acetaminophen was approved in the United States for adults and children above the age of 2 years. The recommended oral dose is 660 to 1000 mg every 4 to 6 hours, but should not to exceed 3 grams per day. Multiple generic formulations of acetaminophen are available (e.g., Tylenol, Anacin Aspirin Free, Feverall, Neopap, Panadol and Tempra) in capsules or tablets of 330 or 500 mg each. Liquid formulations for children are available in concentrations that vary from 15 to 100 mg/mL; the dosage in children should be carefully chosen and kept to less than 75 mg/kg/day. In addition, acetaminophen is a frequent component in many over-the-counter and prescription combinations with decongestants and/or antihistamines for cold and allergy symptoms, or as a sleeping aid and with other analgesics (such as oxycodone, hydrocodone, dilaudid and codeine) for moderate-to-severe forms of pain. Common products in the United States include: Tylenol-PM, Nyquil, Darvocet, Vicodin, and many others. Acetaminophen is one of the most commonly used medications in the United States and more than 25 billion doses are sold yearly. | Chronic therapy with acetaminophen in doses of 4 grams daily has been found to lead to transient elevations in serum aminotransferase levels in a proportion of subjects, generally starting after 3 to 7 days, and with peak values rising above 3-fold elevated in 39% of persons. These elevations are generally asymptomatic and resolve rapidly with stopping therapy or reducing the dosage, and in some instances resolve even with continuation at full dose (Case 1).\n\nWhile acetaminophen has few side effects when used in therapeutic doses, recent reports suggest that its standard use can result in severe hypersensitivity reactions including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Both of these syndromes can be life-threatening and both may be accompanied by evidence of liver injury. However, the hepatic involvement is usually mild and marked only by asymptomatic mild-to-moderate elevations in serum aminotransferase levels.\n\nThe best known form of hepatoxicity from acetaminophen is an acute, serious hepatocellular injury as a result of intentional or unintentional overdose. The injury is due to a direct, toxic effect of the high doses of acetaminophen. Acetaminophen hepatotoxicity most commonly arises after a suicide attempt using more than 7.5 grams (generally more than 15 grams) as a single overdose (Case 2). Hepatic injury generally starts 24 to 72 hours after the ingestion with marked elevations in serum ALT and AST (often to above 2000 U/L), followed at 48 to 96 hours by clinical symptoms: jaundice, confusion, hepatic failure and in some instances death. Evidence of renal insufficiency is also common. Serum aminotransferase levels fall promptly and recovery is rapid if the injury is not too severe. Similar injury can occur with high therapeutic or supratherapeutic doses of acetaminophen given over several days for treatment of pain and not as a purposeful suicidal overdose (Case 3). This form of acetaminophen hepatotoxicity is referred to as accidental or unintentional overdose, and usually occurs in patients who have been fasting, or are critically ill with a concurrent illness, alcoholism or malnutrition, or have preexisting chronic liver disease. Some cases of unintentional overdose occur in patients taking acetaminophen in combinations with controlled substances (oxycodone, codeine), who take more than recommended amounts over several days in attempts to control pain or withdrawal symptoms. Instances of unintentional overdose in children are often due to errors in calculating the correct dosage or use of adult sized tablets instead of child or infant formulations. Because acetaminophen is present in many products, both by prescription and over-the-counter, another problem occurs when a patient ingests full or high doses of several products unaware that several contain acetaminophen.\n\nLikelihood score: A[HD] (well established cause of liver injury, but severe cases occur only with high doses). | The mechanism of acetaminophen hepatotoxicity has been extensively analyzed in humans and in animal models. Acetaminophen is largely converted to nontoxic glucuronate or sulfate conjugates and secreted in the urine. A minor amount of acetaminophen is metabolized via the cytochrome P450 system to intermediates that can be toxic, particularly N-acetyl-p-benzoquinoneimine. Ordinarily, this intermediate is rapidly conjugated to reduced glutathione, detoxified and secreted. If levels of glutathione are low or the pathway is overwhelmed by high doses of acetaminophen, the reactive intermediate accumulates and binds to intracellular macromolecules that can lead to cell injury, usually through apoptotic pathways. Factors that increase the metabolism of acetaminophen through the P450 system (certain drugs, chronic alcohol use) or that decrease the availability of glutathione (fasting, malnutrition, alcoholism) can predispose to acetaminophen toxicity. Factors that affect downstream toxicity of acetaminophen metabolic intermediates may also affect toxicity. These factors are important in designing therapies for acetaminophen hepatotoxicity. | The minor aminotransferase elevations that occur during chronic therapy with acetaminophen are rarely symptomatic, generally go undetected, resolve rapidly with discontinuation of acetaminophen and sometimes even with continuation at the same dose. Such transient aminotransferase elevations do not appear to have lasting effects on the liver but can cause diagnostic confusion and lead to expensive or invasive interventions. Acetaminophen overdose, in contrast, can cause a serious acute liver injury and hepatic failure that can result in death or need for emergency liver transplantation. Currently, acetaminophen is the major cause of acute liver failure in the United States, Europe and Australia. The liver injury from acetaminophen can be prevented or ameliorated by repletion of glutathione levels which can be accomplished with n-acetylcysteine (NAC), which is available in oral and intravenous forms and should be administered immediately upon diagnosis of acetaminophen overdose. A nomogram (Rumack-Matthew Nomogram) to calculate the likelihood of liver injury from acetaminophen is available that plots acetaminophen plasma concentrations against the number of hours post-ingestion that the sample was taken. Patients with plasma levels above the “treatment line” should receive either oral or intravenous NAC. Details of administration and assistance can be obtained from the U.S. National Poison Center: 1-800-222-1222. Patients who recover spontaneously from acetaminophen hepatotoxicity generally return to normal health without evidence of chronic liver injury. The nomogram is less accurate in assessing risk with chronic or unintentional overdose. Recently, tests for acetaminophen adducts have been developed that accurately reflect hepatic damage from acetaminophen overdose and are detectable after plasma acetaminophen levels fall into undetectable range. Thus, the presence of acetaminophen adducts supports the diagnosis and their absence is a reliable in excluding acetaminophen as a cause of acute liver injury (if ALT levels are still elevated).\n\nDrug Class: Nonsteroidal Antiinflammatory Drugs | Acetaminophen – Generic, Various Trade Names | Nonsteroidal Antiinflammatory Drugs | null |
Lonafarnib.nxml | Lonafarnib | 2021-01-07 | Lonafarnib is an oral, small molecule inhibitor of farnesyltransferase that is used to treat Hutchison-Gilford progeria syndrome and is under investigation as therapy of chronic hepatitis D. Lonafarnib is associated with transient and usually mild elevations in serum aminotransferase levels during therapy, but has not been linked to cases of clinically apparent acute liver injury. | Lonafarnib (loe” na far’ nib) is an orally available, specific inhibitor of farnesyltransferase and is approved for the treatment of Hutchinson-Gilford progeria syndrome (HGPS), a rare autosomal dominant form of accelerated aging (arising in 1 in 4 million live births). Persons with HGPS develop cardiovascular disease at a young age and typically die of myocardial infarction, heart failure or stroke before the age of 20. Other manifestations of HGPS include sclerotic skin, joint contracture, bone abnormalities, alopecia, and growth impairment. Lonafarnib acts by prevention of farnesylation of proteins, a post-translational modification which alters membrane attachment. In HGPS a point mutation in the LMNA gene results in an abnormal lamin A protein called “progerin”. Lamin A is a normal component of the nuclear envelope providing structural organization to the nucleus and supporting normal chromatic function, DNA replication, RNA transcription, cell cycling and apoptosis. The abnormal progerin protein, however, lacks the ability to remove the post-translational isoprenyl that allows for membrane attachment. As a result, the abnormal lamin A remains and accumulates, acting as a dominant negative in causing abnormal nuclear membranes. The clinical manifestations of HGPS appear to be due to the abnormalities of nuclear membranes. In animal models and in subsequent human clinical trials, lonafarnib therapy was associated with a decrease in progerin farnesylation as well as a decrease in its accumulation, in clinical abnormalities and cardiovascular complications, resulting in prolonged survival. Lonafarnib was approved for use in HGPS in the United States in 2020. Lonafarnib has also been evaluated in several forms of cancer associated with abnormal RAS (whose activation is dependent on farnesyltransferase) and for chronic hepatitis D virus infection (the HDV replicative cycle requires the same enzyme). Current indications for lonafarnib are limited to patients with HGPS (or other processing-deficient progeroid laminopathies) who are 12 months of age or above with body surface area of at least 0.39/m2. Lonafarnib is available in capsules of 50 and 75 mg under the brand name Zokinvy. The recommended initial dose is 115 mg/m2 twice daily increasing after 4 months to 150 mg/m2 twice daily. Side effects are common, particularly with higher doses and include diarrhea, nausea, vomiting, abdominal pain, musculoskeletal pain, fatigue, electrolyte abnormalities (hypokalemia, hyponatremia, hypocalcemia), cough, hypertension, myelosuppression and infections. Severe adverse events include dehydration, electrolyte imbalance, nephrotoxicity, retinal abnormalities, impaired fertility, and embryo-fetal toxicity. Monitoring of electrolytes, complete blood counts and liver enzymes is recommended. | In the small prelicensure clinical trials conducted in children with progeria, serum aminotransferase elevations occurred in 35% of lonafarnib treated subjects but were usually mild and self-limited, rising to above 3 times the upper limit of normal (ULN) in only 5%. There were no liver related serious adverse events and no patient had a concurrent elevation in serum aminotransferase and bilirubin levels. Since approval of lonafarnib, there have been no published reports of drug induced liver injury associated with its use, although clinical experience with the drug, particularly with long term therapy, has been limited.\n\nLikelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury). | The causes of serum enzyme elevations during lonafarnib therapy are not known. Lonafarnib is metabolized in the liver largely through the cytochrome P450 pathway and specifically by CYP 3A4, and liver injury may be related to production of a toxic or immunogenic intermediate. Because it is a substrate for CYP 3A4, lonafarnib is susceptible to drug-drug interactions with agents that inhibit or induce this specific hepatic microsomal activity. | Monitoring of laboratory tests including routine liver tests is recommended for patients treated with lonafarnib. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to dose reduction or temporary cessation. There are no data to suggest a cross reactivity in risk for hepatic injury between lonafarnib and other small molecule enzyme inhibitors.\n\nDrug Class: Genetic Disease Agents, Protein Kinase Inhibitors | Lonafarnib – Zokinvy® | Genetic Disease Agents, Small Molecule Enzyme Inhibitors | null |
Phenotypes_acutehepa.nxml | Acute Hepatitis | 2019-05-04 | null | null | null | null | null | null | null | null |
Umbralisib.nxml | Umbralisib | 2023-10-10 | Umbralisib is an oral kinase inhibitor that is was given accelerated approved for use in adults with relapsed or refractory marginal zone and follicular lymphoma in 2021, but the approval was withdrawn a year later because of data from a trial showing excess mortality with its use. Umbralisib was associated with a modest rate of serum enzyme elevations during therapy but was not reported to cause clinically apparent acute liver with symptoms or jaundice. | Umbralisib (um" bra lis' ib) is an orally available, small molecule inhibitor of multiple kinases that play a role in B cell malignant cellular pathways and that was used in the therapy of refractory cases of marginal zone and follicular lymphoma. The kinases inhibited by umbralisib include phosphatidylinositol 3-kinase delta (PI3Kδ), which is an essential component in the B cell signaling pathways that drive migration of B cells to lymph nodes and bone marrow. This pathway is upregulated in many B cell malignancies and has been shown to be critical for proliferation and survival of leukemia and lymphomatous malignant B lymphocytes. Inhibition of this pathway inhibits B cell chemotaxis and adherence and reduces cell viability. Umbralisib also has activity against casein kinase epsilon which plays a role in protein synthesis and RNA translation and is altered in some malignancies. Other activities of umbralisib include inhibition of cell adhesion molecules and other kinases including BCR-ABL1. Studies in animal models and in early phase clinical trials showed that umbralisib had activity against several hematologic malignancies. Umbralisib was given tentative approval for use in the United States as therapy for refractory or relapsed marginal zone and follicular lymphoma after failure of one or more systemic therapies in February 2021. A little over a year later, FDA approval was withdrawn because of concerns about excess mortality in patients receiving Umbralisib in follow up clinical trials. The deaths on treatment were not liver related but the nature and relatedness of the mortality to umbralisib therapy was not well defined. Umbralisib was previously available in tablets of 200 mg under the brand name Ukoniq. The recommended dose was 800 mg once daily until disease progression or unacceptable toxicity. Side effects of umbralisib were common but usually mild-to-moderate in severity, and included fatigue, nausea, diarrhea, headache, musculoskeletal pain, stomatitis, fever, pain, rash, and infections. Common laboratory abnormalities included cytopenias, liver enzyme elevations, hyper- or hypo-glycemia, and hyponatremia. Severe potential adverse events included neutropenia, severe infections, severe diarrhea, allergic and hypersensitivity reactions, and embryo-fetal toxicity. Because of excess mortality among umbralisib- in comparison to placebo-treated patients, FDA approval was withdrawn in June 2022 and the product was withdrawn by the sponsor. | In clinical trials of umbralisib in adults with lymphoma, the rates of serum enzyme elevations during therapy ranged from 15% to 35% and were above 5 times the ULN in 5% to 8% and occasionally above 20 times ULN (<1%). The aminotransferase elevations arose within 4 to 12 weeks of starting therapy in most instances and usually resolved without dose modification or temporary discontinuation. Nevertheless, there were no instances of serum enzyme elevations accompanied by jaundice and no liver related deaths.\n\nBecause umbralisib affects B cell function, it may also be capable of inducing reactivation of hepatitis B, although in published trials of the agent, instances of HBV reactivation were not reported.\n\nLikelihood score: E* (unproven, but suspected rare cause of clinically apparent liver injury). | The reason why umbralisib causes serum enzyme elevations is not known, but may be a direct toxicity to hepatocytes caused by inhibition of PI3K activity or the result of change in B cell activity and caused by induction of autoimmunity. Umbralisib is metabolized primarily by aldehyde oxidase which is present in many tissues, but highest concentrations are in the liver. The cytochrome P450 system plays a minor role in the metabolism (CYP 3A4) of umbralisib, but concentrations may be affected by drugs that induce or inhibit CYP 3A activity. | Serum enzyme elevations were not uncommon during chemotherapy with umbralisib and were often dose limiting. The product label recommended that umbralisib not be used with other agents with hepatotoxic potential. Furthermore, regular monitoring of liver tests every 2 to 4 weeks was recommended during the first six months of umbralisib therapy and every 1 to 3 months thereafter, with more frequent monitoring if serum aminotransferase values rise. It was recommended that umbralisib be held if ALT or AST values rise above 5 times ULN, and treatment resumed only if and when values fall into the normal range and then with a reduced dose and careful monitoring. Elevations of aminotransferase values of more than 20 times the ULN, or appearance of jaundice or symptoms of liver injury were considered to require permanent discontinuation. There was no known cross sensitivity to hepatic injury between umbralisib and other protein kinase inhibitors.\n\nDrug Class: Antineoplastic Agents, Protein Kinase Inhibitors\n\nOther PI3 Kinase Inhibitor Drugs: Alpelisib, Copanlisib, Duvelisib, Idelalisib | Umbralisib – Ukoniq® [On June 1, 2022, FDA approval was withdrawn due to safety concerns.] | Antineoplastic Agents | null |
Troglitazone.nxml | Troglitazone | 2018-06-06 | Troglitazone was the first thiazolidinedione approved for use in the United States and was licensed for use in type 2 diabetes in 1997, but withdrawn 3 years later because of the frequency of liver injury including acute liver failure associated with its use. | Troglitazone (troe gli' ta zone) is an insulin sensitizing agent thought to act by engagement of PPAR-γ receptors which induce multiple genes involved in glucose and fatty acid metabolism. In clinical trials, troglitazone was found to lower blood glucose and HbA1c levels and had additive effects with the sulfonylureas and metformin. Troglitazone was approved for use in the United States in 1997 to be used alone or in combination with other antidiabetic medications. However, reports of severe liver injury and death from acute liver failure began to arise soon after its general availability, and it was withdrawn from use in 2000. Troglitazone was sold under the brand name Rezulin and was available in 400 mg tablets. The recommended dosage was 400 to 800 mg once daily. Troglitazone was used as monotherapy as well as in combination with metformin, sulfonylureas or insulin. | Large prospective studies showed that significant elevations in serum aminotransferase levels (equal to or greater than 3 times the upper limit of the normal range [ULN]) occurred in 1.9% of patients with diabetes treated with troglitazone for 24 to 48 weeks, compared to only 0.6% in placebo recipients. These enzyme elevations were usually asymptomatic and often resolved despite continuation of therapy. Nevertheless, elevations >10 times ULN occurred in 0.5% of patients (but in no placebo recipient) and a proportion of these developed symptoms of liver injury and jaundice. Soon after the approval of troglitazone as therapy for type 2 diabetes in the United States, cases of severe acute liver injury began to be reported, and dramatic case reports as well as small case series documented that clinically significant injury was occurring in 1:1000 to 1:10,000 recipients. The latency to onset of injury was typically 1 to 6 months and the onset was marked by fatigue, weakness, dark urine and jaundice, and an acute hepatitis-like elevation in serum enzymes (hepatocellular pattern). Allergic phenomena (rash, fever, eosinophilia) were uncommon and serum autoantibodies were not usually present. Liver biopsies showed acute inflammatory changes and variable degrees of necrosis, ranging from rare spotty necrosis to bridging hepatic necrosis and submassive or massive necrosis. At least two dozen cases of acute liver failure and death or need for liver transplantation were reported to the FDA before troglitazone was withdrawn from use in 2000.\n\nLikelihood score: A (well recognized cause of clinically apparent liver injury). | The mechanism of liver injury due to troglitazone is unknown. Signs and symptoms of allergic and immune reactivity are rare and a metabolic defect in its metabolism is suspected to be the cause. Troglitazone is a potent inducer of CYP 3A4 and has a distinctive alpha tocopherol (vitamin E-like) side chain which can be metabolized to a highly active quinolone-like metabolite, which may account for its occasional aberrant metabolism and hepatotoxicity. | The liver injury from troglitazone can be severe and even fatal. In several cases there was incomplete recovery at the time of the last follow up evaluation, suggesting that the injury can become chronic in some instances. Prednisone has been reported to have a beneficial effect, but only in anecdotal reports. While several patients with mild troglitazone liver injury were later treated with other thiazolidinediones without recurrence of injury, other patients have developed worsening liver injury; switching therapy to other thiazolidinediones is inadvisable and, if done, should be with careful monitoring of serum aminotransferase levels.\n\nReferences to safety and hepatotoxicity of troglitazone are given together with references to the related agents in the Overview section on the Thiazolidinediones (updated June 2018).\n\nDrug Class: Antidiabetic Agents\n\nOther Drugs in the Subclass, Thiazolidinediones: Pioglitazone, Rosiglitazone | Troglitazone – Rezulin® (Withdrawn from U.S. Market) | Hypoglycemic Agents | null |
Acarbose.nxml | Acarbose | 2021-01-10 | Acarbose is an alpha glucosidase inhibitor which decreases intestinal absorption of carbohydrates and is used as an adjunctive therapy in the management of type 2 diabetes. Acarbose has been linked to rare instances of clinically apparent acute liver injury. | Acarbose (ay' kar bose) is an inhibitor of intestinal alpha glucosidase, an enzyme responsible for digestion and absorption of starch, disaccharides and dextrin. Acarbose is a complex oligosaccharide produced in bacteria that has activity against glucoamylase, sucrase, maltase and isomaltase, intestinal brush border glucosidases. The inhibition of the glucosidase activity blocks the breakdown of starch and disaccharides to absorbable monosaccharides, leading to delay in glucose absorption and a degree of carbohydrate malabsorption which results in a blunting of the postprandial rise in blood glucose. Acarbose was approved for use in the United States in 1995 and was the first alpha glucosidase inhibitor introduced into clinical practice. A similar alpha glucosidase inhibitor, miglitol, was approved the following year. The current indications for acarbose are for management of glycemic control in type 2 diabetes used in combination with diet and exercise, with or without other oral hypoglycemic agents or insulin. Acarbose is available generically and under the brand name Precose in tablets of 25, 50 and 100 mg. The typical initial dose in adults is 25 mg with each meal (with the first bite), followed by a gradual increase to a maximum of 100 mg three times daily. Acarbose causes malabsorption and gastrointestinal side effects of flatulence, diarrhea and abdominal boating are not uncommon. More severe but rare adverse events include skin rash and pneumatosis cystoides intestinalis. | In several large clinical trials, serum enzyme elevations above 3 times the upper limit of normal were more common with acarbose therapy (2% to 5%) than with placebo, but all elevations were asymptomatic and resolved rapidly with stopping therapy. These studies reported no instances of clinically apparent liver injury. Subsequent to approval and with wide clinical use, however, at least a dozen instances of clinically apparent liver injury have been linked to acarbose use. The liver injury typically arises 2 to 8 months after starting therapy and is associated with a hepatocellular pattern of serum enzyme elevations with marked increases in serum ALT levels, suggestive of acute viral hepatitis. Immunoallergic features and autoantibody formation are not typical. While most cases are mild, some are associated with marked jaundice and cases with a fatal outcome have been reported to the sponsor. No cases of chronic liver injury or vanishing bile duct syndrome have been linked to acarbose use, and most large series of cases of drug induced liver injury and acute liver failure have not identified cases due to acarbose. Rechallenge has been carried out in several instances and resulted in recurrence with a shortening of the time to onset.\n\nLikelihood score: B (rare but likely cause of clinically apparent liver injury). | The cause of liver injury during acarbose therapy is not known. Acarbose is an oligosaccharide of microbial origin and is minimally absorbed (0.5% to 1.7%), so that systemic toxicity and liver injury were not expected and remain unexplained. Liver injury from acarbose is clearly idiosyncratic and may relate to an immunological reaction to the bacterially derived oligosaccharide molecule or to alterations in the microbiome and absorption of bacterial products. | The liver injury caused by acarbose has generally been mild and self-limited with the injury resolving rapidly once acarbose is discontinued. Cross sensitivity with other hypoglycemic agents has not been described. Furthermore, liver injury has not been described in patients taking the other currently available alpha glucosidase inhibitor, miglitol. Recurrence of injury with reintroduction of acarbose has been reported and should be avoided.\n\nDrug Class: Antidiabetic Agents\n\nOther Drugs in the Subclass Alpha Glucosidase Inhibitors: Miglitol | Acarbose – Generic, Precose® | Antidiabetic Agents | null |
Phenobarbital.nxml | Phenobarbital | 2020-07-30 | Phenobarbital is a barbiturate that is widely used as a sedative and an antiseizure medication. Phenobarbital has been linked to rare instances of idiosyncratic liver injury that can be severe and even fatal. | Phenobarbital (fee" noe bar' bi tal) is a barbiturate and is believed to act as a nonselective depressant. Phenobarbital also has anticonvulsant activity and is thought to act by suppressing spread of seizure activity by enhancing the effect of gamma aminobutyric acid (GABA), raising the seizure threshold. Phenobarbital was introduced into clinical medicine in 1911 but was never subjected to critical controlled studies to demonstrate safety and efficacy. For these reasons, phenobarbital is now considered of unproven benefit in controlling seizures. Nevertheless, it is commonly used for prevention and management of partial and generalized seizures, usually as an adjunctive agent in combination with other anticonvulsants. Phenobarbital is also used for sedation and insomnia although its use for these conditions is now uncommon. Phenobarbital is also used in fixed combinations with other antispasmodics or anticholinergic agents and used for gastrointestinal complaints, including irritable bowel syndrome. The typical starting dose in treating seizures in adults is 60 to 100 mg in three divided doses daily. Oral formulations of tablets or capsules of 15, 16, 30, 60, 90 and 100 mg are available in multiple generic forms. Parenteral formations and oral elixirs for pediatric use are also available. Phenobarbital has declined in general use in recent years with availability of more efficacious and better tolerated agents. Its major advantage is low cost, but it is more sedating than other anticonvulsants. Frequent side effects include drowsiness, sedation, hypotension, and skin rash. Uncommon but potentially severe adverse events included severe sedation, dependence, hypersensitivity reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis. | Prospective studies suggest that less than 1% of subjects develop elevations in serum aminotransferase levels during long term phenobarbital therapy. Clinically apparent hepatotoxicity from phenobarbital is rare but can be abrupt in onset, severe and even fatal. Phenobarbital hepatotoxicity typically occurs in the setting of anticonvulsant hypersensitivity syndrome with onset of fever, rash, facial edema, lymphadenopathy, elevations in white count and eosinophilia occurring 1 week to several months after starting therapy. Liver involvement is common, but is usually mild and anicteric and overshadowed by other features of hypersensitivity (rash, fever). In some cases, hepatic involvement is more prominent with marked elevations in serum enzyme levels, jaundice and even signs of hepatic failure. The typical pattern of serum enzyme elevations is mixed, but can be hepatocellular or cholestatic. Liver biopsy shows mixed hepatitis-cholestatic injury with prominence of eosinophils and occasionally granulomata. Re-exposure usually results in recurrence and should be avoided.\n\nLikelihood score: B (likely rare cause of clinically apparent liver injury). | The mechanism of phenobarbital hepatotoxicity is thought to be hypersensitivity or an immunological response to a metabolically generated drug-protein complex. | Phenobarbital hepatotoxicity is usually rapidly reversible with improvements beginning within 5 to 7 days of stopping the drug and being complete within 1 to 2 months. In cases of severe injury, progression to acute liver failure and death can occur. Corticosteroids have been used but with uncertain effectiveness. Prolonged cholestasis can occur, but chronic injury and vanishing bile duct syndrome have not been reported from phenobarbital therapy. Cross reactivity with other aromatic anticonvulsants (phenytoin, carbamazepine, primidone, and lamotrigine) is common but not invariable. Patients with hypersensitivity to phenobarbital should be monitored carefully if they are to start other aromatic anticonvulsants.\n\nDrug Class: Anticonvulsants, Sedatives and Hypnotics | Phenobarbital – Generic, Luminal® Sodium | Anticonvulsants | null |
Quinupristin-Dalfopr.nxml | Quinupristin-Dalfopristin | 2018-05-21 | Quinupristin and dalfopristin are intravenously administered, streptogramin antibiotics used in fixed combination to treat severe bacterial infections due to susceptible organisms including methicillin resistant Staphylococcus aureus (MRSA). The fixed combination of quinupristin and dalfopristin is associated with a low rate of serum enzyme elevations during therapy but has not been convincingly linked to instances of clinically apparent liver injury. | Quinupristin (kwin" ue pris' tin) and dalfopristin (dal” foe pris’ tin) are streptogramin antibiotics that were initially isolated from Streptomyces pristinaspiralis. Quinupristin, a derivative of pristamycin IA, and dalfopristin, a derivative of pristamycin IIA, are synergistic in activity and are used in a fixed dose combination in a ratio of 30:70 by weight. This combination binds and inhibits the activity of the 50S subunit of bacterial ribosomes, which yields potent bactericidal activity against many gram positive bacteria including methicillin resistant forms of Staphylococcus aureus (MRSA). Quinupristin and dalfopristin also have activity against some gram negative bacteria including Enterococcus species. The combination of quinupristin and dalfopristin under the brand same of Synercid was approved for use in the United States in 1999. Current indications include complicated skin and skin structure infections caused by susceptible strains of Staphylococcus aureus or Streptococcus pyogenes and severe infections due to susceptible vancomycin-resistant Enterococcus faecium. The combination of quinupristin and dalfopristin is available in solution in 10 mL vials of 500 mg (150 mg of quinupristin and 350 mg of dalfopristin) and the typical dose regimen is 7.5 mg/kg intravenously every 8 to 12 hours for 5 to 14 days. Side effects may include nausea, diarrhea, headache, skin rash, myalgia, arthralgia and injection site reactions (burning, irritation, pain). Rare, but potentially severe side effects include anaphylaxis and angioneurotic edema. | Elevations in serum aminotransferase levels occur in a proportion of patients receiving quinupristin and dalfopristin, but rates are minimally higher than with placebo or comparator drugs. The elevations are generally mild-to-moderate, asymptomatic and self-limited, frequently resolving without discontinuation or even interruption of therapy. Elevations above 5 times ULN occur in less than 1% of patients. Quinupristin-dalfopristin can also cause elevations in direct as well as total bilirubin, but these elevations are mild and not accompanied by elevations in serum enzymes or other evidence of liver injury. In the many clinical trials of quinupristin and dalfopristin there were no instances of clinically apparent liver injury that could be attributed convincingly to their use. Patients who receive quinupristin and dalfopristin are often severely ill, septic and receiving multiple medications or parenteral nutrition, so that jaundice arising during therapy is often multifactorial and difficult to assign to a specific cause. Nevertheless, since the approval and more wide spread use of this antibiotic combination, there have been no published reports of hepatitis or jaundice linked specifically to it use. Thus, clinically apparent liver injury from quinupristin and dalfopristin may occur, but is quite rare.\n\nLikelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury). | The cause of the mild-to-moderate serum aminotransferase elevations that occur during quinupristin and dalfopristin therapy is unknown. Both are extensively metabolized in the liver, largely via the cytochrome P450 system (CYP 3A4) and the combination is susceptible to drug-drug interactions with agents that are substrates for 3A4. | null | Quinupristin-Dalfopristin – Synercid® | Antiinfective Agents | [
{
"cas_registry_number": "120138-50-3",
"molecular_formula": "C53-H67-N9-O10-S",
"name": "Quinupristin"
},
{
"cas_registry_number": "112362-50-2",
"molecular_formula": "C34-H50-N4-O9-S",
"name": "Dalfopristin"
}
] |
Brexanolone.nxml | Brexanolone | 2019-04-12 | Brexanolone is a unique, intravenously administered, neuroactive steroidal antidepressant used in the therapy of moderate-to-severe postpartum depression. In prelicensure clinical trials, brexanolone therapy was not associated with an increased rate of serum aminotransferase elevations, and it has not been linked to instances of clinically apparent acute liver injury. | Brexanolone (brex an' oh lone) is allopregnanolone an active metabolite of progesterone which is found in high concentrations during pregnancy and falls precipitously at the time of delivery, shortly before the usual time of onset of postpartum depression. When given intravenously in doses that achieve plasma levels typical of pregnancy, brexanolone was found to be associated with marked improvement in depression symptoms, an effect that was sustained when the infusion was stopped. In vitro assays have shown that brexanolone also modulates synaptic and extra-synaptic GABA receptors, another possible mechanism of antidepressant activity. In two randomized controlled trials, a 60 hour intravenous infusion of brexanolone was found to be more effective than placebo in improving depression symptom scales and, in some instances, reversed the functional impairment that often accompanies severe postpartum depression. Brexanolone was approved in the United States in 2019 for use in treatment of moderate or severe postpartum depression. Brexanolone is available in solution in single use vials of 100 mg in 20 mL (5 mg/mL) under the brand name Zulresso. The recommended regimen starts with a dose of 30 mcg/kg/hour, which is gradually increased to a maintenance dose of 90 mcg/kg/hour which is decreased back 30 mcg/kg/hour before stopping, the total duration being 60 hours. Common, nonserious side effects include infusion site discomfort, sedation, headache, dizziness, dry mouth and flushing. Rare, potentially severe adverse events include loss of consciousness and suicidal thoughts or behaviors. The treatment requires continuous monitoring and is typically given in hospital which is often problematic for a new mother. | In premarketing studies, liver test abnormalities were uncommon in patients receiving brexanolone (<1%) and no more frequent than in placebo recipients. No instances of acute, clinically apparent liver injury attributed to brexanolone have been reported. However, general clinical experience with brexanolone has been limited.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | The mechanism by which brexanolone might cause liver injury is not known. Brexanolone is metabolized largely via non-cytochrome P450 pathways, predominantly by keto-reduction, glucuronidation and sulfation. It has few significant drug-drug interactions. Concurrent use of other antidepressants may lead to excess sedation.\n\nDrug Class: Antidepressant Agents | null | Brexanolone – Zulresso® | Antidepressant Agents | null |
PKEnhancers.nxml | Pharmacokinetic Enhancers | 2017-08-17 | null | null | null | null | null | null | null | null |
Elvitegravir_Cobicis.nxml | Elvitegravir | 2018-01-30 | Elvitegravir is a human immunodeficiency virus (HIV) integrase inhibitor which is used largely in a four drug combination with cobicistat, emtricitabine and tenofovir as therapy of HIV infection. Therapy with this elvitegravir based regimen is often associated with transient serum aminotransferase elevations during therapy, but has not been implicated in cases of clinically apparent acute liver injury. | Elvitegravir (el" vi teg' ra vir) is a 4-quinolone-3-glyoxylic acid and antiretroviral agent that acts by inhibition of viral DNA strand transfer by the HIV integrase, a necessary step in HIV replication. Elvitegravir has been shown to lower serum levels of HIV RNA and to raise CD4 counts. In multiple prospective clinical trials, the combination of elvitegravir with tenofovir and emtricitabine has been found to be as effective as other standard antiretroviral combinations. Elvitegravir is given with cobicistat, a pharmacokinetic enhancer that inhibits CYP 3A4 activity, causing increased levels and more prolonged activity of drugs like elvitegravir that are metabolized by the hepatic cytochrome P450 isomer CYP 3A4. Elvitegravir was approved as a part of a four drug combination including cobicistat, emtricitabine and tenofovir disoproxil fumarate as therapy of HIV infection in 2012 under the brand name Stribild. A similar four drug combination that includes tenofovir alafenamide instead of tenofovir disoproxil fumarate was approved for use in HIV infection in 2016 under the brand name Genvoya. These combinations are available as tablets of 150 mg of elvitegravir with 150 mg of cobicistat, 200 mg of emtricitabine and either 300 mg of tenofovir disoproxil fumarate (Stribild) or 10 mg of tenofovir alafenamide (Genvoya). The recommended dose is one tablet daily, these combination being two of several "single tablet regimens" (STRs) for therapy of HIV infection. Elvitegravir was the second HIV integrase to be approved in the United States and shares structural similarity and resistance patterns with the initial agent, raltegravir. Elvitegravir is also available as a single agent for use with other antiretroviral agents in 85 and 150 mg tablets under the brand name Vitekta. Common side effects of the four drug combination include fatigue, diarrhea, nausea, dizziness, headache, depression, abnormal dreams and skin rashes. Cobicistat has inhibitory activity against several drug metabolizing enzymes besides CYP 3A4, including CYP 2D6 and the P-glycoprotein transporter, making it likely to cause drug-drug interactions and important to avoid when using other agents that are metabolized by the P450 system. Cobicistat also inhibits creatinine secretion, which artificially raises serum creatinine levels without affecting the glomerular filtration rate. With long term use, tenofovir disoproxil fumarate can be associated with decline in kidney function, phosphate wasting and decline in bone mineral density. These adverse effects appear to be less with tenofovir alafenamide which is more potent and is given in a lower dose that the disoproxil fumurate form of tenofovir. | In premarketing clinical trials, serum ALT elevations greater than 5 times the upper limit of normal occurred in 15% of patients treated with elvitegravir combined with cobicistat, emtricitabine and tenofovir. This rate was somewhat lower than what occurred in comparator arms. Most serum enzyme elevations with elvitegravir based regimens were transient and asymptomatic, and occurred in patients with known underlying chronic liver disease such as hepatitis B or C or alcoholic liver disease. In at least one study, 1% of patients on the elvitegravir based four drug regimen developed "acute hepatitis", but the relatedness of the liver injury to elvitegravir was unclear and clinical details were not provided. No specific reports of clinically apparent liver injury attributed to elvitegravir have appeared in the published literature. The product label for elivitegravir mentions two other forms of acute liver injury that have been linked to potent antiretroviral regimens: the immune reconstitution syndrome when these regimens are started and reactivation of hepatitis B when regimens with anti-HBV acitivity (as with tenofovir) are discontinued. Neither of these effects are specific to elvitegravir or other integrase inhibitors.\n\nLikelhood score: E* (unproven but suspected cause of clinically apparent liver injury). | The possible mechanism of liver injury due to elvitegravir is unknown. Elvitegravir is extensively metabolized in the liver via the cytochrome P450 system (predominantly CYP 3A4), and production of a toxic or immunogenic intermediate may trigger liver injury. | null | Elvitegravir – Vitekta® | Antiviral Agents | [
{
"cas_registry_number": "697761-98-1",
"molecular_formula": "C23-H23-Cl-F-N-O5",
"name": "Elvitegravir"
},
{
"cas_registry_number": "1004316-88-4",
"molecular_formula": "C40-H53-N7-O5-S2",
"name": "Cobicistat"
}
] |
Eszopiclone.nxml | Eszopiclone | 2018-02-20 | Eszopiclone is a benzodiazepine receptor agonist that is used for the treatment of insomnia. Eszopiclone has not been implicated in causing serum enzyme elevations or clinically apparent liver injury. | Eszopiclone (es zoe' pi klone) is a non-benzodiazepine, benzodiazepine receptor agonist of the cyclopyrrolone class that acts by binding to the benzodiazepine (BZ) site on the GABA receptor complex, causing neural inhibition and helping to induce sleep. Eszopiclone has selectivity for certain BZ receptor subtypes, and does not have the neuromuscular relaxation or anticonvulsant effects of the standard benzodiazepines. Eszopiclone has a relatively short half life and rapid onset of action. In multiple placebo controlled trials, eszopiclone was shown to decrease the latency to onset of sleep and improve perceived sleep quality, with few next day residual effects and minimal evidence of rebound insomnia after withdrawal. Eszopiclone is the S-isomer of zopiclone that has been available in other countries for more than 20 years. Eszopiclone was approved for use in the United States in 2004 for the treatment of insomnia and remains in common use. Eszopiclone is available in 1, 2 and 3 mg tablets generically and under the brand name Lunesta. The recommended dose is 1 to 3 mg taken orally immediately before bedtime. Like the other benzodiazepine receptor agonists, eszopiclone is classified as a Schedule IV controlled substance (low potential for abuse and limited physical or psychological dependence). Side effects are uncommon, usually mild and may include unpleasant taste (bitter), headache, nausea, dizziness, dry mouth and drowsiness. | In multiple premarketing randomized controlled trials, eszopiclone was not associated with an increased rate of serum enzyme elevations in comparison to placebo therapy, and no instance of clinically apparent liver injury was reported. Since its approval and widescale use, eszopiclone has not been implicated in causing clinically apparent liver disease, although hepatitis and liver injury are listed as a rare adverse reactions in the product label. Eszopiclone is metabolized in the liver by the cytochrome P450 system (predominantly CYP 3A4 and 2E1). Nevertheless, drug-drug interactions appear to be uncommon. Thus, eszopiclone induced liver injury must be rare, if it occurs at all.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).\n\nDrug Class: Sedatives and Hypnotics\n\nOther Drugs in the Subclass, Benzodiazepine Receptor Agonists: Zaleplon, Zolpidem | null | null | Eszopiclone – Generic, Lunesta® | Sedatives and Hypnotics | null |
Ponesimod.nxml | Ponesimod | 2021-07-15 | Ponesimod is an orally available immunomodulatory drug used to treat relapsing forms of multiple sclerosis. Ponesimod is associated with transient serum enzyme elevations during therapy but has not been linked to instances of clinically apparent liver injury with jaundice, although experience with its use has been limited. | Ponesimod (poe nes’ i mod) is an immunomodulatory agent used in the treatment of multiple sclerosis that is believed to act by modulating sphingosine-1-phosphate (S1P) receptors. Ponesimod is an analogue of sphingosine and related in structure to fingolimod, the first S1P receptor modulator approved for use in multiple sclerosis. While fingolimod demonstrates nonspecific S1P receptor binding (subtypes 1, 3, 4 and 5), ponesimod has a more limited specificity and primarily blocks S1P receptor-1 activity. The S1P receptor modulators, once phosphorylated intracellularly, render T and B cells insensitive to signals necessary for egress from lymphoid tissue. In animal models of multiple sclerosis, ponesimod resulted in reduced recirculation of autoaggressive lymphocytes to the central nervous system. Subsequently, in several randomized controlled trials, ponesimod was shown to reduce relapse rates and improve neuro-radiologic outcomes in adult patients with relapsing multiple sclerosis. Ponesimod was approved for use in the United States in 2021 as therapy of relapsing multiple sclerosis in adults. It is available in tablets of 2 to 10 mg for dose initiation and 20 mg for maintenance therapy under the brand name Ponvory. As with other S1P receptor modulators, a period of dose escalation (14 days) is recommended for initiation of therapy with ponesimod. Ponesimod has also been shown to have beneficial effects in plaque psoriasis, but has yet to be approved for that indication. Common side effects of ponesimod (as with most S1P receptor modulators) are lymphopenia, headache, dizziness, diarrhea, cough, rhinorrhea, peripheral edema and back and abdominal pain. Rare, but potentially severe adverse events include severe viral, bacterial or fungal infections, atrial arrhythmias and bradycardia, macular edema, decrease in pulmonary function, progressive multifocal leukoencephalopathy (PML), and embryonal-fetal toxicity. Patients on long term ponesimod should be monitored for infectious complications and for cardiac, pulmonary and ophthalmologic status. | In preregistration trials of ponesimod, serum ALT elevations were common (in up to 23% of recipients) but were typically mild and asymptomatic, returning to baseline values even with continuation of therapy or within a few months of stopping. In one prospective, carefully monitored trial, serum aminotransferase elevations above 3 times upper limit of normal (ULN) were reported in 17% of ponesimod recipients and above 5 times ULN in 4.6%. In these prelicensure clinical trials, there were no cases of acute hepatitis or clinically apparent liver injury with jaundice, but elevations in liver tests led to early discontinuation in at least 2% of subjects. While ponesimod is associated with lymphopenia and long-term therapy is associated with risk for reactivation of herpes simplex and zoster infections, it has not been linked to cases of reactivation of hepatitis B although one such case has been reported with fingolimod. Thus, mild-to-moderate and transient serum enzyme elevations during therapy are common, but clinically apparent liver injury with jaundice due to ponesimod has not been reported, although the clinical experience with its use has been limited.\n\nLikelihood score: E* (suspected but unproven cause of clinically apparent liver injury). | The mechanism by which ponesimod might cause liver injury is not known. It is extensively metabolized by liver via multiple enzymes in the cytochrome P450 system, predominantly CYP 3A4, and drug-drug interactions with agents that induce or inhibit these enzymes are likely to occur. Serum enzyme elevations have been frequent with all of the oral S1P receptor modulators, particularly with fingolimod. | While chronic therapy with ponesimod can be associated with mild-to-moderate serum aminotransferase elevations, it has not been linked to any cases of clinically apparent liver injury. Because of the frequency of enzyme elevations detected during therapy, the product label for ponesimod recommends obtaining baseline liver tests before initiation of treatment. However, no specific recommendations for monitoring liver tests during treatment have been made. Any ALT or AST elevation associated with symptoms or jaundice should lead to prompt discontinuation of ponesimod. Patients with persistent elevations above 3 times ULN should be assessed for other causes of liver injury and discontinue ponesimod if not other cause is found. There is no known cross sensitivity of the hepatic injury from ponesimod with other agents used to treat multiple sclerosis. Because of the similarity in chemical structure and mechanism of action, there may be cross sensitivity to side effects with fingolimod, siponimod and ozanimod.\n\nDrug Class: Multiple Sclerosis Agents\n\nOther Drugs in the Subclass, S1P Receptor Modulators: Fingolimod, Ozanimod, Siponimod | Ponesimod – Ponvory® | Multiple Sclerosis Agents | null |
Hydroxyzine.nxml | Hydroxyzine | 2017-01-16 | Hydroxyzine is a first generation antihistamine that is used largely for symptoms of itching, nausea, anxiety and tension. Hydroxyzine has not been linked to instances of clinically apparent acute liver injury. | Hydroxyzine (hye drox' i zeen) is a first generation antihistamine that is used mostly to treat itching and nausea. Because of its sedating effects, hydroxyzine is also used for anxiety, tension and as a mild sleeping aid. Hydroxyzine belongs to the piperazine class of antihistamines (with cyclizine and meclizine) which are more commonly used for itching, nausea and anxiety than for their effects on symptoms of allergic rhinitis or coryza. Hydroxyzine was approved for use in the United States in 1957 and continues to be widely used. It is available as tablets or capsules of 10, 25, 50 and 100 mg in multiple generic forms and under the trade names Atarax and Vistaril. Hydroxyzine is also available as an oral suspension or syrup and as a liquid for injection. Most formulations are available without prescription. The recommended adult oral dose ranges from 25 to 100 mg three to four times daily. Doses used for itching are generally lower than those for anxiety and tension. Common side effects include sedation, impairment of motor function, confusion, dizziness, blurred vision, dry mouth and throat, palpitations, tachycardia, abdominal distress, constipation and headache. Antihistamines can worsen urinary retention and glaucoma. | Despite widespread use, hydroxyzine has not been linked to liver test abnormalities or to clinically apparent liver injury. Indeed, hydroxyzine is commonly used for the pruritus associated with liver disease. The reason for its safety may relate to low daily dose and limited duration of use.\n\nLikelihood score: E (unlikely to be a cause of clinically apparent liver injury).\n\nReferences on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines.\n\nDrug Class: Antihistamines | null | null | Hydroxyzine – Generic, Atarax®, Vistaril® | Antihistamines | null |
Bacopa.nxml | Bacopa monnieri | 2024-04-24 | Bacopa is an herbal extract made from the leaves of Bacopa monnieri, a herbaceous plant native to the Indian subcontinent which has been used in Ayurvedic medicine for centuries to treat anxiety, insomnia, and epilepsy and to improve memory and cognitive function. Bacopa has not been linked to liver enzyme elevations during therapy nor to instances of clinically apparent acute liver injury. | Bacopa is an herbal extract made from the fresh or dried leaves of Bacopa monnieri, a creeping, herbaceous plant native to the Indian subcontinent that has been used for centuries in Ayurvedic medicine to treat anxiety, depression, memory loss, and epilepsy. Currently it is widely used to boost memory and improve cognitive function and mental focus. Also known as water hyssop, bacopa monnieri leaves and roots have more than 100 components including flavonoids, flavones, saponins, triterpenoids, glycosides, sterols, and lipids. The active ingredients are thought to be saponin glycosides referred to as bacosides. In vitro and in vivo studies suggest that bacosides have anxiolytic, antiinflammatory, antioxidant, antiulcer, and neuroprotective properties leading to purported effects in many diseases and disease conditions including dementia, hyperactivity, memory loss, and depression. However, bacopa has not been shown to be effective for any disease or medical symptom in adequately controlled, prospective trials in humans, and bacopa is not approved in the United States as therapy of any medical condition. Nevertheless, Bacopa monnieri is available in multiple over-the-counter herbal products. The typical dose is 300 to 600 mg of the extract daily, the equivalent of 5 to 10 grams of the dried herb. Bacopa has only minor and usually short-lived side effects which may include abdominal pain, nausea, diarrhea, flatulence, dry mouth, headache, dizziness, insomnia, and rash. The overall rate of adverse events in bacopa-treated subjects has usually been similar to that in placebo controls. In small clinical trials, bacopa has had no serious or severe adverse effects. | Bacopa extract has not been linked to serum enzyme elevations during therapy, although there have been few prospective studies in humans that have reported on laboratory test results during treatment. Importantly, despite widespread use, bacopa has not been implicated in cases of clinically apparent liver disease.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | null | null | Bacopa – Generic | Herbal and Dietary Supplements | null |
Causality.nxml | Causality | 2019-11-20 | null | null | null | null | null | null | null | null |
Riociguat.nxml | Riociguat | 2018-06-04 | Riociguat is a stimulator of guanylate cyclase which causes relaxation of vascular smooth muscle and is used to treat severe pulmonary arterial hypertension. Riociguat has not been linked to significant serum enzyme elevations during therapy or to instances of clinically apparent acute liver injury. | Riociguat (rye" oh sig' ue at) is small molecular weight stimulator of soluble guanylate cyclase, an enzyme responsible for synthesis of cyclic guanine monophosphate (cyclic GMP), an important mediator of endothelial cell relaxation. By stimulating cyclic GMP, riociguat leads to relaxation of vascular smooth muscle cells, particularly in the pulmonary vasculature. In humans, riociguat induces pulmonary arterial vasodilation and reduces pulmonary artery pressure. In several clinical trials, prolonged therapy with riociguat has been shown to improve exercise capacity and pulmonary function in patients with severe idiopathic as well as chronic thromboembolic pulmonary arterial hypertension (PAH). Riociguat was approved for use in chronic idiopathic and thromboembolic PAH in 2013 and it is currently available in tablets of 0.5, 1.0, 1.5, 2.0 and 2.5 mg under the brand name Adempas. The recommended starting dose is 1 mg three times daily which can be increased in 0.5 mg amounts every two weeks based upon tolerance to a maximum of 2.5 mg thrice daily. Side effects are generally dose related and can include hypotension, syncope, dizziness, headache, diarrhea, gastrointestinal upset, nausea, vomiting and constipation, symptoms that are frequent with most vasodilator therapies. Rare, but potentially severe adverse reactions include pulmonary hemorrhage and fetal toxicity. Women of childbearing potential can receive riociguat only as a part of a risk evaluation and mitigation strategy (REMS) program that requires regular monitoring. | In preregistration studies, riociguat was not associated with serum enzyme elevations or with episodes of clinically apparent liver injury. Since approval of riociguat, there have been no published reports of hepatotoxicity, and the product label does not mention liver injury as an adverse event.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | The mechanism by which riociguat might cause serum aminotransferase elevations or liver injury is not known. It is metabolized by the hepatic cytochrome P450 system (predomination 3A4 and is susceptible to drug-drug interactions. The absence of significant hepatotoxicity from riociguat may related to the relatively low daily doses used (3.0 to 7.5 mg). | The serum enzyme elevations associated with riociguat use have been rare, mild-to-moderate and self-limited in course, usually resolving despite drug continuation. Clinically apparent liver injury from riociguat has not been described. There is no information on cross sensitivity to hepatic injury among the various agents used to treat pulmonary artery hypertension.\n\nDrug Class: Pulmonary Arterial Hypertension Agents\n\nOther Drugs in the Subclass, Guanylate Cyclase Inhibitors: Vericiguat\n\nOther Drugs in the Class: Ambrisentan, Bosentan, Macitentan, Selexipag; Prostacyclin Analogs, Epoprostenol, Iloprost, Treprostinil | Riociguat – Adempas® | Pulmonary Arterial Hypertension Agents | null |
Risankizumab.nxml | Risankizumab | 2021-06-09 | Risankizumab is a humanized monoclonal antibody to IL-23 which is used to treat moderate-to-severe plaque psoriasis. Risankizumab is generally well tolerated and is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent liver injury. | Risankizumab (ris” an kiz’ ue mab) is a humanized monoclonal IgG1 antibody directed against the p19 subunit of IL-23, which results in inhibition of IL-23 signaling and decrease in synthesis of proinflammatory cytokines such as IL-17. Risankizumab has been evaluated as therapy of several immune and inflammatory conditions, most extensively in plaque psoriasis. In several large, preregistration randomized controlled trials, 48 weeks of risankizumab therapy resulted in a significant improvement in psoriatic skin lesions in more than 70% of patients. Clinical responses were generally maintained with long term therapy. Risankizumab was approved in the United States in 2019 as therapy for moderate-to-severe plaque psoriasis in adult candidates for systemic therapy. It is also being evaluated in patients with psoriatic arthritis, inflammatory bowel disease and atopic dermatitis. Risankizumab is available in single dose pre-filled syringes of 75 mg in 0.83 mL under the brand name Skyrizi. The recommended dose is 150 mg (two syringes) administered subcutaneously at weeks 0 and 4 followed by every 12 weeks thereafter. Common side effects include mild local injection reactions, nasopharyngitis, fatigue, headache, arthralgia and skin rashes. Uncommon, potentially severe adverse reactions include severe infections, reactivation of tuberculosis and skin cancer. | Mild-to-moderate serum aminotransferase elevations arise in up to 10% of patients treated with risankizumab, but the abnormalities are generally transient and asymptomatic, rarely necessitating drug discontinuation. In large, preregistration trials there were no instances clinically apparent liver injury or severe hepatic adverse events attributed to risankizumab. Since its approval and more general use, there have been no reports of clinically significant liver injury attributed to risankizumab.\n\nLikelihood score: E (unlikely cause of clinically apparent acute liver injury). | The possible mechanisms of liver injury due to risankizumab are unclear. Monoclonal antibodies and immunoglobulins are generally taken up and metabolized intracellularly to short peptides and amino acids. There is no evidence to suggest that inhibition of IL23 signaling would trigger liver injury or autoimmune liver conditions.\n\nDrug Class: Monoclonal Antibodies, Psoriasis Agents | null | Risankizumab – Skyrizi® | Psoriasis Agents | null |
Resveratrol.nxml | Resveratrol | 2024-11-30 | Resveratrol is a plant polyphenol found in high concentrations in red grapes that has been proposed as a treatment for hyperlipidemia and to prevent fatty liver, diabetes, atherosclerosis and aging. Resveratrol use has been associated with rare instances of serum enzyme elevations during therapy but has not been convincingly linked to episodes of clinically apparent liver injury. | Resveratrol is a natural plant polyphenol (3,5,4’-trihydroxystilbene) that is found in highest concentrations in the skin of red grapes and other fruits (mulberries, blueberries, blackberries). In cell culture, resveratrol has antiinflammatory, cytoprotective, and antineoplastic properties which can be reproduced in several animal models. In model systems such as yeast (S. cerevisiae), worms (C. elegans), and fruit flies (Drosophila), chronic administration of resveratrol extends lifespan in a manner similar to caloric restriction. These results were somewhat controversial, but subsequent studies in several mammalian species supported the finding to some extent. Thus, resveratrol extended lifespan in mice fed a high fat diet (but not in normal mice), seemingly by counteracting the detrimental effects of the diet, and improving insulin sensitivity and mitochondrial function. The bases for the beneficial effects of resveratrol are unclear. Resveratrol has direct antioxidant effects, but also stimulates expression of antioxidant enzymes and the activity of sirtuin 1 (SIRT1) and adenosine monophosphate activated protein kinase (AMP-K), both of which have major effects on glucose and fat metabolism and may play a role in aging. Resveratrol is available without prescription as a nutritional supplement in multiple preparations and doses. In human trials, doses of resveratrol have ranged from 20 mg to 5 gm daily, but a typical over-the-counter recommended dose is 500 mg twice daily. Importantly, the purity of commercial products is rarely well defined, its oral bioavailability is poor and the component responsible for its activity is not known. Thus, resveratrol exists in both trans and cis configuration and the major form found in plasma is a sulfated or glucuronidal conjugate rather than free resveratrol. At present, there is no conclusive evidence that resveratrol has beneficial effects in humans. On the other hand, it has few if any side effects. Side effects may include minor gastrointestinal upset, nausea, headache and fatigue and possible supplement-drug interactions with estrogens and anticoagulants. | There have been multiple trials of resveratrol in human subjects, but the dose regimen and duration of therapy has varied greatly and many trials lacked information on adverse events, ALT elevations, and hepatotoxicity. Nevertheless, in most studies there was no mention of serum ALT elevations or only rare and mild-to-moderate increases that were asymptomatic and resolved rapidly upon stopping therapy. However, in studies using high doses of resveratrol (1.5 to 3.0 grams daily), average serum ALT and AST levels rose slightly during therapy and promptly fell into the normal range with stopping. There were, however, no instances of serum ALT elevations with jaundice or symptoms. Furthermore, despite widespread clinical use, there have been no published reports of clinically apparent liver injury attributed to resveratrol. In large case series and nationwide registries on herbal induced liver injury, resveratrol is not listed as a cause. Thus, hepatotoxicity due to resveratrol must be rare, if it occurs at all.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).\n\nDrug Class: Herbal and Dietary Supplements | null | null | Resveratrol – Generic | Herbal and Dietary Supplements | null |
Omega3FattyAcids.nxml | Omega-3 Fatty Acids | 2017-04-08 | Omega-3 fatty acids are essential polyunsaturated fatty acids that have diverse functions in normal metabolism and health and are used as nutritional supplements for general health and for disease prevention and as prescription drugs for treatment of hypertriglyceridemia. The omega-3 fatty acids are generally safe and well tolerated and have not been implicated in causing serum enzyme elevations or clinically apparent liver injury. | The omega-3 fatty acids are essential fatty acids that serve several important functions in normal metabolism and health. Omega-3 refers to their common structural feature of an unsaturated double bond at the third carbon bond from the “omega” end of the long chain fatty acid (n-3). There are three essential omega-3 fatty acids: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is an 18-carbon fatty acid with 3 double bonds (18:3n-3) and is found in plant oils such as walnut, flaxseed and canola oil. EPA, a 21-carbon molecule with 5 double bonds (21:5n-3), and DHA, a 22-carbon molecule with 6 double bonds (22:6n-3), are found in marine oils such as fish oils, squid oils and krill oil. Being essential, these fatty acids are not (or poorly) synthesized by humans and the necessary amounts must be provided in the diet. The amounts of omega-3 fatty acids in a typical Western diet can be marginal or inadequate, particularly EPA and DHA in persons with limited fish intake. For these reasons, the omega-3 fatty acids are some of the most commonly used nutrition supplements. They have been proposed to be not only necessary for good health, but also to be effective in prevention of many chronic conditions, including different forms of cancer, coronary artery disease, cerebrovascular disease, developmental disabilities, depression, bipolar illness, cognitive decline, Alzheimer disease, macular degeneration, rheumatoid arthritis, eczema and allergic conditions. However, efficacy of omega-3 fatty acid supplementation in any of these conditions has not been proven and results of prospective controlled trials have been largely negative or at most conflicting. Nevertheless, omega-3 fatty acids are popular nutritional supplements and hundreds of products are available under many commercial names such as “GNC Krill Oil”, “Nordic Natural DHA”, “Carlson Fish Oil Q”, “iHealth Overga-3”, “Jarrow Formulas Flaxseed Oil”, “ProThera Eicosamax Fish”, and “Swanson EFAs”, among others. These products are usually in the form of capsules and vary widely in concentration of the individual omega-3 fatty acids, but are generally in the range of 250 mg to 1,000 mg of total omega-3 fatty acids and recommended as being taken once daily. Side effects of omega-3 fatty acid and fish oil supplements in these doses are minimal, but may include mild gastrointestinal discomfort, nausea, diarrhea and headache. More clinically significant side effects include platelet dysfunction and an increased risk of bleeding, particularly in patients on anticoagulant and antithrombotic therapy. | In the many, large, randomized controlled trials of the omega-3 fatty acids, side effects have been minimal. Use of omega-3 fatty acids even in high doses has not been linked convincingly to serum enzyme elevations or to instances of clinically apparent liver injury. At high doses used to treat hypertriglyceridemia, minor ALT elevations were identified in up to 12% of patients, but similar rates occurred in placebo treated subjects and the abnormalities were transient, mild and not associated with symptoms or jaundice. Indeed, there have been several clinical trials of various formulations of the omega-3 fatty acids in patients with nonalcoholic fatty liver and preexisting elevations in serum aminotransferase levels. While not demonstrating a convincing beneficial effect in fatty liver disease, the omega-3 fatty acids also did not demonstrate any evidence of hepatic injury or worsening of the preexisting serum enzyme elevations.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | Omega-3 fatty acids are metabolized in the liver by beta-oxidation and broken down locally, usually into short chain fatty acids. They have little effect on hepatic cytochrome P450 or drug transporter activity. Their effects on triglyceride metabolism are more likely to be beneficial than harmful to hepatocytes. | null | Omega-3 Fatty Acids – Generic® | Herbal and Botanical Supplements | [
{
"cas_registry_number": "463-40-1",
"molecular_formula": "C18-H30-O2",
"name": "ALA"
},
{
"cas_registry_number": "1553-41-9",
"molecular_formula": "C20-H30-O2",
"name": "EPA"
},
{
"cas_registry_number": "25167-62-8",
"molecular_formula": "C22-H32-O2",
"name": "DHA"
}
] |
Eculizumab.nxml | Eculizumab | 2017-03-25 | Eculizumab is a humanized monoclonal antibody to complement factor 5 which acts to block complement activation and is used to treat paroxysmal nocturnal hemoglobinuria and hemolytic uremic syndrome. Eculizumab has been linked to several instances of serum enzyme elevations after repeated infusions and to rare instances of clinically apparent acute liver injury. | Eculizumab (e" kue liz' ue mab) is a recombinant, humanized IgG monoclonal antibody to complement factor 5, which inhibits its enzymatic cleavage and activation. Activated complement is an important mediator of immune damage including hemolysis of red blood cells and plays an essential role in the hemolysis and tissue damage that accompanies paroxysmal nocturnal hemoglobinuria (PNH) and hemolytic uremic syndrome (HUS). In clinical trials in PNH, eculizumab was found to reduce hemolysis and the need for blood transfusions with subsequent improvement in symptoms and quality of life. Eculizumab was approved for use in PNH in the United States in 2007. The indications were later broadened to include atypical hemolytic uremic syndrome with complement-mediated thrombotic events in 2011. Eculizumab is available as a solution in single dose vials of 300 mg in 30 mL (10 mg/mL) under the commercial name Soliris. The recommended dose varies by body weight and indication, but it is typically given by intravenous infusion (over 35 minutes) weekly for 5 weeks and every two weeks thereafter. Side effects are not common, but can include headache, diarrhea, nausea, fatigue and upper respiratory tract infections. Rare, but potentially severe adverse reactions include serious infections, including meningococcal infections, for which reason eculizumab is available only as a part of a risk evaluation and mitigation strategy (REMS) that requires physician training in its use and enrollment of the patient in a surveillance program. | In clinical trials of eculizumab in patients with PNH and atypical HUS, serum enzyme levels were rarely mentioned and laboratory test results were described as being stable or unremarkable. In preregistration studies of eculizumab there were no reports of clinically apparent liver injury with jaundice. Indeed, in many studies, a steady improvement in ALT and AST values during treatment was described, perhaps reflecting the decrease in intravascular hemolysis that occurred. After approval and more widespread use of eculizumab, however, a case series of eculizumab therapy in 11 children with atypical HUS, reported that 5 children developed marked serum enzyme elevations during therapy that was accompanied by jaundice in three cases and led to discontinuation of treatment in one patient after development of symptoms and jaundice (Case 1). The onset of injury was within the first 4 doses of eculizumab and tended to recur with subsequent doses, but to a lesser extent. Indeed, 4 children were able to continue eculizumab therapy without recurrence. The pattern of serum enzyme elevations was mixed. There was no mention of immunoallergic symptoms or autoantibody formation. Similar cases have not been reported in other case series or clinical trials. Thus, liver injury may occur with eculizumab therapy but it is typically mild, asymptomatic and self-limited in course, not requiring dose modification or discontinuation. There have been no reports of acute liver failure, chronic hepatitis or vanishing bile duct syndrome associated with eculizumab therapy.\n\nLikelihood score: D (possible cause of clinically apparent liver injury). | The mechanism by which eculizumab might cause liver injury is unknown. Eculizumab is a monoclonal antibody and, like other proteins, is metabolized into amino acids and is unlikely to have intrinsic toxicity. Because it blocks the activation of complement, it might predispose to conditions that depend on complement activation for resolution (such as meningococcemia), but it is not clear whether this applies to any liver diseases. | Eculizumab therapy has been linked to rare instances of mild, transient serum enzyme elevations during therapy, typically arising 1 to 3 weeks after an initial or early infusion of the monoclonal antibody. Instances of jaundice and symptoms from liver injury with eculizumab therapy are rare and not well described, but there have been no reports of acute liver failure, chronic hepatitis, cirrhosis or vanishing bile duct syndrome associated with it use. In patients who develop persistent elevations of serum ALT or alkaline phosphatase or who develop jaundice and symptoms, therapy should be interrupted.\n\nDrug Class: Hematologic Agents, Monoclonal Antibodies | Eculizumab – Soliris® | Hematologic Agents | null |
Lanreotide.nxml | Lanreotide | 2017-04-11 | Lanreotide is a synthetic polypeptide analogue of somatostatin that resembles the native hormone in its ability to suppress levels and activity of growth hormone, insulin, glucagon and many other gastrointestinal peptides. Because its half-life is longer than somatostatin, lanreotide can be used clinically to treat neuroendocrine tumors that secrete excessive amounts of growth hormone (acromegaly) or other active hormones or neuropeptides. Lanreotide has many side effects including suppression of gall bladder contractility and bile production, and maintenance therapy may cause cholelithiasis and pancreatitis as well accompanying liver injury. | Lanreotide (lan ree' oh tide) is a synthetic octapeptide and analogue of somatostatin that is used for its ability to suppress levels and activities of hormones (growth hormone, insulin, gastrin, secretin, glucagon) or active neuropeptides (serotonin, vasoactive intestinal polypeptide [VIP]). Natural somatostatin is produced in the hypothalamus and acts to suppress growth hormone release from the pituitary. Somatostatin is also found in other neurons throughout the body and particularly in intestinal and pancreatic neurons, where it is active in suppressing release of hormones and neuropeptides such as insulin, glucagon, gastrin, secretin, motilin, VIP, serotonin and cholecystokinin. Because of its short half-life (~3 minutes), somatostatin is impractical as a therapeutic agent, and analogues have been developed that have a more favorable pharmacological profile such as octreotide, pasireotide and lanreotide, all three of which have been marketed in long acting release (LRA) forms to allow once weekly or monthly administration. Lanreotide appears to interact largely with the somatostatin subtype 2 and possibly subtype 5 receptors, with little effect on subtypes 1, 3 and 4, but otherwise acts in a similar manner to somatostatin. Lanreotide therapy has been shown to improve symptoms and complications of several neuroendocrine tumors including abnormal growth in acromegaly due to growth hormone-secreting pituitary tumors, diarrhea due to VIP-secreting intestinal tumors, and flushing due to serotonin-producing carcinoid tumors. Lanreotide was approved for use in the United States in 2007 and current listed indications include acromegaly and unresectable, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors. Lanreotide has been used off label for polycystic liver and kidney disease. A long acting form of lanreotide is available under the brand name Somatuline Depot in prefilled syringes of 60 mg in 0.2 mL, 90 mg in 0.3 mL or 120 mcg in 0.5 mL (240 mg/mL). Lanreotide depot is administered as a deep subcutaneous injection every 4 weeks in doses of 60 to 120 mg each. Side effects are common. Adverse events from single injections include influenza-like symptoms of fatigue, headache, nausea and vomiting and local injection reactions. With continued therapy, common adverse events include diarrhea, abdominal pain, back pain, headache, dizziness, hypothyroidism, hypo- and hyperglycemia, arrhythmias and gallbladder disease. | In preregistration studies of lanreotide, serum enzyme levels did not change appreciably and there were no reports of clinically apparent acute liver injury. Pooled analyses reported that there were no overall changes in serum ALT, AST or alkaline phosphatase levels during therapy or instances of clinically meaningful elevations with treatment. Prolonged therapy with lanreotide, as with other somatostatin analogues, was associated with a high rate of biliary sludge and cholelithiasis, probably due to inhibition of gall bladder contractility and decrease in bile secretion. In long term studies, cholelithiasis developed in 20% to 33% of lanreotide treated patients. In some instances, symptomatic cholecystitis occurred which can be accompanied by mild-to-moderate elevations in serum enzymes and bilirubin. However, most lanreotide associated gallstones were asymptomatic. Unlike octreotide, lanreotide and other long acting somatostatin analogues have not been liked to cases of clinically apparent liver injury, independent of cholelithiasis or biliary sludge, although they have had more limited use and have not been used in many of the clinical situations that were treated with octreotide (portal hypertension, variceal hemorrhage and infants with congenital hyperinsulinemia).\n\nLikelihood score: E* (unproven but suspected rare cause of clinically apparent hepatobiliary injury). | Lanreotide, like somatostatin, decreases cholecystokinin secretion, gall bladder contractility and bile secretion, perhaps accounting for the high rate of gall bladder sludge and stone formation with long term use. How lanreotide might cause acute liver injury independent of its effect on bile flow and gall bladder function is uncertain. Lanreotide is a polypeptide and, as such, should not have direct or even indirect hepatic toxicity. On the other hand, lanreotide has multiple effects on the gastrointestinal tract, including effects on gastrointestinal hormone levels, motility, transit time, bacterial flora, and bile acid concentrations, all of which may have indirect effects on the liver. | The liver injury due to the lanreotide is generally due to its effects on the gallbladder and bile flow. Patients with hepatobiliary complications of lanreotide therapy are likely to have recurrence with restarting and have similar response to other somatostatin analogues such as octreotide and pasireotide.\n\nDrug Class: Hormonal Agents; Antineoplastic Agents; Gastrointestinal Agents\n\nOther Drugs in the Subclass, Hormonal Agents, Somatostatin Analogues: Octreotide, Pasireotide | Lanreotide – Somatuline Depot® | Hormonal Agents | [
{
"cas_registry_number": "108736-35-2",
"molecular_formula": "C54-H69-N11-O10-S2",
"name": "Lanreotide"
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"cas_registry_number": "83150-76-9",
"molecular_formula": "C49-H66-N10-O10-S2",
"name": "Octreotide"
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Thiotepa.nxml | Thiotepa | 2020-09-12 | Thiotepa is an intravenously or locally applied alkylating agent which is currently used in the therapy of breast, ovarian and bladder cancer. Thiotepa therapy has been associated with low rates of serum enzyme elevations during therapy and rare instances of acute, clinically apparent injury. | Thiotepa (thye' oh tep' a) is an ethylenimine similar in structure and activity to altretamine and is believed to act as an alkylating agent. The alkylating agents act by causing modification and cross linking of DNA, thus inhibiting DNA, RNA and protein synthesis and causing programmed cell death (apoptosis) in rapidly dividing cells. Thiotepa was approved for use in the United States in 1959. Current indications include ovarian and breast cancer and Hodgkin disease. Thiotepa is also administered locally for bladder cancer, neoplastic effusions and malignant meningeal neoplasms. Thiotepa is available generically in vials of 15 mg. The recommended dose varies by indications, route of administration, and body weight. Thiotepa shares common side effects with other alkylating agents such as nausea, vomiting, diarrhea, alopecia, mucositis, bone marrow suppression, rash and hypersensitivity reactions. Uncommon but potentially serious adverse events include severe myelosuppression, severe infections, sepsis, bleeding, and embryo-fetal toxicity. | Thiotepa is associated with an appreciable rate of serum enzyme elevations during therapy, but these are generally mild and self-limited, not requiring dose adjustment. Rare instances of clinically apparent acute liver injury attributed to thiotepa have been reported, particularly with high doses. In most instances, thiotepa was administered in combination with other agents known to cause liver injury and the specific role of thiotepa was not clear.\n\nThiotepa is often used in combination with other alkylating agents in conditioning regimens for bone marrow ablation in preparation for hematopoietic cell transplantation and as such has been linked to instances of sinusoidal obstruction syndrome. Onset of sinusoidal obstruction syndrome is usually within 1 to 3 weeks of myeloablative or high dose therapy and is characterized by the sudden development of abdominal pain, hepatomegaly, weight gain and ascites followed by jaundice. The pattern of serum enzyme elevations is usually hepatocellular, with marked increases in serum aminotransferase and lactic dehydrogenase levels and minimal increase in alkaline phosphatase. In severe instances, there are elevations in prothrombin time and progressive hepatic failure. Immunoallergic and autoimmune features are uncommon. The fatality rate is high. Liver biopsy shows centrolobular necrosis and congestion with occlusion of small veins and red cells in sinusoids.\n\nLikelihood score: D (possible, rare cause of clinically apparent liver injury). | The potential mechanism of hepatotoxicity from thiotepa is probably similar to that of other alkylating agents, a direct cytotoxic injury to rapidly dividing cells. High doses are likely to injure other cells such as sinusoidal endothelial cells and hepatocytes. The cause of the idiosyncratic liver injury associated with thiotepa is not known. | Liver injury is not uncommon with high doses of thiotepa. The severity of injury in reported cases has generally been mild-to-moderate and self-limited in course, although fatalities attributed to hepatotoxicity have been reported. The sinusoidal obstruction syndrome associated with thiotepa and other alkylating agents can be severe and lead to acute liver failure. There have been no instances of chronic hepatitis or vanishing bile duct syndrome definitely linked to thiotepa therapy. In situations of acute liver injury after thiotepa use, rechallenge should be avoided.\n\nDrug Class: Antineoplastic Agents, Alkylating Agents | Thiotepa – Generic, Thioplex® | Antineoplastic Agents, Alkylating Agents | null |
Betaine.nxml | Betaine | 2017-09-26 | Betaine is a modified amino acid consisting of glycine with three methyl groups that serves as a methyl donor in several metabolic pathways and is used to treat the rare genetic causes of homocystinuria. Betaine has had only limited clinical use, but has not been linked to instances of serum enzyme elevations during therapy or to clinically apparent liver injury. | Betaine (bee' ta een) is a naturally occurring modified amino acid that is used therapeutically to treat genetic homocystinuria. Homocystinuria can be caused by several inherited defects in sulfur amino acid metabolism, the most common of which are cystathionine β-synthase deficiency (CβS) and 5,10-methylenetetrahydrofolate reductase (MTHRF) deficiency. Typically, plasma levels of homocysteine and methionine are elevated while cysteine is decreased. Children with these deficiencies develop mental retardation, ocular lens dislocations, skeletal deformities and early onset atherosclerosis. Most evidence indicates that the high levels of homocysteine are the major cause of the clinical complications. Therapy of homocystinuria includes a low methionine diet, pyridoxine, a cofactor for cystathionine beta-synthase, and betaine which results in a decrease in homocysteine levels and amelioration of the clinical manifestations. Betaine is believed to act by increasing methylation reactions, one of which causes homocysteine to be metabolized to methionine. Betaine is an important nutrient that can be obtained from foods (such as beets), synthesized endogenously from choline, or provided as a supplement in patients with impaired folate status or inherited deficiencies of enzymes involved in transsulfuration pathways. The liver is rich in betaine but levels may be somewhat reduced in patients with liver disease. Betaine was approved as an orphan drug for use in homocystinuria in 1996 and is available as a powder for reconstitution in bottles of 180 grams under the brand name Cystadane. The typical dose is 3 to 10 grams twice daily. Side effects are dose related and can include gastrointestinal upset with diarrhea, bloating, cramps, dyspepsia, nausea and vomiting. Rare, but potentially severe side effects include excessive increases in serum methionine concentrations which may lead to life-threatening cerebral edema. | In small, open label trials of betaine therapy for homocystinuria as well as in small controlled trials of betaine in other conditions (Alzheimer disease, nonalcoholic steatohepatitis), serum enzyme elevations and clinically apparent liver injury were not reported. Indeed, in some studies, betaine has been associated with significant declines in preexisting serum enzyme elevations in a proportion of patients with nonalcoholic fatty liver disease.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | Betaine is a naturally occurring modified form of glycine that aids in the transsulfuration pathways converting homocysteine to methionine. Administration of betaine even in high doses (6 to 20 grams daily) has not been linked to hepatotoxicity.\n\nDrug Class: Genetic Disorder Agents | null | Betaine – Cystadane® | Genetic Disorder Agents | [
{
"cas_registry_number": "107-43-7",
"molecular_formula": "C5-H11-N-O2",
"name": "Betaine"
},
{
"cas_registry_number": "56-40-6",
"molecular_formula": "C2-H5-N-O2",
"name": "Glycine"
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] |
Nelarabine.nxml | Nelarabine | 2020-05-01 | Nelarabine is a purine analogue and antineoplastic agent used in the therapy of T cell lymphoblastic leukemia or lymphoma. Nelarabine is associated with a low rate of transient serum enzyme elevations during therapy and has been linked to rare instances of clinically apparent acute liver injury with jaundice. | Nelarabine (ne lar' a been) is a purine analogue that is used in the treatment of T cell leukemia or lymphoma. Nelarabine is arabinosyl derivative of deoxyguanosine (2-amino-9-beta-D-arabinofuranosyl-6-methoxy-9-H-guanine) that, after removal of the methoxy group by adenosine deaminase in serum, is taken up and converted intracellularly to the active triphosphate, which is believed to compete with guanine triphosphate for use by DNA polymerase leading to inhibition of DNA synthesis. It has selective activity against T lymphocytes and was found to have activity against acute T cell malignancies. Nelarabine was approved for use as an antineoplastic agent in the United States in 2005. Current indications are therapy of acute T cell lymphoblastic leukemia and T cell lymphoblastic lymphoma after failure of prior therapies. Nelarabine is available as a solution for injection under the trade name Arranon. The typical adult dose is 1500 mg/m2 intravenously on days 1, 3 and 5 of 21-day cycles. Common side effects include bone marrow suppression, nausea, vomiting, anorexia, diarrhea, headache, fatigue, mucositis and skin rash. The major dose limiting side effects of nelarabine are neurologic, including somnolence, headache, dizziness, ataxia, delirium, seizures, neuropathy and Guillain Barre syndrome. The neurologic toxicities can be severe and some are not reversible on stopping nelarabine as is stressed by the boxed warning in the product label. | In clinical trials, serum enzymes elevations occurred in a small proportion of patients treated with nelarabine when given as sole therapy for refractory or relapsed acute leukemia. These elevations are generally mild-to-moderate, transient and asymptomatic. Elevations of aminotransferase levels above 5 times the upper limit of normal are reported in 4% of patients with leukemia receiving nelarabine. The elevations rarely require dose adjustment or delay in therapy. Cases of clinically apparent liver injury due to nelarabine have been reported to occur, but few details are available. A single case report of clinically apparent liver injury attributed to nelarabine has been published with rapid onset of jaundice during a second course of nelarabine, a hepatocellular pattern of enzyme elevations, no immunoallergic or autoimmune features and a rapid improvement upon stopping.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury). | Hepatotoxicity from nelarabine is likely due to direct toxicity as is typical for other purine analogues. | The severity of the liver injury linked to nelarabine therapy is generally self-limited and mild and resolves with stopping therapy. There is little evidence of cross sensitivity to liver injury among the various antineoplastic or antiviral purine analogues.\n\nDrug Class: Antineoplastic Agents, Antimetabolites\n\nOther Drugs in the Subclass, Purine Analogues: Azathioprine, Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Pentostatin, Thioguanine | Nelarabine – Generic, Arranon® | Antineoplastic Agents | null |
ErgotAlkaloids.nxml | Ergot Alkaloids | 2018-02-10 | Ergot alkaloids are widely used for therapy of acute migraine headaches and include ergotamine and dihydroergotamine, both of which act by causing vasoconstriction of the carotid artery beds. Ergot alkaloids have multiple side effects, but have little effect on the liver and have not been clearly linked to instances of clinically apparent acute liver injury. | Ergotamine (er got' a meen) and dihydroergotamine are ergot alkaloids that act as vasoconstrictors, probably by stimulating alpha adrenergic receptors particularly in the carotid artery bed. The ergotamines may also have serotoninergic effects which may also be beneficial in migraine. The ergotamines were first reported to alleviate migraine headaches in the 1920s and were introduced into clinical use in the United States in the 1940s. Ergotamine is available in 1 mg tablets in multiple generic forms and under brand names such as Cafergot, Ergomar, Ergostat, Migergot and Wigraine. Various combinations of ergotamine with caffeine (100 mg) and acetaminophen are also available as are rectal suppositories (2 mg with or without caffeine) and sublingual forms (2 mg). The usual recommended dose to abort or treat a vascular headache is 2 mg initially (sublingually or orally) and then 1 to 2 mg every 30 minutes, to a maximum of 6 mg per attack and 10 mg weekly. Dihydroergotamine is available in solution for injection (1 mg/mL) or as a nasal spray (4 mg/mL) in generic forms and under the brand names of DHE 45 and Migranal. The usual recommended dose is 1 mg intramuscularly or intravenously initially, repeated at 1 hour intervals to a total dose of 2 to 3 mg and no more than 6 mg weekly. The nasal spray is given as 0.5 mg to each nostril, repeated every 15 minutes, but to less than 3 mg in 24 hours and 4 mg in one week. The advantage of the nasal and parenteral formulations is the rapid onset of action; the disadvantage is a greater potential for overdose or side effects. Common side effects (ergotism) include nausea, vomiting, light-headedness, numbness and tingling, hypertension, bradycardia, muscle pains and itching. Overdose can cause acute vascular spasm and thrombosis. | Neither ergotamine nor dihydroergotamine have been implicated in causing liver enzyme elevations, but they are generally used in limited amounts for short and intermittent periods of time. Ergotamine abuse can lead to arterial or venous spastic episodes, and at least one case of portal and splenic vein thrombosis with resultant noncirrhotic portal hypertension has been reported. Ergotamine overdose can lead to ischemic injury to limbs or viscera, including the liver. However, the ergotamines have not been implicated in cases of clinically apparent liver injury and product labels do not mention ALT elevations or liver injury as potential adverse events.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | Ergotamine is extensively metabolized by the liver, but it is given in low doses, and intermediates of its metabolism, even if potentially toxic, are likely conjugated and excreted rapidly and without hepatic injury. The vasospastic actions of ergotamines can cause arterial and venous spasms and potentially thromboses to the hepatic artery or portal systems.\n\nAgents used specifically in management of migraines and vascular headaches include: the ergot alkaloids, ergotamine and dihydroergotamine; and, the serotonin receptor agonists (triptans), including almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.\n\nDrug Class: Migraine Headache Agents, Vasoconstrictor Agents | null | Dihydroergotamine – Generic, Migranal® | Migraine Headache Agents | [
{
"cas_registry_number": "511-12-6",
"molecular_formula": "C33-H37-N5-O5",
"name": "Dihydroergotamine"
},
{
"cas_registry_number": "113-15-5",
"molecular_formula": "C33-H35-N5-O5",
"name": "Ergotamine"
}
] |
Amlodipine.nxml | Amlodipine | 2016-03-01 | Amlodipine besylate is a second generation calcium channel blocker that is used in the therapy of hypertension and angina pectoris. Amlodipine has been linked to a low rate of serum enzyme elevations during therapy and to rare instances of clinically apparent acute liver injury. | Amlodipine (am loe' di peen) belongs to the dihydropyridine class of calcium channel blockers and is used in the treatment of both hypertension and angina pectoris. Like other calcium channel blockers, amlodipine acts by blocking the influx of calcium ions into vascular smooth muscle and cardiac muscle cells during membrane depolarization. This action causes relaxation of vascular and arterial smooth muscle cells, resulting in arterial vasodilation and a decrease in cardiac work and oxygen consumption. Amlodipine was approved in the United States in 1992 and it remains in wide use, with several million prescriptions filled yearly. Current indications include hypertension and coronary artery disease (angina pectoris). Amlodipine is available generically and under the brand name of Norvasc. Tablet strengths include 2.5, 5, and 10 mg. The recommended dose in adults is 2.5 to 10 mg once daily, usually starting with the lowest dose. Chronic therapy is typical. Recently, multiple fixed dose combinations of amlodipine with other agents have become available including amlodipine (5 or 10 mg) with aliskiren (150 or 300 mg: Tekamlo), aliskiren with hydrochlorothiazide (12.5 and 25 mg: Amturnide), atorvastatin (10, 20, 40 or 80 mg: Caduet and generic), benzapril (10, 20 or 40 mg: Lotrel, Amlobenz, and generic), benzapril and hydrochlorothiazide (12.5 and 25 mg: Tribenzor), olmesaran (20 and 40 mg: Azor), and telmisartan (40 or 80 mg: Twynsta), valsartan (160 and 320 mg: Exforge) and valsartan with hydrochlorothiazide (25 mg: Exforge HCT). Like most calcium channel blockers, amlodipine is generally well tolerated. Side effects are largely due to the vasodilating activities and can include headache, flushing, dizziness, fatigue, nausea, diarrhea, palpitations, peripheral edema and rash. | Chronic therapy with amlodipine is associated with a low rate of serum enzyme elevations at rates that are similar to matched control populations. The enzyme elevations are usually mild, transient and asymptomatic and may resolve even during continued therapy. Clinically apparent liver injury from amlodipine is rare and described only in isolated case reports. In the few idiosyncratic cases reported, the latency period to onset of liver injury was usually 4 to 12 weeks, but examples with prolonged latency have also been published (10 months and several years). The latency period is shorter with recurrence on reexposure, including several instances of recurrence after liver injury due to other calcium channel blockers. The pattern of serum enzyme elevations is usually mixed or cholestatic. Rash, fever and eosinophilia have not been described and autoantibodies are not typical.\n\nLikelihood score: C (probable but rare cause of clinically apparent liver injury). | The mechanism of amlodipine hepatotoxicity is not known, but liver injury is probably due to production of a toxic intermediate in its metabolism. | The severity of liver injury from amlodipine ranges from mild and transient serum enzyme elevations to self-limited jaundice. Complete recovery is expected after stopping the drug and recovery is usually rapid (4 to 8 weeks). Cases with chronic or fulminant liver injury due to amlodipine have not been reported. Little information is available on recurrence with rechallenge but there may be some degree of cross-sensitivity to hepatotoxicity with other calcium channel blockers.\n\nDrug Class: Cardiovascular Agents, Calcium Channel Blockers\n\nOther Drugs in the Subclass, Calcium Channel Blockers: Diltiazem, Felodipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Verapamil | Amlodipine – Generic, Norvasc® | Cardiovascular Agents | null |
Golimumab.nxml | Golimumab | 2017-02-10 | Golimumab is a human monoclonal antibody to tumor necrosis factor (TNF) alpha that is used in the treatment of rheumatoid arthritis and ulcerative colitis. Golimumab has been linked to a low rate of serum enzyme elevations during therapy, but has not been linked to cases of idiosyncratic, clinically apparent liver injury with jaundice. Because golimumab is a potent inhibitor of TNF alpha, it is likely to cause reactivation of chronic hepatitis B in susceptible patients. | Golimumab (goe lim’ ue mab) is a human monoclonal immunoglobulin antibody to tumor necrosis factor (TNF) alpha, a proinflammatory cytokine that plays a role in cell injury, inflammation and tissue damage in inflammatory, autoimmune diseases. Golimumab is one of several monoclonal antibody inhibitors of TNF and has been shown to be effective in decreasing inflammation and improving symptoms in several autoimmune diseases, including rheumatoid arthritis and ulcerative colitis. Golimumab was approved for use in the United States for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis in 2009, and the indications were broadened to include ulcerative colitis in 2013. Golimumab is available in liquid solution in single use, prefilled syringes of 50 and 100 mg under the brand name Simponi. Golimumab is given by subcutaneous injection and the regimen varies by indication. For inflammatory arthritidies the recommended dose is 50 mg once monthly. For ulcerative colitis, the recommendation is for an initial dose of 200 mg, followed by 100 mg at week 2 and then 100 mg every 4 weeks. Common side effects include injection site reactions, chills, fever, skin rash and fatigue. Less common but potentially severe side effects include hypersensitivity reactions and anaphylaxis, opportunistic infections, reactivation of tuberculosis or hepatitis B, congestive heart failure, lymphoma and other malignancies and demyelinating diseases. | In prelicensure controlled trials, serum ALT elevations occurred in up to 8% of golimumab vs 1% to 3% of placebo treated subjects. The elevations were usually mild-to-moderate in severity, asymptomatic, not accompanied by jaundice and self-limited in course. ALT elevations above 5 times the upper limit of normal (ULN) occurred in 1% to 3% of golimumab and in ~1% of placebo recipients, but only rare patients had to stop therapy because of serum enzyme elevations. There have been no published case reports of clinically apparent, acute liver injury with symptoms or jaundice attributed to golimumab, but experience with its use has been limited.\n\nNevertheless, golimumab is a potent TNF inhibitor, and virtually all TNF antagonists have been linked to cases of reactivation of hepatitis B, which can be severe and lead to acute liver failure and death or need for emergency liver transplantation. More than 100 cases of clinically apparent reactivation of hepatitis B have been attributed to TNF inhibitors such as infliximab, etanercept, adalimumab and certolizumab. Reactivation typically occurs in patients who are HBsAg carriers with inactive liver disease before treatment. The usual sequence of events is appearance of rising levels of HBV DNA in serum shortly after the anti-TNF therapy is started, followed by rise in levels of HBsAg and HBeAg. Between courses, when immune reconstitution begins, serum ALT and AST levels start to rise followed by symptoms and jaundice. The onset of liver injury is usually after 3 to 6 monthly injections of the TNF antagonist. Reactivation of hepatitis B tends to be severe and the mortality rate in jaundiced cases exceeds 10%. Liver histology demonstrates an acute hepatitis-like pattern with focal or confluent necrosis and prominent lymphocytic infiltrates of activated T cells, which is compatible with an immune mediated hepatic injury. There may also be evidence of an underlying chronic hepatitis or cirrhosis. Restarting the TNF inhibitor can result in recurrence of injury, although antiviral treatment usually blocks recurrence.\n\nReactivation of HBV can also occur in persons who have resolved hepatitis B (anti-HBc without HBsAg in serum) with reappearance of HBsAg in serum (“reverse seroconversion”). This form of reactivation is less common than classic reactivation (in an HBsAg carrier), yet tends to be more severe. Reverse seroconversion is rare in patients on anti-TNF therapy, occurring more frequently with rituximab or more rigorous forms of immunosuppression (myeloablation and hematopoietic cell transplantation). Reverse seroconversion has yet to be described as a result of golimumab therapy.\n\nBecause of the possibility of reactivation of hepatitis B with anti-TNF therapy, screening for markers of HBV infection before starting therapy is recommended. Patients with HBsAg in serum should receive prophylaxis with oral anti-HBV therapy. Patients with anti-HBc without HBsAg in serum should be monitored for evidence of reactivation and treated promptly with antiviral therapy if HBV DNA or HBsAg appear.\n\nFinally, golimumab may reactivate other viral infections and acute hepatitis due to an opportunistic viral infection may occur.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury). | The mechanism of liver injury in reactivation of hepatitis B appears to be a brisk immunological response to newly expressed viral antigens. Injury generally arises after anti-TNF therapy has stopped or between courses of treatment. | Guidelines for management of patients who are to receive golimumab recommend routine screening for hepatitis B before starting treatment. Screening should include tests for HBsAg and anti-HBc (and perhaps also anti-HBs as this may help in management). Prophylaxis with a potent oral, antiviral agent effective against hepatitis B is recommended for all persons who have HBsAg in serum and is suggested for those with anti-HBc without HBsAg. An alternative approach is careful monitoring for HBV DNA during therapy and prompt institution of antiviral therapy if levels rise. The choice of antiviral agents includes lamivudine, telbivudine, adefovir, tenofovir or entecavir. All are given once a day and are extremely well tolerated. Lamivudine is less expensive than the other agents, but is associated with a high rate of antiviral resistance particularly if given for more than 6 months. Tenofovir and entecavir are the most potent and have high barriers to antiviral resistance which is important if long term therapy is planned. However, there are no prospectively acquired controlled studies to support use of one of these agents over another. Finally, the appropriate duration of treatment is unclear. The typical recommendation is to continue antivirals for at least 6 months after stopping anti-TNF therapy, but cases of reactivation following withdrawal of antiviral therapy (including fatal instances) have been described and some degree of monitoring during withdrawal of antiviral therapy is perhaps appropriate.\n\nDrug Class: Antirheumatic Agents, Tumor Necrosis Factor Antagonists; Gastrointestinal Agents, Inflammatory Bowel Disease Agents, Monoclonal Antibodies\n\nOther Drugs in the Subclass, Tumor Necrosis Factor Antagonists: Adalimumab, Certolizumab, Etanercept, Infliximab | Golimumab – Simponi® | Antirheumatic Agents | null |
AnthraxAntitoxins.nxml | Anthrax Antitoxins | 2017-03-27 | High titers of antibody to infectious bacteria and viruses can be used to both prevent and treat infectious diseases. In particular, antitoxins have been shown to be beneficial in several forms of severe acute infections such as diphtheria, rabies and anthrax. The recent use of active anthrax spores as a bioweapon, particularly in acts of terror, has renewed research efforts to develop potent, rapidly active means of prevention and treatment of anthrax after purposeful or accidental exposure. Several monoclonal antibodies to anthrax antigens have been developed as part of research efforts in bioterrorism, of which two are commercially available: raxibacumab (2012) and obiltoxaximab (2016). These two agents were approved for use based upon the so called “Animal Rule”, which allows FDA approval based upon efficacy as shown in animal models of severe infectious diseases and upon safety data developed in healthy volunteers. Both monoclonal antibodies have had limited use in humans, but neither has been associated with serum enzyme elevations or with instances of clinically apparent liver injury during the limited preclinical safety evaluation in healthy volunteers. Updated information on prevention and treatment of anthrax is available from the Centers for Disease Control and Prevention on their website: https://www.cdc.gov/anthrax/index.html. | Obiltoxaximab (oh" bil tox ax i mab) is a human-mouse chimeric monoclonal antibody to the Bacillus anthrax protective antigen that is the major immunogenic antigen produced by the bacterial infection. The binding of obiltoxaximab to the anthrax protective antigen blocks the binding of the bacterial toxin to host cells. In several animal models of inhalation anthrax, obiltoxaximab ameliorated the course of the disease and, if given before the onset of signs and symptoms, prevented clinically apparent disease. Obiltoxaximab was approved for use in the United States in 2016 for the prevention and treatment of inhalation anthrax. The approval was based upon the efficacy of obiltoxaximab in animal models of anthrax and on data on safety and pharmacokinetics in healthy human volunteers. Human anthrax is exceedingly rare, but has occurred in the United States as a result of acts of terrorism. Obiltoxaximab is available in single use vials of 600 mg in 6 mL (100 mg/mL) under the brand name Anthim. The recommended dose is 16 mg/kg by slow (90 minute) intravenous infusion in adults and children above 40 kg in weight. Side effects were assessed in studies done in several hundred healthy adult volunteers. While described as “generally well tolerated” adverse events included headache, itching, rash, urticaria and local infusion and hypersensitivity reactions including anaphylaxis. Premedication with diphenhydramine (an antihistamine) is recommended. | In human volunteer studies, obiltoxaximab was associated with local infusion and general hypersensitivity reactions, but clinical laboratory results were said to be unchanged over time. There have been no reports of hepatotoxicity associated with administration of obiltoxaximab.\n\nLikelihood score: E (unlikely cause of liver injury, but it has had very limited use in humans). | Obiltoxaximab is a monoclonal antibody and is unlikely to be inherently hepatotoxic. Recombinant proteins are often metabolized in the cells on which they act but are also metabolized in the liver, largely to small peptides and amino acids which may be reused to synthesize proteins and are unlikely to be toxic or immunogenic.\n\nDrug Class: Antiinfective Agents, Antitoxins; Monoclonal Antibodies | null | Obiltoxaximab – Anthim® | Antiinfective Agents | [
{
"cas_registry_number": "1351337-07-9",
"molecular_formula": "Monoclonal Antibody",
"name": "Obiltoxaximab"
},
{
"cas_registry_number": "565451-13-0",
"molecular_formula": "Monoclonal Antibody",
"name": "Raxibacumab"
}
] |
Crizanlizumab.nxml | Crizanlizumab | 2021-07-12 | Crizanlizumab is a humanized monoclonal antibody to P-selectin which is used to prevent painful crises in sickle cell disease. Crizanlizumab is generally well tolerated and has not been associated with serum aminotransferase elevations during therapy or with instances of clinically apparent liver injury. | Crizanlizumab (kriz an liz ue mab) is a humanized monoclonal IgG2 antibody directed against P-selectin, which is used to prevent painful, vaso-occlusive crises in patients with sickle cell disease. Sickle cell disease is caused by an inherited mutation in the β globin gene that creates hemoglobin S, which is prone to aggregation with deoxygenation resulting in deformation and sickling of red blood cells, hemolytic anemia, and recurrent painful crises involving different organs and tissues. Sickle cell disease affects at least 100,000 Americans and is most common in persons of African descent. Long term complications include disability due to recurrent painful crises, acute chest syndrome, pulmonary hypertension, stroke and cerebral infarcts, end-organ damage and early mortality. Binding of the monoclonal antibody to P-selectin inhibits its attachment to its glycoprotein ligand thereby inhibiting the adhesion of sickled red cells to endothelium, a critical step in the vaso-occlusive crises of sickle cell disease. Thus, crizanlizumab does not prevent sickling of red cells or increase hemoglobin levels or change the oxygen-binding characteristics of hemoglobin, but rather it inhibits the aggregation and binding of the sickled red cells to platelets, leukocytes and endothelial cells which mediates the vascular occlusions that underlie painful crises. In preregistration randomized, placebo-controlled trials, 48 weeks of crizanlizumab therapy resulted in a decrease in the number of painful crises and both duration and numbers of hospitalizations. Crizanlizumab was approved in the United States in 2019 as therapy for prevention of painful crises in sickle cell disease in adults and children above the age of 16 years. Crizanlizumab is available in single dose pre-filled syringes 100 mg in 10 mL (10 mg per mL) under the brand name Adakveo. The recommended dose is 5 mg/kg intravenously over 30 minutes at 0 and 2 weeks, followed by every 4 weeks thereafter. Crizanlizumab can be given with hydroxyurea, the standard therapy for sickle cell disease. Common side effects of crizanlizumab include mild local injection reactions, arthralgias, backpain, diarrhea, pruritus, nausea, vomiting and chest pain. Also reported have been rare instances of severe hypersensitivity reactions. | Mild-to-moderate serum aminotransferase elevations arise a small percentage of treated patients, but are generally asymptomatic and transient and rarely necessitate discontinuation of crizanlizumab injections. In registration trials of crizanlizumab there were no reported instances clinically apparent liver injury or severe hepatic adverse events attributed to the therapy. Since approval and more general use of crizanlizumab there have been no reports of clinically significant liver injury attributed to its use.\n\nLikelihood score: E (unlikely cause of clinically apparent acute liver injury). | Possible mechanisms of liver injury due to crizanlizumab are not known. Monoclonal antibodies and immunoglobulins are generally taken up and metabolized intracellularly to short peptides and amino acids. | Drug Class: Genetic Disorder Agents, Monoclonal Antibodies, Sickle Cell Disease Agents | Crizanlizumab – Adakveo® | Sickle Cell Disease Agents | null |
resource.nxml | DILI Information Resources | 2021-04-01 | null | null | null | null | null | null | null | null |
Delafloxacin.nxml | Delafloxacin | 2020-03-10 | Delafloxacin is a fourth generation fluoroquinolone with expanded activity against gram-positive bacteria as well as atypical pathogens. Delafloxacin has been linked to mild ALT elevations during therapy, but has yet to be linked to instances of idiosyncratic acute liver injury with symptoms and jaundice as have been described with other fluoroquinolones. | Delafloxacin (del" a flox' a sin) is a fourth generation fluoroquinolone with expanded activity against gram-positive bacteria including multidrug resistant strains of Streptococcus pneumoniae. Like other fluoroquinolones, delafloxacin is active against a wide range of aerobic gram-positive and gram-negative organisms. The quinolones are believed to act by inhibition of bacterial DNA gyrase and topoisomerase IV that are required for synthesis of bacterial mRNAs (transcription) and DNA replication. In contrast, DNA gyrases are not present in human [and other eukarotic] cells and the equivalent topoisomerases are not sensitive to fluoroquinolone inhibition. Delafloxacin was approved for use in the United States in 2018 and is available under the commercial name Baxdela. Current indications are limited to skin and skin structure infections due to sensitive organisms. Delafloxacin is available in both oral and parenteral formulations as 450 mg tablets and as 300 mg of a lyophilized powder in a single dose vial for reconstitution. The recommended regimen is an oral dose of 450 mg every 12 hours or by intravenous infusion every 12 hours for 5 to 14 days. Common side effects include gastrointestinal upset, nausea, diarrhea, headache, skin rash and allergic reactions. Less common, but more severe side effects of delafloxacin that are shared by other fluoroquinolones include seizures, hallucinations, peripheral neuropathy, tendon rupture, severe hypersensitivity reactions, Stevens Johnson syndrome, angioedema, photosensitivity and Clostridium difficile-associated diarrhea. | Delafloxacin, like other fluoroquinolones, is associated with a low rate (3% to 4%) of serum enzyme elevations during therapy. These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy. ALT elevations above 5 times the upper limit of normal occur in 1% or less of subjects. Although delafloxacin may not have been clearly linked to cases of clinically apparent liver injury, the other fluoroquinolones, such as ciprofloxacin, levofloxacin and moxifloxacin, rank among the 25 most common causes of drug induced liver injury in many case series. Estimates of the frequency of liver injury from fluoroquinolones have been 1:15,000 to 1:25,000 exposed persons. Delafloxacin has been in clinical use for a short time only, but is likely to have a similar frequency and pattern of liver injury as the other fluoroquinolones.\n\nThe typical presentation of fluoroquinolone associated liver injury is with a short latency (1 day to 3 weeks) and abrupt onset with nausea, fatigue, abdominal pain and jaundice. The pattern of serum enzyme elevations can be either hepatocellular or cholestatic, cases with the shorter times to onset usually being more hepatocellular. In addition, the onset of illness may occur a few days after the medication is stopped. Many (but not all) cases have prominent allergic manifestations with fever and rash, and the liver injury may occur in the context of a generalized hypersensitivity reaction. Autoantibodies are usually not present. Most reported cases of liver injury from fluoroquinolones have been mild and self-limited, with recovery in 4 to 8 weeks from onset. However, the fatality rate of cases with jaundice has been greater than 10%. In addition, cases with a cholestatic pattern of serum enzymes may run a prolonged course and, in rare instances, have progressed to chronic vanishing bile duct syndrome leading to liver failure. Nevertheless, delafloxacin is a relatively recently introduced antibiotic and has yet to be convincingly linked to instances of acute hepatitis or jaundice.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury). | The cause of hepatic injury from the fluoroquinolones is unknown but appears to be hypersensitivity. | Mild-to-moderate injury from fluoroquinolone induced hepatitis should be followed by full recovery within 4 to 8 weeks. Cases of acute liver failure with death or need for liver transplantation have been reported, nor have chronic cases with bile duct loss. Cross reactivity of the hepatic injury between different fluoroquinolones has not been demonstrated but is suspected based upon the similarity of clinical patterns of injury and latency. Thus, patients who developed clinically apparent liver injury from a fluoroquinolone should be advised to avoid delafloxacin. Monitoring of liver tests during therapy is likely to be ineffective as the typical course of treatment is only 5 to 10 days.\n\nDrug Class: Antiinfective Agents\n\nOther Drugs in the Subclass, Fluoroquinolones: Ciprofloxacin, Gemifloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin | Delafloxacin – Baxdela® | Antiinfective Agents | null |
Dostarlimab.nxml | Dostarlimab | 2022-06-08 | Dostarlimab is a human monoclonal antibody to the programmed cell death receptor 1 (PD-1) and a checkpoint inhibitor used in the immunotherapy of cancer. Dostarlimab therapy has many adverse effects and particularly immune related conditions including acute hepatitis, which can be serious and even life threatening. | Dostarlimab (dos tar’ li mab) is a human recombinant monoclonal IgG4 antibody to the programmed cell death receptor 1 (PD-1) and is a checkpoint inhibitor used in cancer immunotherapy. PD-1 is an important checkpoint protein that is expressed on activated T and B cells and macrophages. Binding of the monoclonal antibody to the PD-1 receptor prevents ligand attachment and activation of the programmed cell death pathways, thereby allowing for a continued activation and proliferation of T cells. The subsequent enhancement of cytotoxic reactivity may play a beneficial role in cancer immunotherapy by breaking immunological tolerance to cancer cell neoantigens. In prelicensure clinical studies, dostarlimab therapy resulted in objective responses in 42% of patients with DNA mismatch repair deficient, advanced or recurrent endometrial carcinoma. Tumors with mismatch repair deficiency have high rates of chromosomal changes that are associated with increased expression of neoantigens, which makes these cancers an attractive target for checkpoint inhibition. Dostarlimab was given accelerated approval for use in endometrial carcinoma in the United States in 2021. It is under evaluation in many other cancers, including cervical, ovarian, breast, liver, pancreatic, lung and colorectal carcinoma. Dostarlimab is available in solution in single use vials of 500 mg in 10 mL (50 mg/mL) under the brand name Jemperli. The recommended dose regimen is 500 mg intravenously every 3 weeks for four doses, followed 3 weeks later by 1000 mg every 6 weeks, continuing until disease progression or unacceptable toxicity. Side effects are common and can include fatigue, nausea, vomiting, diarrhea, constipation, musculoskeletal pain, anemia, pruritus, rash and infusion reactions. Up to 30% of patients treated with dostarlimab develop immune related side effects as a result of immune enhancement. These reactions are high grade in 10% of patients and can include enterocolitis, dermatitis, endocrinopathy, pneumonitis, neuropathy, nephritis and hepatitis. Most of these reactions respond to dose interruption and/or immunosuppressive therapy, but some patients relapse and need long term immunosuppression, while some have resulted in fatalities. Early recognition and prompt management of these side effects is an integral component of proper use of checkpoint inhibitors such as dostarlimab. | Mild-to-moderate serum aminotransferase and alkaline phosphatase elevations are common (15% to 25%) during dostarlimab therapy, but are usually self-limited and resolve even with continuing cyclic therapy. Serum ALT elevations above 5 times the upper limit of normal (ULN) occur in 2% to 3% of patients. In addition, a proportion of dostarlimab treated individuals develop immune related liver injury, which usually arises after 2 to 6 cycles of therapy and is associated with enzyme elevations that are usually hepatocellular but may be mixed or even cholestatic. Most cases are hepatocellular or mixed and are anicteric and self-limited in course. Cholestatic forms of injury are more likely to be icteric and prolonged and can result in chronic injury. Monitoring of serum enzymes is recommended during dostarlimab therapy with dose interruption or discontinuation based upon the height of the elevations in relationship to baseline. When serum aminotransferase levels are extremely high or are associated with symptoms or jaundice, or remain elevated despite discontinuation of the checkpoint inhibitor, early intervention with immunosuppressive therapy is prudent and generally results in rapid resolution. Liver histology usually demonstrates an acute hepatitis-like pattern with focal or confluent necrosis and prominent lymphocytic infiltrates of activated T cells, which is compatible with an immune mediated hepatic injury. Autoantibodies are usually not present and immunoglobulin levels may not be elevated. Restarting monoclonal antibody therapy can result in recurrence of injury, although corticosteroid treatment may block recurrence. Immune mediated hepatitis appears to be more frequent with anti-CTLA-4 than with anti-PD-1 or anti-PD-L1 checkpoint inhibitors. Among 444 patients treated with dostarlimab in prelicensure studies, 9 (2%) developed immune related hepatitis.\n\nThe checkpoint inhibitors can also cause cholestatic hepatitis and cholangiopathies with prominent elevations in alkaline phosphatase that can be severe and prolonged. Examples of vanishing bile duct syndrome and immune related sclerosing cholangitis have been reported with the more frequently used checkpoint inhibitors such as nivolumab, pembrolizumab and durvalumab.\n\nThe effects of PD-1 inhibition on chronic hepatitis B are not well defined but convincing examples of reactivation of hepatitis B have been described. Most cases have occurred in patients with preexisting HBsAg, but rare instances were reported in individuals suspected of having anti-HBc without HBsAg. Thus, screening patients for HBsAg, anti-HBc and anti-HBs is appropriate before initiating immunotherapy with checkpoint inhibitors. Patients with HBsAg should be considered for prophylaxis with an antiviral agent with potent activity against HBV such as entecavir or tenofovir. In patients with anti-HBc without HBsAg, monitoring and close attention to liver test abnormalities is probably adequate if antiviral therapy can be introduced rapidly for early evidence of reactivation. There has not been adequate experience with dostarlimab in regard to the risk of reactivation of hepatitis B to provide rates of reactivation with and without antiviral prophylaxis.\n\nLikelihood score: C (probable cause of clinically apparent liver injury, although experience with the therapy has been limited). | The liver injury due to dostarlimab is likely to be immunologically mediated, and many cases of checkpoint inhibitor-related hepatitis appear to respond to corticosteroid or other immunosuppressive agents allowing continuation or restarting of therapy. | Guidelines for management of patients receiving dostarlimab recommend monitoring of liver tests and interrupting therapy for patients who develop serum aminotransferase elevations above 3 times the ULN, and discontinuing treatment for values above 8 times the ULN in patients without preexisting abnormalities or tumor involvement of the liver (in whom elevations of 5 and 10 times the ULN are used). Corticosteroid therapy can be considered for patients with persistent ALT elevations or if symptoms or jaundice arise, initiating therapy with high dose intravenous methylprednisolone and switching to oral prednisone after 1 to 2 days, continuing tapering doses for at least 30 days. In cases with unusual features, liver biopsy may help to exclude other causes (sepsis, opportunistic infections, cancer involvement). Most cases of hepatitis due to checkpoint inhibitors resolve with prompt institution of immunosuppressive therapy. In some cases, adding a second agent (such as mycophenolate mofetil, azathioprine, antithymocyte globulin, or tacrolimus) and prolonged immunosuppression may be necessary. The few fatal cases that have been reported during immunotherapy with checkpoint inhibitors occurred in patients who had other severe immune related adverse events (Stevens Johnson syndrome, capillary leak syndrome) or who had an immune related cholangiopathy resistant to immunosuppressive therapy. Patients with immune related adverse events due to dostarlimab can frequently restart therapy once the adverse event has resolved, although concurrent immunosuppressive agents may be necessary.\n\nDrug Class: Antineoplastic Agents, Monoclonal Antibodies, Checkpoint Inhibitors | Dostarlimab – Jemperli® | Antineoplastic Agents | null |
Temazepam.nxml | Temazepam | 2023-06-22 | Temazepam is an orally available benzodiazepine used in the therapy of insomnia. As with most benzodiazepines, temazepam has not been associated with serum aminotransferase or alkaline phosphatase elevations during therapy, and clinically apparent liver injury from temazepam has not been reported and must be very rare, if it occurs at all. | Temazepam (tem az' e pam) is a benzodiazepine that is used as a sleeping aid in the therapy of insomnia. The soporific activity of the benzodiazepines is mediated by their ability to enhance gamma-aminobutyric acid (GABA) mediated inhibition of synaptic transmission through binding to the GABA A receptor. Temazepam was approved in the United States in 1981 and is still widely used with more than 2 million prescriptions written yearly. Current indications are limited to the short term treatment of insomnia. Temazepam is available in capsules of 7.5, 15, 22.5 and 30 mg in several generic forms and under the brand name Restoril. The recommended initial dose for insomnia is 7.5 mg before bedtime, increasing as needed to a maximum dose of 30 mg. The most common side effects of temazepam are dose related and include daytime drowsiness, lethargy, ataxia, dysarthria and dizziness. Tolerance develops to these side effects, but tolerance may also develop to the effects on insomnia. Rare but severe adverse events include hallucinations, restlessness, agitation, and hypersensitivity reactions including angioedema. Temazepam like all oral benzodiazepines has a boxed warning in its product label stressing the risks of severe sedation and potentially fatal respiratory depression when combined with opiates, the risks of abuse, misuse, and addiction with prolonged use which can lead to overdose and death, and the risks of dependence with continued use and severe potentially life-threatening withdrawal symptoms if discontinued suddenly. | Temazepam, like other benzodiazepines, is rarely associated with serum ALT elevations, and clinically apparent liver injury from temazepam is extremely rare, if it occurs at all. There have been no case reports of symptomatic, acute liver injury from temazepam. Isolated single cases of clinically apparent liver injury have been reported with other benzodiazepines including alprazolam, chlordiazepoxide, clonazepam, diazepam, flurazepam, lorazepam, and triazolam. The clinical pattern of acute liver injury from benzodiazepines is typically cholestatic and mild-to-moderate in severity with a latency of 1 to 6 months and rapid resolution with discontinuation. Fever and rash are uncommon as is autoantibody formation.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | Temazepam is metabolized by the liver to inactive metabolites. Liver injury from benzodiazepines is probably due to the toxic effects of a rarely produced intermediate metabolite. | The case reports of hepatic injury due to benzodiazepines were followed by prompt and complete recovery upon stopping the medication, without evidence of residual or chronic injury. No cases of acute liver failure or chronic liver injury due to temazepam have been described. There is no information about cross reactivity with other benzodiazepines, but some degree of cross sensitivity may occur.\n\nDrug Class: Sedatives and Hypnotics, Benzodiazepines | Temazepam – Generic, Restoril® | Sedatives and Hypnotics | null |
ImmuneFeatures.nxml | Immunological Features | 2019-05-04 | null | null | null | null | null | null | null | null |
Pergolide.nxml | Pergolide | 2017-07-20 | Pergolide is an oral dopamine receptor agonist used predominantly in the therapy of Parkinson disease. Pergolide therapy is associated with low rate of transient serum enzyme elevations during treatment and has been implicated in rare cases of acute liver injury. | Pergolide (per' goe lide) is an ergot derivative similar to bromocriptine which acts as a dopamine receptor agonist. Pergolide, unlike bromocriptine, has agonist activity on both D1 and D2 dopamine receptors and acts directly on the substantia nigra. Pergolide was approved for use in the United States in 1988 and has been in use since in the therapy of symptomatic Parkinson disease, usually in combination with levodopa/carbidopa. Pergolide is available in tablets of 0.05, 0.25 and 1.0 mg in generic forms and under the brand name of Permax. The typical initiating dose of pergolide is 0.05 mg once daily for the first 2 days, with gradual increase thereafter based upon tolerance and effect. The average therapeutic dose in clinical studies was 3 mg per day given in 3 divided doses. Common side effects include profound hypotension (with the first dose), somnolence, fatigue, vivid dreams, insomnia, anxiety, confusion, depression, dizziness, headache, nausea and gastrointestinal upset. | Pergolide has been reported to cause serum aminotransferase elevations in a small proportion of patients, but these abnormalities are usually mild, asymptomatic and self-limiting even without dose adjustment. In addition, pergolide has been implicated in a small number of cases of clinically apparent, acute liver injury, but the frequency, severity, clinical characteristics and typical pattern of enzyme elevations have not been characterized. Thus, pergolide is may be a rare cause of clinically apparent liver injury.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury). | Pergolide is metabolized extensively by the liver and metabolic byproducts excreted rapidly in the urine. | Most instances of suspected hepatotoxicity of pergolide have been mild and self-limited. There have been no published reports of acute liver failure or chronic hepatitis due to pergolide. There is likely cross sensitivity to hypersensitivity reactions among the different ergot alkaloids, such as bromocriptine.\n\nDrug Class: Antiparkinson Agents\n\nOther Drugs in the Subclass, Dopamine Receptor Agonists: Apomorphine, Bromocriptine, Pramipexole, Ropinirole, Rotigotine | Pergolide – Generic, Permax® | Antiparkinson Agents | null |
Panitumumab.nxml | Panitumumab | 2020-04-15 | Panitumumab is a human monoclonal antibody to the epidermal growth factor (EGF) receptor, which is used in the treatment of refractory metastatic colorectal cancer. Panitumumab has been linked to minor serum enzyme elevations during therapy, but has not been implicated in cases of clinically apparent liver injury. | Panitumumab (pan” i toom’ ue mab) is a human monoclonal IgG2 antibody to the epidermal growth factor receptor (EGFR, HER1), which is used to treat EGFR-expressing metastatic colorectal cancer. Panitumumab has been shown to induce objective responses in metastatic colorectal cancer and to improve progression free survival. Effects appear to be greater in patients with the wild type as opposed to mutant KRAS status. Panitumumab was approved for use in the United States in 2006 and was the second monoclonal antibody to EGFR approved for use in metastatic colorectal cancer, the other agent being cetuximab (a chimeric mouse-human monoclonal IgG1 antibody) which has a similar profile of efficacy and safety. Panitumumab is available in liquid solution of 100, 200 and 400 mg in single dose vials (20 mg/mL) under the brand name Vectibix. The recommended regimen is 6 mg/kg intravenously every 14 days until disease progression or unacceptable toxicity. Skin toxicity is the most common side effect, occurring in 90% of patients and being severe in 16% to 19%. Other side effects include fatigue, abdominal pain, nausea, anorexia, diarrhea, electrolyte disturbance, leukopenia and infections. Less common, but potentially severe side effects include infusion reactions, hypersensitivity reactions, severe skin toxicity, severe diarrhea and dehydration, pulmonary embolism and ocular toxicities. | The rates of serum aminotransferase elevations during panitumumab therapy have not been reported in any detail from clinical trials, but nor has the absence of such elevations. In the FDA review of panitumumab, ALT elevations above 5 times the upper limit of normal (ULN) were reported to be 6% and not greater than with placebo (5%) and there were no early discontinuations because of liver test abnormalities or hepatic serious adverse events. If present, serum aminotransferase elevations must have been self-limited and resolved even with continuing cyclic therapy. No individual case reports of clinically apparent, acute liver injury with symptoms or jaundice attributed to panitumumab have been published and the product label does not discuss hepatotoxicity.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | The cause of the transient enzyme elevations during monoclonal antibody therapies is generally unknown, but may relate to direct effects of the antibody reactivity to cell surface markers that may be over-expressed on cancer cells, but are also present in lower density on normal epithelial cells.\n\nDrug Class: Antineoplastic Agents, Monoclonal Antibodies | null | Panitumumab – Vectibix® | Antineoplastic Agents | null |
Mepenzolate.nxml | Mepenzolate | 2017-07-07 | Mepenzolate is an anticholinergic agent used to treat gastrointestinal conditions such as acid peptic disease and irritable bowel syndrome. Mepenzolate has not been implicated in causing liver enzyme elevations or clinically apparent acute liver injury. | Mepenzolate (me pen' zoe late) is a synthetic quaternary ammonium anticholinergic agent which inhibits the muscarinic actions of acetylcholine on autonomic nerve endings, decreasing gastrointestinal secretions and intestinal motility. Mepenzolate has broad activity against muscarinic acetylcholine receptors, but its highly polar quaternary ammonium group makes it less likely to cross lipid membranes such as the blood brain barrier, which is believed to decrease the potential for central nervous system effects. Mepenzolate has been used largely for gastrointestinal conditions including peptic ulcer disease and gastrointestinal conditions associated with pain and spasm. Mepenzolate is approved for use in the United States for the treatment of peptic ulcer disease but is now not commonly used, having been replaced by more effective antiulcer agents. Mepenzolate is available in tablets 25 mg under the brand name Cantil. The typically recommended oral dose in adults is 25 to 50 mg two to four times daily. Common side effects are those of parasympathetic stimulation and include dryness of the mouth and eyes, decreased sweating, headache, visual blurring, constipation, and urinary retention. Because of its structure, mepenzolate is believed to be less likely than other anticholinergics to cross the blood brain barrier and cause central nervous system effects such as restlessness, confusion and hallucinations. Anticholinergic agents can precipitate acute narrow angle glaucoma and acute urinary retention. | Like other anticholinergic agents, mepenzolate has not been linked to episodes of liver enzyme elevations or clinically apparent liver injury. The metabolism of mepenzolate is not well defined, but it is likely metabolized by the liver.\n\nReferences on the safety and potential hepatotoxicity of anticholinergics are given together after the Overview section on Anticholinergic Agents.\n\nDrug Class: Anticholinergic Agents | null | null | Mepenzolate – Cantil® | Anticholinergic Agents | null |
Azacitidine.nxml | Azacitidine | 2023-07-27 | Azacitidine is a cytosine analogue and antineoplastic agent used in the therapy of myelodysplastic syndromes. Azacitidine is associated with a low rate of transient serum enzyme elevations during therapy and has not been convincingly implicated in cases of clinically apparent acute liver injury with jaundice. | Azacitidine (ay" za sye' ti deen: also spelled azacytidine) is a pyrimidine analogue (5-azacytidine) which is converted intracellularly to a triphosphate which becomes incorporated into RNA and DNA. While azacitidine has anticancer effects, it proved to have limited usefulness in solid tumors and lymphomas. In low doses, azacitidine inhibits methylation of DNA and results in the expression of silenced genes, including tumor suppressor genes. Studies done in vitro and in vivo have shown that azacitidine induces differentiation of bone marrow cells and results in normalization of bone marrow in a proportion of patients with myelodysplasia. Azacitidine was approved for use in the United States in 2004 and the current single indication is for therapy of myelodysplastic syndromes. It is also under evaluation as therapy of acute myelogenous leukemia. Azacitidine is available as a powder for injection in 100 mg vials under the trade name of Vidaza. The usual initial dosage regimen in adults is 75 mg/m2 body surface area subcutaneously or intravenously each day for 7 days, with repeat courses after 28 days. A minimum of 4 courses is recommended and the dose can be increased to 100 mg/m2 based upon tolerance and response. An oral form of azacitidine was approved in 2021 as maintenance therapy in patients with acute myelogenous leukemia after a first remission. Oral azacitidine is available in tablets of 200 and 300 mg under the brand name Onureg, the recommended dose being 300 mg on days 1 to 14 in 28-day cycles. Common side effects include bone marrow suppression, nausea, vomiting, diarrhea, stomatitis, bruising, abdominal pain, myalgias, headache, dizziness, fatigue, fever, rash and pruritus. Uncommon but potentially severe adverse events include severe myelosuppression, febrile neutropenia, pneumonitis, sepsis, tumor-lysis syndrome, and embryo-fetal toxicity. | In clinical trials, serum enzyme elevations occurred in up to 16% of patients on azacitidine therapy for cancer or myelodysplasia who had concurrent, underlying liver disease or liver metastases, but rarely in persons without a preexisting hepatic illness. In subsequent studies, liver adverse reactions attributed to azacitidine have rarely been reported, at least when it is given in conventional doses. Nevertheless, monitoring of serum enzyme levels is recommended in treating patients who have concurrent liver disease. Cases of clinically apparent liver injury attributed to azacitidine in patients without underlying liver disease have not been reported in the literature.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury, particularly in persons with pre-existing liver disease). | Hepatotoxicity from azacitidine appears to be rare and confined mostly to patients with underlying liver disease. For these reasons, the liver injury is likely due to direct toxicity. | The severity of the liver injury linked to azacitidine therapy is usually mild-to-moderate in severity occurring in patients with preexisting liver disease. Azacitidine has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There is no information on cross sensitivity to hepatic injury between azacitidine and other nucleoside or cytidine analogues.\n\nDrug Class: Antineoplastic Agents\n\nOther drugs for myelodysplastic syndromes: Decitabine, Decitabine/Cedazuridine, Luspatercept | Azacitidine (powder for solution) – Vidaza® | Antineoplastic Agents | null |
Phenotypes_chol.nxml | Cholestatic Hepatitis | 2019-05-04 | null | null | null | null | null | null | null | null |
Lorcaserin.nxml | Lorcaserin | 2020-06-05 | Lorcaserin is a selective serotonin agonist that was used as a weight loss agent. Lorcaserin was in clinical use for eight years when it was withdrawn because of concerns regarding an excess in cancer risk after long term use. In prelicensure studies and while in clinical use, lorcaserin was not found to be associated with serum enzyme elevations during therapy or to instances of clinically apparent liver injury. | Lorcaserin (lor ka' ser in) is a serotonin agonist that is relatively selective for the serotonin 2C (5-HT2C) receptor, that is located almost exclusively in the brain. Activation of this receptor activates pathways important in hunger and satiety, including those that induce proopiomelanocortin which decreases appetite. In several premarketing controlled trials, lorcaserin was found to lead to greater weight loss than placebo. Lorcaserin was officially approved for use in the United States in 2012, but was recommended only for patients who were obese (BMI ≥30) or who were overweight (BMI ≥27-30) and had a significant obesity related condition. In early 2020, lorcaserin was withdrawn from clinical use because of long term studies suggesting an increased risk of cancer with its use. Lorcaserin was available in 10 mg tablets under the commercial name Belviq. The recommended dose was 10 mg twice daily. An extended release formulation, available as 20 mg tablets (Belviq XR), was developed which allowed for once daily administration. Commonly reported side effects were headache, dry mouth, nausea, fatigue and dizziness which occasionally required discontinuation or dose adjustment. Severe side effects were rare and possibly included depression, serotonin syndrome and cardiac valvulopathy, although these side effects were not appreciably increased among lorcaserin treated patients in prelicensure clinical trials nor were they identified in subsequent postmarketing studies. A recent reanalysis of a large, long term trial of lorcaserin identified an excess incidence of cancer with treatment, including pancreatic, colorectal and lung cancer. | In premarketing clinical trials, serum aminotransferase elevations were no more common among patients receiving lorcaserin than placebo. Clinically apparent liver injury due to lorcaserin has not been reported, but the numbers of patients treated has been limited.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | null | No instances of acute liver failure or chronic liver injury have been linked to lorcaserin, but it has had limited general clinical use and now has been withdrawn because of an increased risk for cancer with long term use.\n\nDrug Class: Weight Loss Agents | Lorcaserin – Belviq® | Weight Loss Agents | null |
Dacarbazine.nxml | Dacarbazine | 2017-11-10 | Dacarbazine (also known as DTIC) is an intravenously administered alkylating agent used in the therapy of Hodgkin disease and malignant melanoma. Dacarbazine therapy has been associated with serum enzyme elevations during therapy and occasional cases of severe and distinctive acute hepatic failure, probably caused by acute sinusoidal obstruction syndrome. | Dacarbazine (da kar' ba zeen) is a triazene analogue of 5-aminoimidazole-4-carboxamide, a precursor in purine biosynthesis. Its mechanism of action in cancer chemotherapy is unclear. Dacarbazine may act as a purine analogue and antimetabolite. In addition, it is extensively metabolized in the liver and produces intermediates some of which have alkylating activity, causing methylation, modification and cross linking of DNA, thus inhibiting DNA, RNA and protein synthesis. Dacarbazine is popularly known as DTIC and was approved for use in the United States in 1975. Current indications include Hodgkin lymphoma and metastatic malignant melanoma usually in combination with other antineoplastic agents. Dacarbazine is available for injection in vials of 10 mg/mL and the recommended dose varies by indication and body weight (2 to 4.5 mg/kg/day or 150 mg/m2/day). Dacarbazine is given by intravenous infusion typically for five to ten days in cycles of every 3 to 4 weeks. Common side effects are hypotension, alopecia, anoxia, nausea, vomiting, headache, peripheral neuropathy, and flu-like illness. Rare potentially severe adverse events include severe bone marrow suppression, neutropenia, sepsis, embryo-fetal toxicity and de novo cancinogenesis from long term use. | Mild and transient elevations in serum aminotransferase levels are not uncommon during courses of systemic combination chemotherapy and the role of dacarbazine in these abnormalities is not clear. However, dose modification for serum enzyme elevations is rarely necessary. More importantly, dacarbazine is associated with a severe and distinctive liver injury which typically arises during the second or third cycle of therapy and most likely represents severe acute sinusoidal obstruction syndrome. Patients typically develop the sudden onset of severe abdominal pain, hemodynamic instability and rapidly rising levels of serum aminotransferase levels and prothrombin time, with death within 1 to 10 days (Cases 1 and 2). Liver biopsy and necropsy findings indicate centrolobular necrosis with occlusion of sinusoids and small and large hepatic veins. In some cases, hepatic infarcts are found as well. Eosinophilic infiltrations are common and peripheral eosinophilia may also be present. Unlike with other alkylating agents, sinusoidal obstruction syndrome caused by dacarbazine is associated with the usual chemotherapy doses, not the higher doses used in myeloablation in preparation for bone marrow transplantation. This syndrome is now rarely reported, probably because of use of dacarbazine in somewhat lower doses.\n\nLikelihood score: B (highly likely cause of clinically apparent liver injury). | The mechanism of hepatotoxicity from dacarbazine is not known; however, clinical and pathologic features suggest direct injury to sinusoidal endothelial cells causing their death and extrusion into sinusoids with subsequent obstruction. The injury may be immunologically mediated as it usually occurs with the second or third cycle and is accompanied by eosinophilia. In several cases, the initial cycle of dacarbazine was marked by eosinophilia and fever. | The severity of sinusoidal obstruction syndrome varies considerably, but most published cases have been severe and rapidly fatal. Anecdotal reports suggest that corticosteroids may be beneficial, but many cases have demonstrated fatal hepatic injury by the time of recognition. Rechallenge should not be done. Defibrotide has been approved for treatment of severe sinusoidal obstruction syndrome with solid organ failure in patients undergoing hematopoietic cell transplantation, but has not been specifically approved for the acute liver failure associated with dacarbazine use.\n\nDrug Class: Antineoplastic Agents, Alkylating Agents | Dacarbazine – Generic, DTIC,® DTIC-Dome® | Antineoplastic Agents, Alkylating Agents | null |
Ipilimumab.nxml | Ipilimumab | 2022-06-23 | Ipilimumab is a human monoclonal antibody to the cytotoxic T lymphocyte antigen-4, which acts as an immune checkpoint inhibitor and is used in immunotherapy of several forms of advanced or metastatic cancer. Ipilimumab like other checkpoint inhibitors has major side effects and particularly immune related conditions, including acute hepatocellular and cholestatic liver injury which can be serious and even life-threating. | Ipilimumab (ip” i lim’ ue mab) is a human recombinant monoclonal immunoglobulin G1 antibody to the cytotoxic T lymphocyte antigen-4 (CTLA-4), which has distinctive immunomodulatory activity and is used as a checkpoint inhibitor in cancer immunotherapy. The CTLA-4 antigen is an important checkpoint molecule that modulates and down regulates T cell responses. Inhibition of CTLA on the surface of activated T cells prevents its binding to the costimulatory factor B7 which allows for a continued activation and proliferation of T cells. The subsequent enhancement of cytotoxic reactivity caused by the checkpoint inhibitor can play a beneficial role in cancer immunotherapy by breaking immunological tolerance to cancer neoantigens. In several large multicenter studies, ipilimumab therapy resulted in a prolongation of survival in patients with advanced, metastatic or unresectable malignant melanoma, and a proportion of patients had a long term remission. Ipilimumab was approved for use in advanced malignant melanoma in the United States in 2009, the first monoclonal checkpoint inhibitor approved for use in treating neoplastic diseases. Subsequently, its indications have been expanded to several other forms of advanced or metastatic cancer including renal cell carcinoma, colorectal cancer, esophageal cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC) and mesothelioma, usually in combination with nivolumab, a monoclonal checkpoint inhibitor of the programmed cell death receptor-1 (anti-PD-1). Ipilimumab is available in liquid solution in 50 and 200 mg vials (5 mg/mL) under the brand name Yervoy. The dose and regime of ipilimumab varies by indication. The typical regimen is 1 or 3 mg/kg as an intravenous infusion every 3 weeks for a total of four doses. Ipililmumab is also approved for adjuvant therapy of melanoma where it is given in higher doses long term.\n\nSide effects of ipilimumab are common and can include fatigue, headache, musculoskeletal pain, arthralgia, abdominal pain, diarrhea, nausea, vomiting, decreased appetite, weight loss, fever, cough, dyspnea, pruritus, and rash. Importantly, as a result of immune enhancement, between 15% and 25% of ipilimumab treated patients develop immune related side effects, including enterocolitis, dermatitis, endocrinopathy, pneumonitis, neuropathy, nephritis and hepatitis. Most of these reactions respond to stopping ipilimumab and administration of immunosuppressive therapy, but some have resulted in fatalities and some have required permanent discontinuation of checkpoint inhibitor therapy and long term immunosuppressive therapy. These immune related adverse events are more frequent with combination therapy with nivolumab. Baseline screening and regular monitoring for these adverse events during ipilimumab therapy is recommended. Early recognition and prompt management of side effects is an integral component of proper use of checkpoint inhibitors. Checkpoint inhibitors should be used only by health care professionals with training in immunotherapy and experience in management of the side effects of immunomodulatory agents. Other rare but potentially severe adverse effects of ipilimumab also include infusion reactions and embryo-fetal toxicity. | Mild-to-moderate serum aminotransferase elevations are not uncommon (10% to 30%) during ipilimumab therapy, but are usually self-limited and resolve even with continuing cyclic therapy. Serum ALT elevations above 5 times the upper limit of normal (ULN) occur in 1% to 4% of patients and generally lead to temporary discontinuation. Importantly, in 1% to 2% of patients the serum enzyme elevations evolve into an immune mediated liver injury that can be clinically apparent and can be severe. Immune related liver injury is more frequent and severe in patients receiving the combination of ipilimumab and nivolumab. The onset is usually after 2 to 4 cycles, 3 to 9 weeks after initiation of treatment. The pattern of enzyme elevation is most frequently hepatocellular, but can be mixed or even cholestatic. Liver histology demonstrates an acute hepatitis-like pattern with focal or confluent necrosis and prominent lymphocytic infiltrates of activated T cells, which is compatible with an immune mediated hepatic injury. Fibrin ring granulomas have been described in some cases and considered somewhat pathognomic of ipilimumab hepatic immune injury. Despite features of immune mediated injury, autoantibodies are generally not present and immunoglobulin levels are normal. Restarting ipilimumab can result in recurrence of injury, although corticosteroid treatment may block recurrence. Switching to another type of checkpoint inhibitor (anti-PD-1 or anti-PD-L1) may be better tolerated than restarting ipilimumab, but there is little evidence that restarting checkpoint inhibitor therapy after a severe immune related adverse event improves survival or the outcome of cancer chemotherapy.\n\nRarely the liver injury associated with checkpoint inhibitor therapy is characterized by a progressive cholestatic injury accompanied by prominent elevations in serum alkaline phosphatase with modest or only moderate aminotransferase elevations. Imaging studies may show irregular dilatation of the intra- and/or extra-hepatic bile ducts and thickening of the gall bladder and bile duct walls, but without evidence of frank obstruction. Liver biopsy shows portal inflammation and bile duct injury and endoscopic biopsy of the bile duct epithelium shows inflammation and scarring. The general features suggest a secondary form of sclerosing cholangitis referred to as checkpoint inhibitor cholangiopathy. Therapy with immunosuppression may improve alkaline phosphatase and bilirubin levels but rarely causes complete recovery, and long term cholestasis and hepatic failure can occur. Some patients with a cholestatic form of immune related hepatitis do not show the bile duct changes but demonstrate loss and paucity of portal bile ducts resulting in a vanishing bile duct syndrome similar to primary biliary cholangitis (PBC).\n\nThe effects of ipilimumab on chronic hepatitis B are not well defined but convincing examples of reactivation of hepatitis B have been described with it as well as with other checkpoint inhibitors. Most cases have occurred in patients with preexisting HBsAg, but rare instances were reported in individuals suspected of having with anti-HBc without HBsAg. Thus, screening patients for HBsAg, anti-HBc and anti-HBs is appropriate before initiating immunotherapy with checkpoint inhibitors. Patients with HBsAg should be considered for prophylaxis with an antiviral agent with potent activity against HBV such as entecavir or tenofovir. In patients with anti-HBc without HBsAg, monitoring and close attention to liver test abnormalities is probably adequate if antiviral therapy can be introduced rapidly for early evidence of reactivation. There has not been adequate experience with ipilimumab in regard to the risk of reactivation of hepatitis B to provide rates of reactivation with and without antiviral prophylaxis.\n\nLikelihood score: A (well known cause of clinically apparent liver injury and likely cause of reactivation of hepatitis B). | The mechanism of liver injury due to ipilimumab is likely to be immunologically mediated, and most cases appear to respond at least in part to corticosteroid or immunosuppressive therapy. Liver biopsies in cases of hepatocellular injury and bile duct epithelial cell biopsies in cholangiopathic injury demonstrate necrosis and inflammatory cell infiltration with cytotoxic CD8+ T cells, suggesting that the checkpoint inhibition allowed for activation of T cells directed at hepatocyte or cholangiocyte cell surface antigens. | Guidelines for management of patients receiving ipilimumab recommend monitoring of liver tests and interrupting therapy for patients who develop serum aminotransferase elevations above 3 times the upper limit of normal (ULN) and discontinuing treatment for values above 5 times the ULN in patients without preexisting abnormalities or HCC involvement of the liver (in whom elevations of 5 and 10 times the ULN are used). Corticosteroid therapy can be considered for patients with high or persistent ALT elevations or if symptoms or jaundice arise, initiating therapy with high dose intravenous methylprednisolone and switching to oral prednisone after 1 to 2 days, continuing tapering doses for at least 30 days.\n\nMost cases of liver injury due to ipilimumab resolve with discontinuation and prompt institution of immunosuppressive therapy which can be discontinued after 1 to 3 months. In some more protracted and resistant instances, corticosteroids have only a limited effect and adding a second agent is needed. Mycophenolate mofetil or azathioprine are most commonly recommended. Other immunosuppressive agents that have been reported to be beneficial include antithymocyte globulin, tacrolimus, infliximab and cycloserine. In refractory cases, immunosuppressive therapy may be needed long term. The few fatal cases due to checkpoint inhibitors have typically occurred in patients who have cholestatic forms of liver injury or have other severe immune related adverse events (Stevens Johnson syndrome, capillary leak syndrome). Restarting ipilimumab after severe liver injury requiring corticosteroid therapy can be followed by recurrence of liver injury and is not recommended. Switching to other checkpoint inhibitors is more likely to be tolerated. Interestingly, survival rates do not seem to be improved by re-introduction of checkpoint inhibitor therapy after severe immune related adverse events. Thus, restarting therapy should be undertaken only after careful evaluation of the residual cancer status.\n\nDrug Class: Antineoplastic Agents, Monoclonal Antibodies, Checkpoint Inhibitors | Ipilimumab – Yervoy® | Antineoplastic Agents | null |
Ethambutol.nxml | Ethambutol | 2020-12-24 | Ethambutol is a first line but adjunctive antituberculosis medication which is used only in combination with other agents such as isoniazid and rifampin. Ethambutol therapy has been associated with minor, transient and asymptomatic elevations in serum aminotransferase levels, and is a reported but rare cause of clinically apparent acute liver injury. | Ethambutol (eth am' bue tol) is a semisynthetic antibiotic which is bacteriostatic against Mycobacterium tuberculosis. Ethambutol interferes with the incorporation of mycolic acid into the mycobacterial cell wall, thus inhibiting its cell wall synthesis. Ethambutol has a broader spectrum of activity against mycobacterial species than isoniazid or rifampin and is therefore used largely in patients with suspected resistance or in atypical mycobacterial infections. Ethambutol is available in generic forms in tablets of 100 and 400 mg. The recommended dose is 15 mg/kg once daily in combination with other antituberculosis medications such as isoniazid, rifampin, pyrazinamide, and streptomycin. Higher doses are recommended for patients being retreated after a relapse. It is most typically given with pyrazinamide for the first two months of combination therapy of suspected resistant tuberculosis with isoniazid and rifampin, the latter two continuing for at least six months. Common side effects include gastrointestinal upset, nausea, dizziness, fever, and rash.\n\nThe management of drug-resistant tuberculosis is challenging and should be under the direction of physicians with expertise in tuberculosis therapy and management of its side effects. Optimal regimens of therapy for tuberculosis are complex and change frequently. Regularly updated recommendations on use of drugs for tuberculosis, including indications, contraindications, warnings, dosages and monitoring recommendations are available at the Centers for Disease Control and Prevention website: https://www.cdc.gov/tb/publications/guidelines/Treatment.htm. | Because ethambutol is almost always used in combination with isoniazid, rifampin or other antituberculosis agents, the frequency of serum aminotransferase elevations attributable to ethambutol alone cannot be estimated with any confidence. The addition of ethambutol to isoniazid, rifampin or pyrazinamide does not appear to increase the rate of transient ALT elevations during therapy. In addition, ethambutol is a rare cause of acute, symptomatic liver injury. Despite 50 years of use, ethambutol has been linked to clinically apparent liver injury in only a few case reports. In the best described instance (Case 1), the onset of symptoms was 2 months after starting combination antituberculosis therapy and, in contrast to liver injury due to isoniazid or pyrazinamide, the pattern of serum enzymes was distinctly cholestatic. The recurrence of liver injury upon rechallenge with ethambutol but not isoniazid made the attribution convincing. Other case reports have described liver injury occurring in the context of DRESS syndrome, arising within 2 to 6 weeks of starting antituberculosis therapy with fever, rash, eosinophilia and other organ involvement such as liver, kidney and lung. Several published instances have described recurrence of injury after rechallenge with ethambutol.\n\nLikelihood score: C (probable cause of clinically apparent liver injury often in the context of DRESS syndrome). | The cause of liver injury due to ethambutol is not known, but is likely due to hypersensitivity. | Ethambutol is one of the few antituberculosis medications that is generally safe in the setting of liver disease. In the unlikely event of clinically apparent liver injury or allergic reaction to ethambutol, rechallenge, if necessary, should be done with caution. There does not appear to be cross sensitivity to liver injury with other antituberculosis medications.\n\n[First line medications used in the therapy of tuberculosis in the US include ethambutol, isoniazid, pyrazinamide, rifabutin, rifampin, and rifapentine. Second line medications include streptomycin, capreomycin, cycloserine, ethionamide, bedaquiline, pretomanid, fluoroquinolones such as levofloxacin and moxifloxacin, aminoglycosides such as amikacin, and para-aminosalicylic acid (PAS).]\n\nDrug Class: Antituberculosis Agents\n\nOther Drugs in the Class: Bedaquiline, Capreomycin, Cycloserine, Ethionamide, Isoniazid, Pretomanid, Pyrazinamide, Rifabutin, Rifampin, Rifapentine, Streptomycin | Ethambutol – Generic, Myambutol® | Antituberculosis Agents | null |
Abacavir.nxml | Abacavir | 2016-01-04 | Abacavir sulfate is a nucleoside analogue and reverse transcriptase inhibitor which is used in combination with other agents in the therapy of the human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Abacavir is a rare cause of clinically apparent drug induced liver injury. | Abacavir (a bak' a vir) (cyclopropylaminopurinylcyclopentene: ABC) is a structural analogue of guanosine and acts by competing with naturally occurring nucleosides for incorporation into the HIV DNA strand during viral replication, causing inhibition of the viral polymerase and chain termination. Abacavir is indicated for the treatment of HIV infection in combination with other HIV medications such as lamivudine and zidovudine. Abacavir is available generically and under the trade name Ziagen in a 20 mg/mL oral solution and a 300 mg oral tablet. Abacavir is also available in fixed combination with lamivudine as Epzicom and Kivexa, with zidovudine and lamivudine as Trizivir and with dolutegravir and lamivudine as Triumeq. The recommended dose of abacavir is 300 mg orally twice daily or 600 mg orally once daily in adults and 8 mg/kg orally twice daily in children larger than 15 kg, with a maximum daily dose of 300 mg. Abacavir was approved for use in the United States in 1998 and is currently used in many antiretroviral regimens. Common side effects include diarrhea, loss of appetite, nausea, headache, and fatigue. | Elevations in serum aminotransferase levels above 5 times the upper limit of normal occur in up to 6% of patients on abacavir. These elevations are usually mild, transient and do not require dose adjustment. Clinically apparent hepatotoxicity is rare, but isolated cases [usually anicteric] have been published. The liver injury usually arises in the context of abacavir hypersensitivity syndrome and may be overshadowed by the allergic syndromes of fever, rash and fatigue. The onset is usually within 1 to 3 months of starting abacavir. The serum enzyme pattern can be hepatocellular or cholestatic. Patients typically recover rapidly within 4 weeks of stopping therapy.\n\nLikelihood score: C (probable cause of clinically apparent liver injury). | The cause of the clinically apparent hepatotoxicity from abacavir is hypersensitivity in some cases and is typically associated with the HLA-B*57:01 haplotype. Abacavir binds to the antigen-binding cleft of the HLA-B*57:01 molecule and alters its peptide binding repertoire. Testing for this allele is available in the United States and is recommended before starting abacavir. There are few cases of nonhypersensitivity abacavir induced hepatitis (Case 1) in which the mechanism is unknown. | Most cases of liver injury associated with abacavir have been mild and anicteric and resolved rapidly within 4 weeks of discontinuation. There have been no convincing published cases of acute liver failure or vanishing bile duct syndrome due to abacavir. Patients with hepatotoxicity due to abacavir can generally tolerate other antiretroviral agents, rechallenge should be avoided, particularly in cases with features of hypersensitivity.\n\nDrug Class: Antiviral Agents, Antiretroviral Agents\n\nOther Drugs in the Subclass, Nucleoside Analogues: Adefovir, Didanosine, Emtricitabine, Entecavir, Lamivudine, Stavudine, Telbivudine, Tenofovir, Zidovudine | Abacavir – Ziagen® | Antiviral Agents | null |
Osimertinib.nxml | Osimertinib | 2017-06-01 | Osimertinib is a small molecule tyrosine kinase receptor inhibitor and antineoplastic agent that is used in the therapy of selected forms of advanced non-small cell lung cancer (NSCLC). Osimertinib is associated with a moderate rate of serum aminotransferase elevations during therapy and rare instances of clinically apparent acute liver injury. | Osimertinib (oh" sim er' ti nib) is a small molecule tyrosine kinase receptor inhibitor with potent activity against the epidermal growth factor receptor (EGFR) that is rearranged and mutated in selected cancers including approximately 5% of non-small cell lung cancer (NSCLC). The mutated, rearranged EGFR promotes unregulated cell growth and proliferation, and inhibition of its activity can result in death of cells that overexpress the receptor. Osimertinib has been found to inhibit mutated EGFR in cell culture and, in several clinical trials, was found to induce objective responses in a proportion of patients with advanced EGFR mutated (T790M) NSCLC. Osimertinib received accelerated approval for use refractory, EGFR T790M-positive NSCLC in the United States in 2015. Osimertinib is available in tablets of 40 and 80 mg under the brand name Tagrisso. The recommended initial dose is 80 mg once daily, continued until progressive disease or intolerable toxicity occurs. Side effects are common and include diarrhea, rash, dry skin and nail toxicity. Uncommon, but potentially severe side effects include interstitial lung disease, prolongation of the QTc interval, cardiomyopathy and embryo-fetal toxicity. | Elevations in serum aminotransferase levels are uncommon during osimertinib therapy occurring in 4% to 5% of patients and rising above 5 times the upper limit of the normal range in only 1% or less. In preregistration trials, there was a single incidence of clinically apparent liver injury attributed to osimertinib therapy, but the clinical features and relatedness to therapy were not defined. Since its approval and more widespread use, there have been no published cases of liver injury due to osimertinib.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury). | The mechanism by which osimertinib might cause liver injury is not known. Osimertinib is metabolized by the liver predominantly by CYP 3A4 and is susceptible to drug-drug interactions with agents that induce or inhibit FYP 3A4. | Serum enzyme elevations during osimertinib therapy are uncommon, but elevations above 5 times the upper limit of normal (if confirmed) should lead to temporary discontinuation, which should be permanent if laboratory values do not improve significantly or resolve within a few weeks or if symptoms or jaundice arises. There does not appear to be cross reactivity with other EGFR inhibitors and, in some situations, switching to another protein kinase inhibitor may be appropriate.\n\nDrug Class: Antineoplastic Agents, Protein Kinase Inhibitors | Osimertinib – Tagrisso® | Antineoplastic Agents | null |
Neratinib.nxml | Neratinib | 2018-10-20 | Neratinib is an orally available tyrosine kinase receptor inhibitor that is used in the extended adjuvant therapy of early stage breast cancer. Neratinib is associated with a low rate of transient elevations in serum aminotransferase levels during therapy, but has not been convincingly linked to cases of clinically apparent liver injury with jaundice. | Neratinib (ne ra' ti nib) is a small molecule tyrosine kinase receptor inhibitor with potent activity against human epidermal growth factor receptor 2 (HER2 or ErbB2). These tyrosine kinase receptors are often mutated and over expressed in tumor tissue and cause unregulated cell growth and proliferation. This mutation is present in 20% of breast cancers and is particularly overexpressed in early stage cancers. Inhibition of the unregulated receptor can lead to reversal of progression of the cancer, although clinical responses are sometimes limited by the development of tumor resistance caused by further mutations in the receptor gene. In several large controlled trials, adjuvant therapy with neratinib was shown to improve progression free survival in patients with early stage, HER2-positive breast cancer. Neratinib received approval for use in the United States in 2017. Current indications are as extended adjuvant therapy for early stage, HER2-positive breast cancer following trastuzumab treatment. Neratinib is available in tablets of 40 mg under the brand name Nerlynx. The recommended dose is 240 mg (6 tablets) once daily for one year or until intolerable toxicity occurs. Side effects are common and particularly diarrhea [95%], which can be severe and dose limiting and for which prophylaxis with antidiarrheal agents is recommended. Other frequent side effects include nausea, abdominal pain, anorexia, weight loss, abdominal distension, fatigue, rash, stomatitis, dry skin, paronychia, muscle spasms and urinary treat infections. Uncommon, but potentially severe side effects include severe diarrhea leading to dehydration and renal failure, and embryo-fetal toxicity. | Elevations in serum aminotransferase levels are not uncommon during neratinib therapy occurring in up to 10% of patients, but rising above 5 times the upper limit of the normal range in only 1% to 2%. In prelicensure studies, there were no instances of neratinib related clinically apparent liver injury and serum enzyme elevations were typically mild and self-limited and not associated with symptoms or jaundice. Hepatotoxicity may be a class effect among protein kinase inhibitors of HER2, although the frequency and severity vary among the different agents. Specific details of the liver injury associated with neratinib such as latency, serum enzyme pattern, clinical features and course, have not been published. Other tyrosine kinase receptor inhibitors typically cause liver injury arising within days or weeks of starting therapy and presenting abruptly with hepatocellular enzyme elevations and a moderate-to-severe course. Immunoallergic and autoimmune features are not common. The rate of clinically significant liver injury and hepatic failure is increased in patients with preexisting cirrhosis or hepatic impairment due to liver tumor burden. Nevertheless, neratinib has not been convincingly linked to instances of clinically apparent liver injury.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury). | The abrupt and severe nature of the clinically apparent liver injury attributed to EGF receptor inhibitors suggests that it is immunologically mediated. On the other hand, the transient serum enzyme elevations that are not uncommon during therapy suggest a direct, intrinsic hepatotoxicity, perhaps caused by inhibition of critical tyrosine kinase receptors in hepatocytes. Neratinib is metabolized in the liver largely by the cytochrome P450 system and is susceptible to drug-drug interactions with inhibitors or inducers of CYP 3A4. | Liver injury due to neratinib has largely been in the form of asymptomatic, transient serum enzyme elevations. Monitoring of liver tests during neratinib therapy is recommended before treatment, monthly for the first 3 months and every 3 months thereafter or as clinically indicated. Serum aminotransferase elevations above 5 times the upper limit of normal should lead to temporary discontinuation, which should be permanent if laboratory values worsen or do not resolve or improve significantly within a few weeks, or if symptoms or jaundice arises. Restarting therapy is usually, but not always followed by recurrence of the serum enzyme elevations. There does not appear to be cross reactivity with other tyrosine kinase receptor inhibitors and, in some situations, switching to another protein kinase inhibitor may be appropriate.\n\nDrug Class: Antineoplastic Agents, Protein Kinase Inhibitors | Neratinib – Nerlynx® | Antineoplastic Agents | null |
Voriconazole.nxml | Voriconazole | 2017-05-17 | Voriconazole is a triazole antifungal agent used primarily in the treatment or prevention of aspergillosis and candidal infections. Voriconazole therapy is associated with transient, asymptomatic serum aminotransferase elevations and is a known cause of clinically apparent acute drug induced liver injury. | Voriconazole (vor" i kon' a zole) is a synthetic triazole and a derivative of fluconazole, which is believed to act through inhibition of the fungal 14α-ergosterol demethylase that is responsible for converting lanosterol to ergosterol, which blocks cell membrane synthesis. Voriconazole has a broad spectrum of activity particularly against candida and aspergillus. Voriconazole was approved for use in the United States in 2002. Current indications include treatment of invasive aspergillosis, esophageal candidiasis and serious candidal infections. It is also used as empiric antifungal therapy in patients with neutropenia and persistent fever as well as preventive antifungal therapy in high risk individuals. Voriconazole is available as tablets of 50 and 200 mg, in an oral suspension (40 mg/mL) and in a parenteral formulation generically and under the brand name Vfend. Serious fungal infections are typically treated initially with intravenous voriconazole (4 to 6 mg/kg every 12 hours) for 3 to 10 days, followed by more prolonged therapy with oral forms (20 mg every 12 hours). Common side effects include nausea, photosensitivity, hallucinations, headache, visual disturbances and rash. | Transient elevations in serum aminotransferase levels occur in 11% to 19% of patients on voriconazole. These elevations are usually asymptomatic and self-limited, but approximately 1% of patients require discontinuation of voriconazole because of ALT elevations. Clinically apparent hepatotoxicity is uncommon, but may be more frequent than with fluconazole and itraconazole. The injury arises within the first month of therapy and the pattern of serum enzyme elevations has been variable from cholestatic to hepatocellular. Several cases of acute liver failure attributed to voriconazole have been reported. Immunoallergic features and autoantibodies are uncommon. Recovery upon stopping therapy generally takes 6 to 10 weeks but, in some cases, the time to complete resolution may be prolonged.\n\nLikelihood score: B (likely cause of clinically apparent liver injury). | The cause of clinically apparent hepatotoxicity from voriconazole is unknown; however, it may have some correlation to the ability of voriconazole to alter human sterol synthesis. Because voriconazole is a substrate for several P450 enzymes (CYP 2C19, 2C9, 3A4), it has the potential to cause significant drug-drug interactions, including elevations in plasma levels of other medications that are metabolized by these P450 enzymes, sometimes resulting in toxicity. Alternatively, voriconazole plasma levels might be affected by CYP inhibitors. | The severity of the liver injury from voriconazole ranges from mild and transient enzyme elevations to symptomatic or severe hepatitis leading to liver transplantation or death. Cases of acute liver failure have been described due to voriconazole, but not chronic liver injury or vanishing bile duct syndrome. Most cases of voriconazole hepatotoxicity resolve with discontinuation of the medication, but the improvements may be delayed and typically require 1 to 3 months. Rechallenge may lead to recurrence and should be avoided. Testing for serum bilirubin and aminotransferase levels is rercommended at the time of starting and weekly during the first month of voriconazole therapy and monthly thereafter. The relationship between voriconazole trough plasma levels of hepatotoxicity is, however, controversial. There is little information on cross reactivity of hepatic injury between voriconazole and other antifungal azoles, such as ketoconazole, itraconazole, fluconazole and posaconazole. While a few reports suggest that there is little cross reactivity, other azoles should be started with caution in patients who have suffered clinically apparent hepatotoxicity attributed to voriconazole.\n\nDrug Class: Antifungal Agents | Voriconazole – Generic, Vfend® | Antifungal Agents | null |
Sulfonylureas.nxml | Sulfonylureas | 2018-03-16 | null | null | null | null | null | null | null | null |
Terbinafine.nxml | Terbinafine | 2018-01-01 | Terbinafine is an orally and topically active allylamine fungicidal agent which is used to treat superficial fungal infections of the skin and nails. Terbinafine has been clearly linked to rare instances of acute liver injury that can be severe and sometimes fatal. | Terbinafine (ter' bin a feen) is a synthetic allylamine derivative that has potent activity against many dermatophytes that affect skin and nails, including Epidermophyton floccosum, Trichophyton mentagrophytes and Trichophyton rubrum. The antifungal activity of terbinafine is believed to be due to the selective inhibition of fungal squalene epoxidase, which increases squalene to toxic levels, thus killing the fungal cell. Terbinafine was approved for use in the United States in a topical form in 1992 and as an oral antifungal agent in 1998. Topical terbinafine is available over-the-counter as a 1% cream or spray for treatment of dermatophyte infections of the skin (tinea pedis, cruris or corporis). Oral terbinafine is available by prescription only in tablets of 250 mg generically and under the brand name of Lamisal. Oral terbinafine is used in the therapy of onychomycosis or fungal infections of the fingernails or toenails (tinea unguium) typically in a dose of 250 mg once daily for 6 weeks (fingernails) or 12 weeks (toenails). The most common side effects of terbinafine include gastrointestinal disturbances, headache, change in taste and rash. | Drug induced liver injury due to terbinafine was identified shortly after its introduction into medical use. Oral therapy with terbinafine is associated with elevations in serum aminotransferases in less than 1% of patients and the elevations are generally asymptomatic and resolve without stopping therapy. The estimated probability of developing elevated serum aminotransferase levels requiring stopping treatment is about 0.31% for 2 to 6 weeks' treatment and 0.44% for treatment longer than 8 weeks.\n\nClinically apparent liver injury from terbinafine occurs rarely (1 in 50,000 to 120,000 prescriptions), but many case reports and even case series have been described in the literature. Liver injury usually arises within the first 6 weeks of therapy. The pattern of injury can be either hepatocellular or cholestatic initially, but typically evolves into a cholestatic pattern which can be prolonged (Cases 1 and 2). Some cases may progress to vanishing bile duct syndrome. Signs of hypersensitivity (rash, fever, eosinophilia) are not common and, when present, are generally mild-to-moderate in severity. Autoantibody formation is rare. In addition, cases with severe hepatocellular injury with acute liver failure have been described. These instances are marked by precipitous onset with marked elevations in serum aminotransferase levels and progressive jaundice and hepatic failure. Terbinafine has also been implicated in cases of Stevens-Johnson syndrome, in which case the hepatic injury may be overshadowed by rash and allergic symptoms.\n\nLikelihood score: B (highly likely cause of clinically apparent liver injury). | The acute hepatotoxicity caused by terbinafine appears to be part of a hypersensitivity reaction, although the mechanism has not been defined. Genome-wide association studies identified polymorphisms within the HLA region of chromosome six to be linked to cholestatic cases of drug induced liver injury, and particularly terbinafine. HLA sequencing has confirmed these associations and shown that most subjects of European ancestry with terbinafine hepatotoxicity are carriers of HLA-A* 33:01 (heterozygosity), an allele found in less than 1% of control populations. The HLA-A* 33:03 allele which shares 99% sequence identity with 33:01 has been linked to terbinafine hepatotoxicity in a small number of Asian subjects. These associations indicate that the injury is immunologically mediated. | Most cases of acute hepatic injury from terbinafine resolve within 3 to 6 months of stopping the medication. In some instances, however, the injury is severe and unremitting, leading to acute liver failure and either death or need for liver transplantation. A severe outcome is more likely if terbinafine is continued after the appearance of symptoms and signs of liver injury. Terbinafine has also been implicated in several cases of acute bile duct injury, followed by prolonged cholestasis associated with vanishing bile duct syndrome. There appears to be no cross sensitivity to hepatic injury between terbinafine and griseofulvin, another agent used for onychomycosis.\n\nDrug Class: Antifungal Agents | Terbinafine – Generic, Lamisil® | Antifungal Agents | null |
Phenotypes_chron.nxml | Chronic Hepatitis | 2019-05-04 | null | null | null | null | null | null | null | null |
Cisplatin.nxml | Cisplatin | 2020-09-15 | Cisplatin is the prototype platinum coordination complex classified as an alkylating agent and used intravenously in the treatment of several forms of cancer. Cisplatin has been associated with a low rate of serum enzyme elevations and with rare cases of clinically apparent, acute liver injury. | Cisplatin (sis pla' tin) was the first chemotherapeutic agent of its subclass to be discovered. It is an inorganic, water soluble complex containing a central platinum atom surrounded by 2 chlorine atoms and ammonia moieties in the cis position in the horizontal plane. Cisplatin forms irreversible covalent links with DNA, causing cross linking of DNA chains as well as breaks in the DNA chain and missense mutations. The DNA injury triggers cell death and inhibits RNA and protein synthesis, particularly in rapidly dividing cells. Cisplatin has activity against multiple tumor types and was approved for use by the United States in 1978. Current indications include testicular, ovarian and bladder cancer. It is also used in combination with other agents in head and neck, breast, lung and colon cancer. Cisplatin is administered parenterally and is available in 50 and 100 mg vials in generic forms and under the brand name Platinol. The recommended dose varies by indication, tumor type, patient age and body weight. Common side effects include nausea, vomiting, bone marrow suppression, electrolyte imbalance, neuropathy, ototoxicity and nephrotoxicity. Cisplatin is mutagenic, teratogenic and carcinogenic and its use has been show to increase the risk of secondary malignancies, particularly leukemia. | The platinum compounds generally are not considered to be hepatotoxic, but cisplatin has been associated with a low rate of serum enzyme elevations during therapy. These elevations are usually mild, self-limited and asymptomatic, rarely requiring dose modification. There have been only rare case reports of clinically apparent liver injury attributed to cisplatin. In one instance, steatosis and necrosis (steatohepatitis) was found by liver biopsy in a patient who developed liver enzyme elevations 4 weeks after starting a regimen of cisplatin. In another instance, hepatocellular liver injury was described. The number of cases of liver injury attributed to cisplatin have been too few to characterize the liver injury clinically. Autoimmune and immunoallergic features have not been described and cases have all been self-limited. Cisplatin is usually given in combination with other antineoplastic agents and adverse events that occur with these combinations cannot always be attributed to cisplatin. In this regard, individual case reports of reactivation of hepatitis B, sinusoidal obstruction syndrome and severe hyperammonemic coma (without liver injury) have been described after chemotherapeutic regimens that include cisplatin and other platinum coordination complexes such as carboplatin and oxaliplatin.\n\nLikelihood score: C (probable rare cause of clinically apparent liver injury). | The cause of hepatotoxicity from cisplatin is not known. There have been extremely few cases of cisplatin induced hepatotoxicity described and generally, the platinum coordination complexes have not been considered to be hepatotoxic. Recently however, oxaliplatin when given in multiple courses has been linked to development of nodular regenerative hyperplasia and non-cirrhotic portal hypertension. | Liver injury from cisplatin is rare and when it does occur, the severity in published cases was generally mild and the outcome benign. There is likely to be cross sensitivity to liver toxicities of the various platinum coordination complexes and rechallenge should be avoided.\n\nDrug Class: Antineoplastic Agents, Alkylating Agents\n\nOther Drugs in the Subclass, Platinum Coordination Complexes: Carboplatin, Oxaliplatin | Cisplatin – Generic, Platinol® | Antineoplastic Agents, Alkylating Agents | null |
Delavirdine.nxml | Delavirdine | 2017-12-27 | Delavirdine is a nonnucleoside reverse transcriptase inhibitor used in combination with other agents in the therapy of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Delavirdine is associated with a low rate of transient serum aminotransferase elevations during therapy and is a rare cause of clinically apparent acute liver injury. | Delavirdine (del a' vir deen) is an antiretroviral agent that acts by noncompetitive binding to and inhibition of the HIV reverse transcriptase. Delavirdine is a nonnucleoside reverse transcriptase inhibitor and is similar to nevirapine, efavirenz, etravirine and rilpivirine in its mechanism of action, but shares minimal structural features with the other antiviral agents in this class. Delavirdine in combination with other antiretroviral agents lowers HIV RNA levels and delays onset of AIDS related complications. Delavirdine was approved by the FDA in 1998 and current indications are for the treatment of HIV infection in combination with other HIV medications. Delavirdine is available under the brand name Rescriptor in tablets of 100 and 200 mg. The recommended dose of delavirdine is 400 mg orally three times daily. Because of its requirement for thrice daily dosing, delavirdine is not widely used. Common side effects include fatigue, dizziness, headache, and skin rashes. | Serum aminotransferase elevations occur in 25% or more of patients on delavirdine therapy, but rise above 5 times the upper limit of normal in 4% or less; this rate is higher in patients who have chronic hepatitis C coinfection. Clinically apparent hepatotoxicity due to delavirdine must be rare, as individual case reports of hepatitis or jaundice have not been published. Nevertheless, cases of hepatitis, jaundice and hepatic failure have been reported to the sponsor and are mentioned in the product label. The liver injury may be immunoallergic and similar in pattern to that attributed to nevirapine and efavirenz. In immunoallergic hepatitis due to nonnucleoside reverse transcriptase inhibitors, injury usually arises within 1 to 8 weeks of starting therapy. Signs of hypersensitivity are common including rash, fever, and eosinophilia and sometimes facial edema, lymphadenoapthy and lymphocytosis. The serum enzyme pattern can be cholestatic, hepatocellular or mixed. Recovery is rapid upon stopping therapy.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury). | Hepatotoxicity from delavirdine is rare, but is likely due to hypersensitivity. Delavirdine is a substrate for and an inhibitor of the cytochrome P450 enzyme, CYP 3A4 and can cause significant drug-drug interactions. | The severity of the liver injury due to delavirdine can range from mild and transient enzyme elevations to acute hepatitis with jaundice. Description of cases with acute liver failure leading to liver transplantation or death have not been reported in association with delavirdine. In immunoallergic forms of acute liver injury, rechallenge may lead to recurrence and should be avoided. Despite the similarity in causing immunoallergic hepatitis, there does not seem to be cross sensitivity to the hepatic injury with nevirapine or other nonnucleoside reverse transcriptase inhibitors, although there may be cross reactivity in occurrence of rash.\n\nDrug Class: Antiviral Agents, Antiretroviral Agents\n\nOther Drugs in the Subclass, Nonnucleoside Reverse Transcriptase Inhibitors: Doravirine, Efavirenz, Etravirine, Nevirapine, Rilpivirine | Delavirdine – Rescriptor® | Antiviral Agents | null |
Avanafil.nxml | Avanafil | 2017-08-02 | Avanafil is a selective inhibitor of phosphodiesterase type 5 (PDE5) and is used as therapy of erectile dysfunction. Avanafil is a relatively new medication and has yet to be linked to instances of serum enzyme elevations or with clinically apparent acute liver injury. | Avanafil (a van' a fil) is a selective inhibitor of phosphodiesterase type 5 (PDE5) which mediates the breakdown of cyclic guanosine monophosphate (cGMP), inducing smooth muscle relaxation in the corpus cavernosum of the penis and in the pulmonary vasculature where this specific phosphodiesterase is found. Avanafil is effective in prolonging erection and was approved for use in the United States in 2012. Avanafil is available in tablets of 50, 100 and 200 mg under the brand name of Stendra. The recommended dose is 100 mg as a single dose as needed one-half hour before sexual activity. The dose can be increased or decreased based upon effect and tolerance with a recommended maximum frequency of once daily and maximum dosage of 200 mg. Common side effects include dizziness, headache, flushing, hypotension, rhinitis and dyspepsia. Rare, but potentially serious adverse events include vision and hearing loss, hypotension, cardiovascular events and priapism. | Avanafil has had limited general use, but in premarketing studies it was not associated with cases of clinically apparent liver injury and serum enzyme elevations were not reported. The related PDE5 inhibitors, sildenafil and tadalafil, have been linked to isolated, rare instances of acute liver injury and jaundice. The latency to onset ranged from a few days to 3 months and the pattern of injury was usually cholestatic. Autoimmune and immunoallergic features were not observed and all cases were self-limited without residual injury or acute liver failure. Whether avanafil can cause a similar form of acute liver injury is not yet known.\n\nLikelihood score: E* (unproved but suspected rare cause of clinically apparent liver injury). | While avanafil has not been associated with hepatotoxicity, its potential for causing hypotension and use in patients with cardiac disease may lead to instances of acute ischemic liver injury. Avanafil, like the other PDE5 inhibitors, is metabolized in the liver via the cytochrome P450 system (CYP 3A4). | There is no known cross sensitivity between avanafil and the other PDE5 inhibitors currently in use in the United States. However, switching to another PDE5 inhibitor after an episode of clinically apparent liver injury should be done with caution.\n\nReferences to the safety and potential hepatotoxicity of avanafil are provided in the Overview section on PDE5 Inhibitors.\n\nDrug Class: PDE5 Inhibitors\n\nOther Drugs in the Class: Sildenafil, Tadalafil, Vardenafil | Avanafil – Stendra ® | PDE5 Inhibitors | null |
SGLT-2_Inhibitors.nxml | Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors | 2023-02-10 | The sodium-glucose cotransporter-2 (SGLT2) inhibitors are diabetic agents that act by inhibiting the reabsorption of glucose in the proximal renal tubule, resulting in loss of glucose in the urine and reduction in serum levels. SGLT2 is the major enzyme responsible for glucose reabsorption in the kidney and its inhibition causes a reduction in the threshold for glucose loss in urine. The excess loss of glucose causes a loss of calories, reduction in serum glucose and mild osmotic diuresis. The SGLT2 inhibitors also cause a modest weight loss and slight decrease in blood pressure, both of which may contribute to their beneficial effects. Five specific SGLT2 inhibitors, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin and ertugliflozin, have been shown to result in improvements in glycemic control in type 2 diabetes and introduced into clinical use. Canagliflozin, dapagliflozin and empagliflozin have also been shown to decrease cardiovascular complications and mortality in patients with type 2 diabetes and cardiovascular disease, and to reduce the risk of hospitalization for heart failure and development of end stage renal disease in patients with type 2 diabetes and chronic kidney disease. In prelicensure studies, none of the five agents was reported to be associated with increases in serum aminotransferase or alkaline phosphatase levels and, since licensure, there have been only very rare, isolated, and not completely convincing reports of clinically apparent liver injury associated with their use. | Bexagliflozin (bex’ a gli floe' zin) is a specific SGLT2 inhibitor that in clinical trials was shown to result in a reduction in serum HbA1c levels and better glycemic control in type 2 diabetes, both as monotherapy (in patients who failed to achieve adequate control on diet and exercise) or in combination with insulin, metformin and sulfonylureas. Bexagliflozin was approved for use in the United States in 2023 for management of hyperglycemia in patients with type 2 diabetes in conjunction with diet and exercise, with or without other antidiabetic medications. Bexagliflozin is available in tablets of 20 mg under the brand name Brenzavvy, the recommended dose being 20 mg once daily. Common side effects shared by all SGLT2 inhibitors include symptoms of thirst, urinary tract infections and mycotic genital infections. Less common side effects are hypersensitivity reactions, ketoacidosis, hypoglycemia, dehydration, hypovolemia and serum creatinine elevations. Bexagliflozin may be associated with an increased risk of lower limb amputations and necrotizing fasciitis of the perineum in patients with type 2 diabetes.\n\nCanagliflozin (kan" a gli floe' zin) is a specific SGLT2 inhibitor that in clinical trials was shown to result in a reduction in serum HbA1c levels and improved glycemic control in type 2 diabetes, both as monotherapy (in patients who failed to achieve adequate control on diet and exercise) or in combination with insulin, metformin and/or sulfonylureas. Canagliflozin was approved for use in the United States in 2013 and current indications are for management of hyperglycemia in patients with type 2 diabetes in conjunction with diet and exercise, with or without other antidiabetic medications. After long term controlled trials, canagliflozin was also shown to reduce the risk of major adverse cardiovascular events (myocardial infarction, stroke and death) for patients with type 2 diabetes at risk for cardiovascular disease and was later shown to reduce the risk of end stage renal disease and hospitalization of heart failure for patients with diabetic nephropathy. For these reasons, canagliflozin is now recommended for these indications as well. Canagliflozin is available in tablets of 100 and 300 mg under the brand name Invokana, the recommended dose being 100 to 300 mg once daily. Combinations of canagliflozin including extended release forms with metformin are also available (Invokamet and Invokamet XR). Common side effects shared by all SGLT2 inhibitors include symptoms of thirst, urinary tract infections and mycotic genital infections. Less common side effects are hypersensitivity reactions, bone fractures, ketoacidosis, hypoglycemia, dehydration, hypovolemia and serum creatinine elevations. Canagliflozin may also be associated with an increased risk of lower limb amputations and necrotizing fasciitis of the perineum in patients with type 2 diabetes.\n\nDapagliflozin (dap' a gli floe' zin) is a specific SGLT2 inhibitor that has been shown to result in a reduction in serum HbA1c levels and better control of type 2 diabetes, both as monotherapy (in patients who failed to achieve adequate glycemic control on diet and exercise) or in combination with insulin, metformin and or sulfonylureas. Dapagliflozin was approved for use in the United States in 2014 and current indications are to improve glycemic control in patients with type 2 diabetes in conjunction with diet and exercise, with or without other antidiabetic medications. Long term therapy is also recommended for reduction in major cardiovascular outcomes (myocardial infarction, stroke, death), progression of renal disease and end stage renal failure, and hospitalization and death from heart failure in patients with type 2 diabetes at risk for these complications. Dapagliflozin is available in tablets of 5 and 10 mg under the brand name Farxiga, the recommended dose being 5 to 10 mg once daily. Fixed combinations of dapagliflozin with saxagliptin are available (Qtern) as are extended release combinations with metformin (Xigduo XR). Common side effects shared by all SGLT2 inhibitors include symptoms of thirst, urinary tract infections and mycotic genital infections. Less common side effects are hypersensitivity reactions, ketoacidosis, hypoglycemia, dehydration, hypovolemia and serum cholesterol and creatinine elevations. Dapagliflozin may also be associated with an increased risk of necrotizing fasciitis of the perineum in patients with type 2 diabetes.\n\nEmpagliflozin (em" pa gli floe' zin) is a specific SGLT2 inhibitor that in clinical trials was shown to result in a reduction in serum HbA1c levels and better glycemic control in type 2 diabetes, both as monotherapy (in patients who failed to achieve adequate control on diet and exercise) or in combination with insulin, metformin and or sulfonylureas. Empagliflozin was approved for use in the United States in 2014 for management of hyperglycemia in patients with type 2 diabetes in conjunction with diet and exercise, with or without other antidiabetic medications. In 2017, the indications for empagliflozin were extended to decrease the risk of cardiovascular death in adults with type 2 diabetes and cardiovascular disease, and later to decrease the risk of hospitalization or death from heart failure in adults with type 2 diabetes with heart failure. Empagliflozin is available in tablets of 10 and 25 mg under the brand name Jardiance, the recommended initial dose being 10 mg once daily, which can be increased to 25 mg daily. Fixed dose combinations of empagliflozin with metformin (Synjardy) and with linagliptin (Glyxambi) are also available. Common side effects shared by all SGLT2 inhibitors include symptoms of thirst, urinary tract infections and mycotic genital infections. Less common side effects are hypersensitivity reactions, ketoacidosis, hypoglycemia, dehydration, hypovolemia and serum creatinine elevations. Empagliflozin may also be associated with an increased risk of necrotizing fasciitis of the perineum in patients with type 2 diabetes.\n\nErtugliflozin (er" too gli floe' zin) is a specific SGLT2 inhibitor that in clinical trials was shown to result in a reduction in serum HbA1c levels and better glycemic control in type 2 diabetes, both as monotherapy (in patients who failed to achieve adequate control on diet and exercise) or in combination with insulin, metformin and sulfonylureas. Ertugliflozin was approved for use in the United States in 2018 for management of hyperglycemia in patients with type 2 diabetes in conjunction with diet and exercise, with or without other antidiabetic medications. Ertugliflozin is available in tablets of 5 and 15 mg under the brand name Steglatro, the recommended initial dose being 5 mg once daily, which can be increased to 15 mg daily. Fixed dose combinations of ertugliflozin with metformin (Segluromet) and with sitagliptin (Steglujan) are also available. Common side effects shared by all SGLT2 inhibitors include symptoms of thirst, urinary tract infections and mycotic genital infections. Less common side effects are hypersensitivity reactions, ketoacidosis, hypoglycemia, dehydration, hypovolemia and serum creatinine elevations. Ertugliflozin may be associated with an increased risk of lower limb amputations and necrotizing fasciitis of the perineum in patients with type 2 diabetes. | In multiple large randomized controlled trials, canagliflozin, dapagliflozin, empagliflozin and ertugliflozin were not associated with serum enzyme elevations during therapy. Indeed, in retrospective analyses, therapy with SGLT2 inhibitors was associated with improvements in ALT levels, probably as a result of concurrent improvements in fatty liver disease due to improved glycemic control or weight loss or both. During prelicensure studies, no instances of clinically apparent acute liver injury were convincingly linked to use of the SGLT2 inhibitors, and serum enzyme elevations accompanied by jaundice occurred equally in the actively treated and placebo groups. Since their approval and more widespread use, at least one report of liver injury possibly due to a SGLT2 inhibitor has been published. A woman with nonalcoholic fatty liver disease and cirrhosis developed decompensation with jaundice, ascites and encephalopathy 10 weeks after starting dapagliflozin. She improved somewhat after stopping therapy, but ultimately required liver transplantation several months later. Thus, hepatotoxicity from canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and bexagliflozin is quite rare, if it occurs at all.\n\nBexagliflozin likelihood score: E (unlikely cause of clinically apparent liver injury).\n\nCanagliflozin likelihood score: E (unlikely cause of clinically apparent liver injury).\n\nDapagliflozin likelihood score: D (possible rare cause of clinically apparent liver injury).\n\nEmpagliflozin likelihood score: E (unlikely cause of clinically apparent liver injury).\n\nErtugliflozin likelihood score: E (unlikely cause of clinically apparent liver injury). | The relative lack of hepatotoxicity of the SGLT2 inhibitors may relate to their minimal hepatic metabolism which is largely via UDP-glucuronylsyltransferase (UGT-1A9 and 2B4 among others). | Liver injury from the SGLT2 inhibitors is rare, and they have not been associated with acute liver failure, vanishing bile duct syndrome or chronic hepatitis. The similarity of structure and function of the SGLT2 inhibitors suggests that there may be some degree of cross sensitivity to their adverse events.\n\nDrug Class: Antidiabetic Agents | Bexagliflozin – Brenzavvy® | Antidiabetic Agents | [
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"molecular_formula": "C24-H25-F-O5-S.1/2H2-O",
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Methyldopa.nxml | Methyldopa | 2020-01-10 | Methyldopa (alpha-methyldopa or α-methyldopa) is a centrally active sympatholytic agent that has been used for more than 50 years for the treatment of hypertension. Methyldopa has been clearly linked to instances of acute and chronic liver injury that can be severe and even fatal. | Methyldopa (meth" il doe' pa) is a centrally active sympatholytic agent that reduces sympathic drive to the heart and peripheral circulation, leading to decreased cardiac output and lowered peripheral arterial resistance. Introduced in 1960, methyldopa rapidly became a leading antihypertensive agent, but in the last two decades its use has decreased markedly, replaced by better tolerated and more effective antihypertensive medications. Currently, the major use of methyldopa is treatment of hypertension during pregnancy, a use based upon its established record of safety during pregnancy and breast feeding. Methyldopa is available generically and formerly under the trade name Aldomet as 125, 250 and 500 mg tablets. Fixed combinations with hydrochlorothiazide are also available (Aldoril). The recommended maintenance dose in adults is 500 mg to 2 g daily in 2-4 divided doses. Common side effects include nausea, diarrhea, headache, dizziness, sedation, dry mouth and rash. Rare but potentially severe adverse effects include hemolytic anemia (Coombs positive), lupus-like syndrome, mycocarditis, pancreatitis and hepatotoxicity. | Drug induced liver injury due to methyldopa was identified shortly after its introduction into medical use in the 1960’s. Chronic use of methyldopa is associated with mild and transient elevations in serum aminotransferase levels in 5% to 35% of patients, these elevations often resolving despite continuation of the medication. In contrast, clinically apparent or significant liver injury from methyldopa is relatively uncommon, although several hundred cases have been reported. Two patterns of hepatotoxicity have been described: an acute hepatitis that appears within weeks to months of starting treatment, and a chronic hepatitis that arises months to years after initiation of methyldopa therapy.\n\nThe acute liver injury from methyldopa generally arises within 2 to 12 weeks of starting therapy and is typically hepatocellular with marked elevations in ALT and AST (5- to 100-fold) and modest increases in alkaline phosphatase, although in a small proportion of patients the pattern of enzyme elevations is mixed or cholestatic (Case 1 and 2). Most patients become jaundiced. Symptoms resemble those of acute viral hepatitis, including fever, headache, fatigue, anorexia and nausea. Signs of hypersensitivity other than fever are uncommon. The injury can be severe and fatal. While some cases are associated with marked cholestasis and prolonged jaundice, most patients recover within 4 to 12 weeks. Autoantibodies including Coombs and antinuclear antibody positivity may be present (but also can arise independent of liver injury). Liver biopsy shows an acute hepatitis-like picture with marked inflammatory infiltrates and fatty change, with variable amounts of necrosis. Rechallenge leads to rapid recurrence of liver injury and can result in severe hepatitis, acute liver failure and death.\n\nThe chronic liver injury from methyldopa usually arises after 6 months, but may become first evident after several years of therapy (Case 3). This chronic hepatitis-like clinical picture has a more insidious onset typically with fatigue, weakness and nausea associated with mild or no jaundice. Clinical features may include liver enlargement and tenderness and spider angiomata. The clinical and laboratory pattern often resembles autoimmune hepatitis, with moderate to marked elevations in ALT and AST, modest alkaline phosphatase elevations, increases in immunoglobulin levels (particularly IgG), and high titers of autoantibodies such as antinuclear antibody (ANA) and smooth muscle antibody (SMA). Liver biopsy demonstrates findings of chronic active hepatitis with variable amounts of fatty change and fibrosis. Plasma cell infiltrates may be prominent. Cirrhosis and end stage liver disease can occur if the drug is continued. The disease resolves slowly but completely with discontinuation of methyldopa. Chronic liver injury now appears to be the most common form of drug induced liver injury from this agent. Some cases of methyldopa induced liver injury have features of both acute and chronic injury and the two forms of hepatic injury may share a common etiology.\n\nAfrican Americans appear to have a higher risk for liver injury from methyldopa than Caucasians or Hispanic individuals. The course may be more severe and outcome less favorable in Africans Americans as well. Granulomatous hepatitis can also occur with methyldopa therapy, usually in association with drug fever and systemic symptoms (and granulomas elsewhere), and sometimes with granulomatous myocarditis which can be fatal. In these situations, the liver injury is usually mild and anicteric.\n\nLikelihood score: A (well known cause of clinically apparent liver injury). | null | Both the acute and the chronic forms of liver injury from methyldopa can be severe, particularly if the medication is continued despite appearance of clinically significant injury. Recovery usually occurs within 6 to 8 weeks, but patients with chronic hepatitis can be left with inactive cirrhosis. Methyldopa ranks as one of the ten most common causes of acute liver failure due to medications, although its frequency is decreasing as its use has become more restricted. Because of its cost, methyldopa is still used widely for treatment of hypertension in developing nations, where cases of liver injury are likely to continue to arise. Patients with methyldopa induced liver injury should not be reexposed to this medication, but there is no evidence that there is cross susceptibility to liver injury with other antihypertensive agents. Prednisone has been used to treat both the acute and the chronic injury from methyldopa with unclear benefit. Management should focus on early withdrawal of methyldopa, and treatment with corticosteroids should be restricted only to severe or persistent cases and withdrawn in a timely manner.\n\nDrug Class: Antihypertensive Agents | Methyldopa – Generic, Aldomet® (Currently discontinued) | Antihypertensive Agents | null |
Ixabepilone.nxml | Ixabepilone | 2017-01-05 | Ixabepilone is a semisynthetic epothilone analogue that acts to stabilize microtubules thereby preventing mitosis and causing growth arrest in cancer cells. Ixabepilone is approved for use in refractory cases of advanced breast cancer. Its use is associated with a low rate of serum enzyme elevation, but ixabepilone has not been linked to cases of clinically apparent liver injury with jaundice. | Ixabepilone (ix" a bep' i lone) is semisynthetic analogue of epothilone B, epothilones being cytotoxic macrolides that cause cell growth arrest by binding to microtubules and preventing mitosis. Ixabepilone is similar in activity to taxanes, but differs structurally and is not affected by taxane resistance. Therapy with ixabepilone has been shown to prolong relapse-free as well as overall survival in women with locally advanced or metastatic breast cancer that has not responded or has relapsed after standard therapies such as with taxanes, capecitabine and anthracyclines. Ixabepilone was approved for use in the United States in 2007 and current indications are for locally advanced or metastatic breast cancer given as monotherapy or in combination with capecitabine after failure of other treatments. Ixabepilone is available in vials of 15 and 45 mg supplied with diluent under the brand name Ixempra. The recommended starting dose is 40 mg/m2 intravenously [infused over 3 hours] every 3 weeks. Common side effects include peripheral neuropathy, fatigue, muscle and joint pains, stomatitis, diarrhea, anorexia, weight loss, constipation, hair loss, hand-foot syndrome and myelosuppression. Rare, but potentially serious side effects include severe peripheral neuropathy, neutropenia, hypersensitivity reactions and fetal toxicity. Toxicity of ixabepilone is greater in patients with preexisting liver abnormalities which should trigger use of lower doses when given as monotherapy and avoidance of its use in combination with capecitabine. | In preregistration controlled trials, serum aminotransferase elevations and other liver test abnormalities were rarely mentioned. A high proportion of patients treated had mild-to-moderate serum enzyme elevations at the time of starting ixabepilone, probably because of hepatic metastases and the use of other antineoplastic agents. During ixabepilone therapy, worsening of serum enzyme elevations occurred in up to 15% of patients, but ALT elevations above 5 times the upper limit of normal were rare, and there were no reports of severe hepatic adverse events or discontinuations because of enzyme elevations or clinically apparent liver disease. Nevertheless, jaundice and acute liver failure as well as elevations in serum ALT, AST, alkaline phosphatase, and bilirubin are mentioned as occurring in clinical trials in the product label. Since the approval and more widescale use of ixabepilone, there have been no publications or descriptions of the clinical features of hepatotoxicity with jaundice associated with its use. Thus, clinically apparent liver injury probably occurs in a small proportion of patients receiving ixabepilone, but its relationship with the drug is unclear.\n\nLikelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury). | The cause of the liver enzyme elevations that occur during enzalutamide therapy is unknown. Ixabepilone is extensively metabolized in the liver predominantly by CYP 3A4 and 2D6 and is a strong inducer of CYP 3A4 and a moderate inducer of 2D6. Ixabepilone is susceptible to drug-drug interactions with inhibitors, inducers or substrates of these microsomal enzymes. | The liver injury linked to ixabepilone therapy has been generally mild, consisting of transient and asymptomatic elevations in serum aminotransferase levels. Ixabepilone has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There is no information on cross sensitivity to hepatic injury between ixabepilone and other therapies of advanced or metastatic breast cancer.\n\nDrug Class: Antineoplastic Agents, Breast Cancer Agents | Ixabepilone – Ixempra® | Antineoplastic Agents | null |
Hydroxyurea.nxml | Hydroxyurea | 2021-07-12 | Hydroxyurea is an antimetabolite that is used in the treatment of cancer and to stimulate fetal hemoglobin production in sickle cell disease. Hydroxyurea is associated with a low rate of transient serum enzyme and bilirubin elevations during therapy, and has been implicated in rare cases of clinically apparent acute liver injury with jaundice. | Hydroxyurea (hye drox” ee ure ee’ a) is a hydroxylated analogue of urea and an antimetabolite which inhibits the enzyme ribonucleotide reductase, which is necessary for DNA synthesis and cell cycle replication. Blocking the enzyme results in cell cycle arrest in the S phase, but does not interfere with RNA or protein synthesis. Hydroxyurea is used in the treatment of solid tumors and myeloproliferative diseases, the latter because of its effects in reducing excessive production of red blood cells (polycythemia vera), white blood cells (chronic myelogenous leukemia) or platelets (essential thrombocythemia). Hydroxyurea also increases the production of fetal hemoglobin, via an unknown mechanism of action, which increases overall hemoglobin levels and decreases sickling in patients with sickle cell anemia. In controlled clinical trials, hydroxyurea has been shown to increase hemoglobin concentrations, decrease transfusion requirements and lessen painful crises in patients with sickle cell disease. Hydroxyurea was first approved for use in the United States in 1967 as an antineoplastic agent for therapy of melanoma, chronic myelogenous leukemia, ovarian carcinoma, and head and neck cancers. The indications were expanded to sickle cell disease in 1998, which is the major indication for its use at present. Hydroxyurea is available in capsules of 200, 300, 400 and 500 mg generically and under brand names as Droxia (for sickle cell disease) and Hydrea (for cancer). The usual dose in sickle cell disease is 15 mg/kg/day, with subsequent dose adjustments based upon efficacy and tolerance to a maximum of 35 mg/kg/day. Common side effects include bone marrow suppression (particularly thrombocytopenia), nausea, vomiting, anorexia, diarrhea, mucositis, hair loss, headache, rash and fever. Uncommon, but potentially severe adverse reactions include severe vasculitic skin ulcers, neuropathy, renal dysfunction, severe bone marrow suppression, pulmonary fibrosis, and embryo-fetal toxicity. Long term hydroxyurea therapy may increase the risk of cancer. | Serum aminotransferase and bilirubin elevations occur in a small proportion of patients on conventional doses of hydroxyurea and a greater proportion at higher doses. However, the serum enzyme elevations are rarely associated with symptoms and are generally self-limited and resolve rapidly, rarely requiring dose modification.\n\nCases of clinically apparent liver injury attributed to hydroxyurea have been reported, but are rare. Two clinical presentations have been described: an acute syndrome of drug fever and mild hepatitis that resolves rapidly with stopping, and a less well characterized acute hepatitis-like injury which can be severe and even fatal, arising after several months of treatment and usually in patients on other hepatotoxic medications.\n\nDrug fever occurs in up to 1% of patients treated with hydroxyurea, typically arising within 1 to 3 weeks of starting and presenting with high fevers and mild constitutional symptoms of fatigue and nausea (Case 1 below). The fevers are typically cyclic and temperature can rise to 41oC at intervals of every 1 to 3 days as long as therapy is continued. The fevers are generally well tolerated, although they may be accompanied by nausea, diarrhea, anorexia or fatigue. Approximately one third of patients will also have some degree of serum enzyme elevations, typically increases in both aminotransferase and alkaline phosphatase levels, with minimal increases in serum bilirubin. The liver injury is usually mild and asymptomatic and the symptom of fever predominates. White blood cell and eosinophil counts are usually normal at the time of onset, but may arise if therapy is continued. Rash and other signs of hypersensitivity are uncommon. Both the fever and liver test abnormalities resolve promptly once hydroxyurea is stopped–the fever within 24 to 48 hours and the liver test elevations within 2 to 4 weeks. The fever recurs with reexposure, generally within 24 hours.\n\nIn addition, rare instances of acute hepatitis that can be severe and lead to hepatic failure and death have been described in patients taking hydroxyurea and antiretroviral therapy for HIV/AIDS. This presentation is clearly different from the hepatitis that accompanies drug fever from hydroxyurea, and resembles acute viral hepatitis with marked elevations in serum aminotransferase levels and jaundice and only mild-to-moderate elevations in alkaline phosphatase. Immunoallergic and autoimmune features are not usually present. Some cases have been fatal; others have been marked by slow, but ultimately full recovery. The cases of severe hepatitis attributed to hydroxyurea have been described largely in patients with HIV infection on antiretroviral regimens that include agents associated with hepatotoxicity, but the addition of hydroxyurea appeared to be responsible for the liver injury, these patients later tolerating resumption of antiretroviral therapy without recurrence.\n\nLikelihood score: C (probable cause of clinically apparent liver injury). | The syndrome of fever and acute hepatitis arising within 1 to 3 weeks of starting hydroxyurea is probably due to hypersensitivity. The cause of acute liver failure attributed to hydroxyurea is unknown, but may be related to drug-drug interactions with other potentially hepatotoxic agents. Hydroxyurea is metabolized in the liver via the cytochrome P450 enzymes at least in part, but its drug-drug interactions have not been well characterized. | The severity of the liver injury linked to hydroxyurea therapy is usually mild and self-limited. It has not been linked to cases of chronic hepatitis or vanishing bile duct syndrome. There is no information to suggest that there is cross sensitivity to hepatic injury between hydroxyurea and other antimetabolites or anticancer agents.\n\nDrug Class: Antineoplastic Agents, Miscellaneous; Genetic Disorder Agents, Hematologic Agents, Sickle Cell Disease Agents | Hydroxyurea – Generic, Hydrea® (for cancer), Droxia® (for sickle cell disease) | Antineoplastic Agents; Sickle Cell Disease Agents | null |
Inebilizumab.nxml | Inebilizumab | 2024-05-14 | Inebilizumab is a monoclonal antibody to CD19 that is used to treat adults with neuromyelitis optica spectrum disorder accompanied by an autoantibody to aquaporin-4. Inebilizumab therapy is associated with an increased risk of infections and possibly reactivation of hepatitis B and tuberculosis, but it has not been associated with serum aminotransferase elevations during therapy or to instances of clinically apparent liver injury. | Inebilizumab (in eb” i liz’ ue mab) is a humanized, cytolytic monoclonal antibody to CD19 that is used to treat adults with neuromyelitis optica spectrum disorder (NMOSD), a severe neurologic disease marked by bilateral optic neuritis and transverse myelitis that is accompanied by a distinctive autoantibody to aquaporin-4 (antiAQP4). In many ways, NMOSD resembles multiple sclerosis (MS) and is similarly marked by spontaneous relapses and remissions. Yet NMOSD differs from MS by the absence of typical brain findings on magnetic resonance imaging and by the presence of antiAQP4, a possibly pathogenic antibody. Inebilizumab dramatically lowers peripheral B cells, and chronic therapy is effective in lowering immunoglobulin levels and reducing relapses of NMSOD. Inebilizumab was approved for treatment of adults with neuromyelitis optica spectrum disorder positive for anti-AQP4 in the United States in 2020. Inebilizumab is available in solution in single use vials of 100 mg/10mL under the brand name Uplizna. The recommended dose regimen is 300 mg by intravenous infusion at time 0 and 2 weeks later, followed by every 6 months. Patients should be screened for hepatitis B and tuberculous before starting therapy and should have serum immunoglobulin levels measured and be given any needed live viral vaccines beforehand. Premedication with acetaminophen, antihistamines, or corticosteroids is recommended. In prelicensure trials, common adverse events included infusion reactions, reduction in immunoglobulin levels, arthralgias, and urinary tract infections. Serious adverse events associated with inebilizumab therapy include severe infections, hypersensitivity reactions, and embryo-fetal toxicity. Because it lowers peripheral B cells, inebilizumab may cause reactivation of tuberculosis, hepatitis B, and herpes virus infections, and possibly lead to progressive multifocal leukoencephalitis. | In registration controlled trials, serum ALT elevations occurred in 21% of inebilizumab vs 23% of placebo recipients and were above 3 times the upper limit of normal (ULN) in 5 of 161 (3.1%) on inebilizumab vs only 1 of 51 (2%) on placebo. One patient receiving inebilizumab developed acute cholangitis with ALT and AST elevations above 5 times ULN but without jaundice and responding rapidly to antibiotics and biliary drainage. Since the approval of inebilizumab in 2020, there have been no case reports of clinically apparent liver injury attributed to its use. Monoclonal antibodies to CD19 have been used for other indications and similarly have been free of liver injury. These B cell directed monoclonal antibodies, however, are considered possible causes of reactivation of hepatitis B and prescreening for hepatitis B status is often recommended.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | The causes of the mild liver test abnormalities during inebilizumab therapy are not clearly known but appear to be related to the underlying condition or comorbidities such as nonalcoholic fatty liver disease or gallstone disease. Inebilizumab can cause hypersensitivity reactions including urticaria and rash, and liver injury might be a part of the immunoallergic reaction. Cases of reactivation of hepatitis B were not observed during prelicensure studies and should not occur with adequate prescreening and prophylaxis against reactivation. | The product label for inebilizumab does not recommend monitoring of routine liver tests during therapy but does recommend screening for hepatitis B before starting therapy and obtaining advice from a hepatologist regarding prophylaxis. Nevertheless, de novo elevations of serum aminotransferase levels above 5 times the ULN or baseline values should lead to temporary discontinuation and evaluation for other possible causes of liver injury, restarting therapy only when values return to normal or near normal and with careful subsequent monitoring.\n\nDrug Class: Neurological Disease Agents; Monoclonal Antibodies | Inebilizumab – Uplizna® | Neurological Disease Agents | null |
UsnicAcid.nxml | Usnic Acid | 2018-04-25 | Usnic acid is a furandione found uniquely in lichen that is used widely in cosmetics, deodorants, toothpaste and medicinal creams as well as some herbal products. Taken orally, usnic acid can be toxic and has been linked to instances of clinically apparent, acute liver injury. | Usnic acid is a dibenzo-furandione which is uniquely found in lichen (Usnea) species, which are distributed worldwide. In vitro usnic acid has antibacterial, antifungal and antiviral activities, and lichen extracts containing usnic acid have been used in folk medicine externally for wound healing and athlete’s foot and internally for sore throat, toothache and fever. Usnic acid has also found several commercial uses, largely in perfumery and cosmetic products, but also in medicinal creams. However, usnic acid appears to be toxic when taken orally in high doses and, for instance, can cause ataxia and paralysis in animals grazing on lichen contaminated crops and grains. Usnic acid has been purified and extensively studied in vitro and has been shown to uncouple oxidative phosphorylation in isolated mitochondria, which may account for its broad antimicrobial activity. Uncoupling of oxidative phosphorylation by decreasing the efficacy of energy use and causing increased thermogenesis has been proposed as an approach to treatment of obesity. However, this approach is potentially dangerous and has not been shown to be effective in causing weight loss other than by extreme toxicity. Nevertheless, usnic acid has been used in several commercial over-the-counter weight loss products. | Several cases of clinically apparent acute liver injury have been attributed to commercial dietary supplements that contain usnic acid. “LipoKinetix” was one such supplement advertised as a weight loss and body building supplement. Each tablet contained sodium usniate (100 mg), norephedrine (25 mg), diiodothyronine (100 mg), yohimbine (3 mg) and caffeine (100 mg). The product has been linked to multiple instances of acute liver injury. The time to onset was 2 to 12 weeks and the clinical presentation resembled acute viral hepatitis with onset of fatigue and nausea, followed by jaundice. The pattern of serum enzyme elevations was hepatocellular, with marked elevations in serum ALT and minimal increases in alkaline phosphatase levels. Liver biopsy demonstrated acute hepatocellular necrosis and inflammation. Immunoallergic features (fever, rash and eosinophilia) were not common and autoantibodies were usually not present. Recovery was rapid with stopping the dietary supplement, but some cases were severe and led to acute liver failure and either death or need for emergency liver transplantation. Instances of acute hepatitis have also been reported with other multi-ingredient dietary supplements that contain usnic acid, but much more rarely than with LipoKinetix which was withdrawn from distribution after a FDA warning letter. Rare instances of hepatotoxicity have also been reported with use of lichen based teas known as Kombucha tea, but whether these were due to usnic acid or another contaminant of the tea was not shown.\n\nLikelihood score (usnic acid): B (highly likely cause of clinically apparent liver injury).\n\nLikelihood score (Kombucha tea): C (probable cause of clinically apparent liver injury). | The hepatotoxicity of usnic acid is probably caused by uncoupling of oxidative phosphorylation in the liver, which can produce hepatocyte lysis and apoptosis and induces acute liver injury in animal models. | Hepatotoxicity attributed usnic acid and products such as LipoKinetix is often clinically apparent, but is usually reversible with prompt discontinuation of the nutritional supplement. Usnic acid is a direct hepatotoxin and thus is unlikely to share cross sensitivity to liver injury with other agents.\n\nDrug Class: Herbal and Dietary Supplements | Usnic Acid – Generic | Herbal and Dietary Supplements | null |
Olaratumab.nxml | Olaratumab | 2017-05-29 | Olaratumab is a human monoclonal antibody to the platelet-derived growth factor (PDGF) receptor alpha and an antineoplastic agent used in the therapy of advanced soft tissue sarcoma. Olaratumab has not been linked to serum enzyme elevations during therapy or to idiosyncratic acute liver injury. | Olaratumab (oh" lar at' ue mab) is a recombinant human monoclonal IgG1 antibody to the platelet-derived growth factor receptor alpha. Signaling through PDGF receptors promotes cell proliferation and angiogenesis. Inhibition of the PDGF signaling decreases formation of new blood vessels, which plays an important role in growth and spread of cancer cells. When used in combination with other antineoplastic agents, olaratumab has been shown to extend recurrence-free survival in several forms of advanced cancer. Olaratumab was approved in the United States in 2016 for use in combination with doxorubicin for refractory, advanced soft tissue sarcoma. Olaratumab is available in solution in single use vials of 500 mg in 50 mL or 190 mg in 19 mL (10 mg/mL) under the brand name Lartruvo. The typical dose is 15 mg/kg intravenously over 60 minutes on days 1 and 8 of each 21-day cycle. Premedication with diphenhydramine and dexamethasone is recommended with the initial dose. Olaratumab is administered with doxorubicin and this combination has significant adverse side effects, including nausea and vomiting, diarrhea, fatigue, anorexia, abdominal pain, alopecia, peripheral neuropathy, neutropenia, and stomatitis. Uncommon, but potentially severe adverse events include severe infusion reactions, hypersensitivity reactions, and embryofetal toxicity. | In preregistration clinical trials, serum aminotransferase elevations were no more frequent in patients receiving olaratumab and doxorubicin than in those receiving doxorubicin alone (17.5% vs 16.1%), and no patient developed elevations above 5 times ULN or required dose modification or discontinuation for liver test abnormalities. Hepatotoxicity was not listed as a cause of serious adverse events or a reason for discontinuation of olaratumab. Subsequent to its approval and more general use, olaratumab has not been implicated in published cases of clinically apparent liver injury. Olaratumab is generally given with other potent antineoplastic agents and it is often difficult to attribute serum enzyme elevations or clinically apparent liver injury to a specific agent being used.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | The possible mechanism of liver injury caused by olaratumab is not known. It is a recombinant protein and unlikely to be inherently hepatoxic. Proteins are metabolized to small polypeptides and amino acids in many cells including hepatocytes and do not alter the activity of drug metabolizing enzymes or hepatic transporter molecules. Blocking of PDGF signaling does not seem to harm liver cells or alter hepatic function.\n\nDrug Class: Antineoplastic Agents, Monoclonal Antibodies | null | Olaratumab – Lartruvo® | Antineoplastic Agents | null |
Bisoprolol.nxml | Bisoprolol | 2017-01-15 | Bisoprolol is a cardioselective beta-blocker used in the treatment of hypertension. Bisoprolol has not been linked to instances of clinically apparent drug induced liver injury. | Bisoprolol (bis" oh proe' lol) is considered a “selective” beta-adrenergic receptor blocker in that it has potent activity against beta-1 adrenergic receptors which are found in cardiac muscle, but has little or no activity against beta-2 adrenergic receptors found on bronchial and vascular smooth muscle. Bisoprolol was approved for use in the United States in 1992 and is currently widely used in the therapy of hypertension alone or in combination with other agents. At present, more than 4 million prescriptions for bisoprolol are filled yearly. Bisoprolol is available in 5 and 10 mg tablets in generic forms as well as under the trade name of Zebeta. Bisoprolol is also available in fixed combinations with hydrochlorthiazide (Ziac and other generic forms). The usual initial oral dose of bisoprolol in adults is 2.5 to 5 mg once daily, with subsequent adjustment based upon clinical response and tolerance, the usual maintenance dosage being 5 to 20 once mg daily. Common side effects include bradycardia, hypotension, fatigue, dizziness, depression, insomnia, memory loss and impotence. At high doses, bisoprolol is less cardioselective and can induced acute bronchospasm. As with all beta-blockers, sudden withdrawal can trigger rebound hypertension. | Bisoprolol therapy has been associated with a low rate of mild-to-moderate elevations of serum aminotransferase levels which are usually asymptomatic and transient and resolve even with continuation of therapy. There have been no well documented cases of clinically apparent, acute liver injury attributable to bisoprolol. Thus, hepatotoxicity due to bisoprolol must be very rare, if it occurs at all. Most commonly used beta-blockers have been linked to rare instances of clinically apparent liver injury, typically with onset within 2 to 12 weeks, a hepatocellular pattern of liver enzyme elevations, rapid recovery upon withdrawal, and little evidence of hypersensitivity (rash, fever, eosinophilia) or autoantibody formation.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | The mechanism of drug induced liver injury from beta-blockers such as bisoprolol is not known. Bisoprolol is extensively metabolized by the liver and excreted as inactive metabolites. The few rare cases reported were likely idiosyncratic. | The severity of liver injury due to beta-blockers ranges from mild serum aminotransferase elevations to acute hepatitis with jaundice. In large case series of drug induced liver injury and acute liver failure due to medications, bisoprolol has not been listed as a potential cause. There is little information about cross reactivity among the beta-blockers to hepatic injury. Switching from a beta-blocker that has caused acute liver injury to another should be done with caution and active monitoring.\n\nReferences to the safety and potential hepatotoxicity of bisoprolol are provided in the overview on Beta-Adrenergic Receptor Antagonists, last updated in June 2019.\n\nDrug Class: Beta-Adrenergic Receptor Antagonists | Bisoprolol – Generic, Zebeta® | Beta-Adrenergic Receptor Antagonists | null |
Midostaurin.nxml | Midostaurin | 2019-04-10 | Midostaurin is an orally available small molecule inhibitor of FMS-like tyrosine kinase 3 (FLT3) which is used as an antineoplastic agent in the treatment of acute myeloid leukemia with FLT3 mutations. Midostaurin is associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to cause rare instances of clinically apparent acute liver injury. | Midostaurin (mye" doe staw' rin) is a potent small molecule multi-kinase inhibitor with specific activity against FLT3 (FMS-like tyrosine kinase 3), a tyrosine kinase receptor that is mutated in to up one-third of patients with acute myeloid leukemia (AML). The mutated FLT3 activates an intracellular signaling cascade of RAS-MEK-PI3K-AKT-STAT-5, promoting unregulated cell growth and proliferation. Midostaurin also has activity against other kinases including Kit, platelet derived growth factor receptor, vascular endothelial growth factor receptor 2 and members of the protein kinase C family. Midostaurin has been found to induce objective responses in a proportion of patients with refractory AML with detectable FLT3 mutations and in patients with advanced systemic mastocytosis. Midostaurin received accelerated approval for these indication in the United States in 2017 and is available in tablets of 25 mg under the brand name Rydapt. For newly diagnosed AML with FLT3 mutations, the recommended dose is 50 mg orally twice daily in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. For advanced systemic mastocytosis, the recommended dose is 100 mg orally twice daily, continued until progressive disease or intolerable toxicity occurs. Side effects are common and can include fatigue, myalgia, arthralgia, fever, cytopenias, diarrhea, nausea, abdominal pain, dizziness, headache, hypotension, cough and stomatitis. Potentially severe side effects include febrile neutropenia and sepsis, interstitial lung disease and embryo-fetal toxicity. | Elevations in serum aminotransferase levels are common during midostaurin therapy occurring in up to 71% of patients with AML also receiving standard induction therapy and rising above 5 times the upper limit of the normal range in 20%. In patients with systemic mastocytosis receiving midostaurin monotherapy, ALT elevations arose in 31% of patients and rose to above 5 times ULN in 4%. Hyperbilirubinemia was also common in these studies but instances of clinically apparent liver injury with jaundice, severe hepatoxicity and deaths from hepatic failure were not reported. However, because of the limited clinical experience with the use of midostaurin and other FLT3 inhibitors, their potential for causing liver injury is not well defined.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury). | The possible cause of the liver injury due to midostaurin is not known. Midostaurin is metabolized in the liver largely by the cytochrome P450 system (largely CYP 3A4) and is susceptible to drug-drug interactions with inhibitors or inducers of the microsomal enzyme system, and strong modulators of CYP 3A4 should be avoided in patients receiving midostaurin. | Midostaurin therapy has been associated with transient serum aminotransferase elevations during therapy but has not been linked to instances of acute liver injury with jaundice or symptoms. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to temporary discontinuation, which should be permanent if laboratory values do not improve significantly or resolve within a few weeks or if symptoms or jaundice arise.\n\nDrug Class: Antineoplastic Agents, Protein Kinase Inhibitors | Midostaurin – Rydapt® | Antineoplastic Agents | null |
ModafinilArmodafinil.nxml | Modafinil | 2021-08-18 | Modafinil and its R-enantiomer armodafinil are central nervous system stimulants used to improve wakefulness in patients with excessive sleepiness. Both modafinil and armodafinil are associated with a low rate of serum aminotransferase elevations during therapy, but they have not been implicated in cases of clinically apparent acute liver injury. | Modafinil (moe daf' i nil) is a non-amphetamine central nervous system (CNS) stimulant whose mechanism of action is not entirely clear. Modafinil is structurally unrelated to the amphetamines, and it does not appear to affect release of CNS norepinephrine or dopamine. Modafinil is a racemic mixture of S and R enantiomers, whereas armodafinil (ar" moe daf' i nil) is the R enantiomer only. Both enantiomers have CNS activating actions, but they differ in pharmacokinetics and half-life. Modafinil and armodafinil increase wakefulness and both have been shown to be helpful in conditions with excessive sleepiness including narcolepsy, obstructive sleep apnea and shift-work sleep disorder. They have also been studied off label to treat fatigue associated with chronic illness such as cancer, Parkinson’s disease, HIV/AIDs and multiple sclerosis. Modafinil was approved for use in the United States in 1998 and armodafinil in 2007. Their indications are for improvement in wakefulness in adults with excessive sleepiness due to narcolepsy, obstructive sleep apnea, and shift-work disorder. Modafinil is available in tablets of 100 and 200 mg in generic forms and under the brand name Provigil, the usual dose in adults being 200 mg once daily in the morning or an hour before a work shift. Armodafinil is available in tablets of 50, 150, 200 and 250 mg generically and under the brand name Nuvigil, the usual dose in adults being 150 to 250 mg once daily. Armodafinil is also approved for treatment of sleepiness due to jet lag, a lower dose of 50 to 150 mg being recommended. The most common side effects of both agents include headache, anxiety nervousness, nausea, decreased appetite, palpitations and disturbed sleep. Modafinil and armodafinil are now classified as category IV controlled substances, indicating that they have a potential for abuse and can lead to physical or psychological dependence. Rare but potentially severe adverse reactions include rash and severe hypersensitivity reactions such as drug-reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, and toxic epidermal necrolysis. Also reported are cardiac adverse events and acute psychiatric syndromes such as mania, delusions, hallucinations, and suicidal ideation. | In clinical trials, modafinil and armodafinil were associated with a low rate of serum aminotransferase and alkaline phosphatase elevations (<1%). Furthermore, despite widescale use, there have not been reports of clinically apparent liver injury due to modafinil or armodafinil. Rare instances of hypersensitivity reactions and even Stevens Johnson syndrome have been reported after modafinil use and these reactions may be accompanied by evidence of hepatic involvement or injury.\n\nLikelihood score: E (unlikely causes of clinically apparent liver injury). | The mechanism by which modafinil and armodafinil might cause liver injury is unknown. Modafinil and armodafinil are extensively metabolized in the liver largely by CYP 3A4 and 2C91 and are susceptible to drug-drug interactions with agents that are substrates for these microsomal enzymes.\n\nDrug Class: CNS Stimulants, Narcolepsy Agents\n\nOther Drugs in the Subclass, Narcolepsy Agents: Amphetamines, Dextroamphetamine, Methylphenidate, Oxybate, Pitolisant, Solriamfetol | null | Armodafinil – Generic, Nuvigil® | Central Nervous System Stimulants | [
{
"cas_registry_number": "112111-43-0",
"molecular_formula": "C15-H15-N-O2-S",
"name": "Armodafinil"
},
{
"cas_registry_number": "68693-11-8",
"molecular_formula": "C15-H15-N-O2-S",
"name": "Modafinil"
}
] |
Ritlecitinib.nxml | Ritlecitinib | 2024-03-25 | Ritlecitinib is an orally available small molecule inhibitor of Janus kinase 3 (JAK3) that is used to treat severe alopecia areata. Ritlecitinib is associated with a low rate of transient and usually mild elevations in serum aminotransferase levels during therapy but has yet to be linked to cases of clinically apparent acute liver injury. | Ritlecitinib (rit" le sye' ti nib) is an orally available, specific inhibitor Janus-associated kinases (mainly irreversible inhibition of JAK3) that is used to treat moderate-to-severe alopecia areata. Alopecia areata is an autoimmune disorder that is characterized by hair loss resulting in patches and even complete baldness of the scalp, along with thinning or loss of eyebrows and eyelashes. The Janus kinases are critical steps in immune activation that transmit signals for different cytokine receptors and promote expression of genes involved in production of pro-inflammatory cytokines. JAK3, in particular, is a critical kinase in the cellular responses of interferon gamma, a cytokine found to be over-expressed in patients with alopecia areata. In multiple randomized controlled trials, ritlecitinib was found to decrease or reverse hair loss in patients with alopecia areata. Ritlecitinib was approved for this use in the United States in 2023, the 4th small molecule JAK inhibitor to receive approval, after ruxolitinib (JAK1/2 inhibitor) in 2011, tofacitinib (JAK1/3 inhibitor) in 2012, and baricitinib (JAK 1/2 inhibitor) in 2018, and the 2nd JAK inhibitor approved as therapy for alopecia areata, after baricitinib in 2022. Ritlecitinib is available in capsules of 50 mg under the brand name Litfulo (Pfizer). The recommended dose is 50 mg once daily. Current indications are severe alopecia areata (as defined by 50% hair loss or greater) in adults and adolescents 12 years and older. Common side effects are headache, dizziness, diarrhea, pyrexia, stomatitis, infections, nasopharyngitis, acne, atopic dermatitis, folliculitis, urticaria, and rash. Ritlecitinib can also cause anemia, and creatine kinase elevations. Potential severe adverse events may include reactivation of fungal, viral, and opportunistic infections such as tuberculosis, herpes simplex, and herpes zoster and malignancies. Other JAK inhibitors have been linked to a higher rate of all-cause mortality and rarely to venous and arterial thromboses and to major atherosclerotic cardiovascular and cerebrovascular events (myocardial infarction, stroke, and cardiovascular death). | In the prelicensure clinical trials in alopecia areata, serum aminotransferase elevations occurred in 1% to 3% of ritlecitinib treated subjects, but similar rates were found in placebo recipients. The elevations were typically mild and transient, and values above 5 times the upper limit of normal (ULN) occurred in less than 1% of patients. The elevations rarely led to early discontinuations, and often resolved even without dose adjustment. In prelicensure studies in alopecia areata and other autoimmune conditions, there were no instances of liver related severe adverse events or clinically apparent liver injury attributed to ritlecitinib. Since approval and more widescale availability of ritlecitinib, there have been no published reports of hepatotoxicity associated with its use.\n\nFinally, ritlecitinib is an immune modulatory agent and has the potential of causing reactivation of viral infections including hepatitis B. Other JAK inhibitors have been implicated in rare instances of reactivation of hepatitis B, although the episodes were usually asymptomatic and self-limited in course. The risk of reactivation of hepatitis B in patients with HBsAg or with anti-HBc without HBsAg who are treated with ritlecitinib has not been defined.\n\nLikelihood score: E* (unlikely cause of idiosyncratic clinically apparent liver injury, but is a potential cause of reactivation of hepatitis B). | The cause of mild serum enzyme elevations during ritlecitinib therapy is not known. Ritlecitinib is metabolized in the liver largely via CYP 3A4 and coadministration with strong inducers of CYP 3A4 should be avoided. Ritlecitinib is also an inhibitor of CYP 3A and 1A2 and can result in increases in serum levels of substrates of these two enzymes. The pharmacokinetics of ritlecitinib are not affected my mild-to-moderate liver impairment (Child-Pugh A or B), but its use is not recommended in patients with severe impairment (Child-Pugh C). | Serum aminotransferase elevations are uncommon during ritlecitinib therapy, but routine monitoring of liver tests is recommended in the product label “according to routine patient management.” Aminotransferase elevations above 5 times the upper limit of normal (ULN) should lead to at least temporary interruption of therapy until levels fall into the normal or near normal range. Elevations above 20 times the ULN or any elevations accompanied by symptoms or jaundice should lead to permanent discontinuation.\n\nBecause of its potential to cause reactivation of hepatitis B, routine screening for HBsAg and anti-HBc before starting therapy with ritlecitinib is appropriate. Patients with HBsAg in serum should be treated prophylactically with an oral antiviral agent with activity against HBV such as entecavir or tenofovir. An alternative is to monitor patients carefully for HBV DNA levels to detect evidence of reactivation early and initiate appropriate therapy for HBV infection.\n\nDrug Class: Dermatologic Agents, Protein Kinase Inhibitors\n\nOther Drugs for Alopecia areata: Baricitinib | Ritlecitinib – Litfulo® | Dermatologic Agents | null |
Nitrofurantoin.nxml | Nitrofurantoin | 2020-05-01 | Nitrofurantoin is an oral antibiotic widely used either short term to treat acute urinary tract infections or long term as chronic prophylaxis against recurrent infections. Nitrofurantoin is one of the most common causes of drug induced liver disease and can cause either an acute or a chronic hepatitis-like syndrome that can be severe and lead to liver failure or cirrhosis. | Structurally, nitrofurantoin (nye" troe fure an' toyn) is a nitrated 5-member furan ring with a side chain of hydantoin. Nitrofurantoin inhibits several bacterial enzyme systems and has broad antibacterial activity. Its precise mechanism of action is not known. Importantly, antibacterial resistance to nitrofurantoin is rare, which makes it an attractive choice for long term treatment. In addition, nitrofurantoin is well absorbed orally and is rapidly excreted in the urine so that drug levels in urine are high while serum levels are minimal, which makes it an appropriate agent to treat urinary tract but not systemic infections. Nitrofurantoin was first approved for use in the United States in 1953 and is still in wide use with more than 3 million prescriptions filled yearly. Current indications are treatment of acute and prophylaxis against chronic or recurrent urinary tract infections due to susceptible organisms. For treatment of acute infections, the recommended regimen is 50 to 100 mg orally four times daily for one week. For prophylaxis against chronic or recurrent infections, the recommended dose is 50 to 100 mg daily long term. Generic formulations are available (25, 50, and 100 mg); specific commercial names include Macrodantin, Macrobid and Furadantin, among others. Common side effects include nausea, diarrhea, dyspepsia, dizziness, drowsiness and rash. Nitrofurantoin has multiple rare, but potentially severe side effects that arise particularly with long term use and include interstitial pneumonitis, peripheral neuropathy, exfoliative dermatitis, hemolytic anemia, lupus-like syndromes and hepatotoxicity. | Nitrofurantoin is currently one of the most common causes of drug induced liver injury. Liver injury from nitrofurantoin can cause either an acute or chronic hepatitis-like syndrome. The acute form is typically associated with a 1 or 2 week course of treatment with nitrofurantoin and is rare (~0.3 cases per 100,000 prescriptions). Acute liver injury typically presents within a few weeks of starting nitrofurantoin and can arise up to a few weeks after stopping a defined course of treatment. The pattern of liver injury is usually hepatocellular with or without jaundice, and typically is accompanied by symptoms of fever and rash. The acute injury due to nitrofurantoin usually resolves rapidly once the medication is stopped, but severe and fatal instances have been reported. In some instances, autoimmune features are present, but these are more common with the chronic presentation of nitrofurantoin hepatotoxicity. The course and outcome of acute nitrofurantoin hepatotoxicity is variable, severe forms with acute liver failure can occur, and nitrofurantoin is regularly listed as one of the major causes of acute liver failure due to medications.\n\nThe chronic form of nitrofurantoin hepatotoxicity is more common than the acute form and typically presents months to years after initiation of long term prophylactic therapy. The estimated incidence of liver injury from nitrofurantoin is approximately 1 per 1500 persons exposed. The presentation is usually insidious and marked initially by fatigue and weakness followed by dark urine and jaundice. The clinical pattern and laboratory features can mimic autoimmune hepatitis with marked elevations in serum ALT levels, increases in gamma globulin levels, and the presence of antinuclear and anti-smooth muscle antibodies. In some instances, the onset is abrupt and resembles acute hepatitis. However, immunoallergic features of fever and rash are less common than with the acute form of nitrofurantoin hepatotoxicity. Liver histology typically demonstrates features of chronic hepatitis with inflammation, interface hepatitis, focal or centrilobular bridging necrosis and variable degrees of fibrosis. Cirrhosis as a result of nitrofurantoin hepatotoxicity has been reported and, if not recognized as due to the medication, can progress to end stage liver disease. There is a female preponderance and the risk of injury appears to increase with age particularly the chronic forms.\n\nLikelihood score: A (well known cause of clinically apparent liver injury). | The mechanism of nitrofurantoin hepatotoxicity is not well known. Its nitro-reductive metabolism produces injurious oxidative free radicals which can damage hepatocytes. Many cases demonstrate evidence an autoimmune etiology and some studies have shown a linkage with HLA-DR6 and DR2. | The severity of nitrofurantoin induced liver injury ranges from mildly symptomatic elevations in serum aminotransferase levels (Cases 1 and 2), hepatitis with jaundice (Case 3) to fulminant liver failure and death (Case 4). Complete recovery is expected after stopping the drug, but recovery may be slow (2 to 6 months). In rare instances, evidence of chronic liver injury persists. Because of the autoimmune features of many cases of nitrofurantoin hepatotoxicity, corticosteroids are often used particularly in cases that are severe or slow to resolve. In many instances, corticosteroid therapy appears to lead to improvement. However, the ultimate benefit of immunosuppressive therapy remains to be proven and corticosteroids should be used cautiously and withdrawn as soon as possible, and with careful follow up to document lack of relapse after stopping. Rechallenge leads to recurrence and should be avoided. There does not appear to be cross reactivity to hepatic injury between nitrofurantoin and other commonly used antibiotics.\n\nDrug Class: Antiinfective Agents | Nitrofurantoin – Generic (Various), Furadantin®, Macrodantin® | Antiinfective Agents, Urinary (Nitrofuran Derivative) | null |
Aztreonam.nxml | Aztreonam | 2017-08-02 | Aztreonam is a parenterally administered, synthetic monobactam antibiotic that is specifically active against aerobic gram-negative bacilli is resistant to many beta-lactamases. Aztreonam therapy is often accompanied by mild, asymptomatic elevations in serum aminotransferase levels, but it has not been reported to cause clinically apparent liver injury. | Aztreonam (az tree' oh nam) is a monocyclic beta-lactam compound (monobactam) that was originally isolated from Chromobacterium violaceum. It acts by binding to penicillin binding proteins inhibiting cell wall synthesis and decreasing bacterial growth. Aztreonam is active mostly against gram negative organisms and more closely resembles aminoglycosides rather than penicillins. Aztreonam was approved for use in the United States in 1986 and is indicated in the treatment of various moderate-to-severe systemic or skin, intra-abdominal, genitourinary, and respiratory gram-negative infections. Aztreonam is available in generic forms and under the brand name Azactam as a powder or a solution for injection, and under the brand name Cayston as a powder for solution to use in inhalational therapy. The recommended dosage is 0.5 to 2 g by intravenous or intramuscular injection every 8 to 12 hours, typically for 5 to 14 days. The most common side effects of aztreonam are injection site phlebitis, rash and gastrointestinal symptoms. | Aztreonam has systemic toxicities that are similar to those of other beta lactam antibiotics, but it is unclear whether it can cause hepatic injury similar to that of the penicillins or cephalosporins. Asymptomatic serum aminotransferase elevations are common during high dose, intravenous aztreonam therapy (10% to 38%). The enzyme abnormalities are usually mild-to-moderate, asymptomatic, self-limited and not requiring drug discontinuation. Enzyme elevations occur slightly more commonly during aztreonam therapy than with other comparative antibiotics. Cases of frank liver injury and jaundice attributable to aztreonam must be extremely rare as no individual cases have been reported. For this reason, there is no data regarding the latency or pattern of the injury. Instances of marked aminotransferase elevations within 3 to 5 days of starting aztreonam have been reported, but these cases were without jaundice and resolved rapidly once the drug was stopped.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | null | In the majority of cases, aztreonam induced liver injury appears to be transient, mild and asymptomatic, being marked by serum enzyme elevations only. Full recovery is expected after stopping the medication.\n\nDrug Class: Antiinfective Agents | Aztreonam – Azactam® | Antiinfective Agents | null |
Lazertinib.nxml | Lazertinib | 2025-03-23 | Lazertinib is a small molecule inhibitor of the epidermal growth factor (EGF) receptor that is used in combination with amivantamab to treat adults with locally advanced or metastatic non-small cell lung cancer that harbors EGF receptor mutations. The combination of lazertinib and amivantamab is associated with transient elevations in serum aminotransferase levels during therapy but has not been linked to episodes of clinically apparent liver injury with jaundice. | Lazertinib (laz’ er tin ib) is an orally available, specific inhibitor of the epidermal growth factor (EGF) receptor that is used in combination with amivantamab in the therapy of advanced or metastatic non-small cell lung cancer (NSCLC) with EGF receptor mutations. EGF receptors are frequently mutated in lung cancer and can account for drug resistance using conventional EGF receptor inhibitors. Lazertinib has activity against wild type EGF receptors and has potent activity against receptors that harbor exon 19 deletions and exon 21 L858R, which are found in 10% to 15% of patients diagnosed with NSCLC. In a large, controlled trial, lazertinib in combination with amivantamab (a bispecific monoclonal antibody to the EGF receptor and MET) was compared to the current standard EGF receptor kinase inhibitor (osimertinib) for patients with advanced or metastatic NSCLC. The median progression-free survival was superior with the combination (23.7 months) compared to osimertinib (16.6 months). Lazertinib in combination with amivantamab was approved as a first line treatment for patients with metastatic NSCLC harboring mutations of exon 19 deletions or exon 21 L858R in 2024. Lazertinib is available in tablets of 80 and 240 mg under the brand name Lazcluze. The recommended dose is 240 mg once daily in combination with amivantamab (brand name Rybrevant) given intravenously once weekly for 4 weeks followed by every 3 weeks until unacceptable intolerance or disease progression arises. Side effects are common with lazertinib and amivantamab combination therapy. Common, mild-to-moderate side effects include rash, nail toxicity, infusion related reactions, fatigue, stomatitis, nausea, diarrhea, constipation, decreased appetite, edema, musculoskeletal pain, paresthesia, pruritus, and abdominal pain. Less frequent but potentially severe adverse events include severe infusion related reactions, interstitial lung disease, venous thromboembolic events, severe skin rash, ocular toxicity and embryo-fetal toxicity. The combination has a boxed warning about thromboembolic events and routine anticoagulation is recommended for the first 4 months of treatment. | In the prelicensure trial of the combination of lazertinib and amivantamab, liver test abnormalities were frequent, with elevations in ALT of 65%, AST 65%, and GGT 39% but without bilirubin elevations. The enzyme elevations were usually transient, mild-to-moderate in severity and not associated with symptoms or jaundice. ALT elevations above 5 times the upper limit of normal (ULN) arose in 7% of subjects and were self-limited in course and not associated with jaundice. The ALT elevations led to dose interruptions in 6% of patients but not to drug discontinuations. Some of the aminotransferase elevations may have been due to amivantamab rather than lazertinib or even to the anticoagulants that are used during the first 4 months of therapy. There were no deaths or episodes of life threatening liver injury among the 421 patients receiving combination therapy in the preregistration safety cohort. Since approval and more widespread use of lazertinib and amivantamab, there have been no published case reports of clinically apparent liver injury with jaundice. Nevertheless, several instances of severe and even fatal liver injury have been linked to use of other EGF kinase inhibitors such as afatinib, erlotinib, and gefitinib.\n\nLikelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury). | The causes of serum enzyme elevations or liver injury from lazertinib therapy are probably the result of direct toxicity of the multi-kinase receptor inhibition. Lazertinib is metabolized in the liver largely via the CYP 3A4 pathway, and liver injury might also be caused by production of a toxic or immunogenic intermediate of its metabolism. Because it is a substrate for CYP 3A4, lazertinib is susceptible to drug-drug interactions with agents that inhibit or induce this specific hepatic microsomal activity. | The product label for lazertinib recommends monitoring of liver tests before initiating therapy and frequently during treatment. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to at least temporary cessation. There is no evidence to suggest a cross reactivity in risk for adverse events, hypersensitivity, or hepatic injury between lazertinib and other EGF receptor inhibitors such as afatinib, mobocertinib, or osimertinib.\n\nDrug Class: Antineoplastic Agents, Protein Kinase Inhibitors\n\nOther EGF Receptor Targeted Kinase Inhibitors Used to Treat NSCLC: Axitinib, Erlotinib, Gefitinib, Mobocertinib,
Osimertinib | Lazertinib – Lazcluze® | Antineoplastic Agents | null |
Phenotypes_enzy.nxml | Enzyme Elevations Without Jaundice | 2019-05-04 | null | null | null | null | null | null | null | null |
Brivaracetam.nxml | Brivaracetam | 2017-10-02 | Brivaracetam is a relatively unique anticonvulsant that is typically used in combination with other antiepileptic medications for partial onset seizures. Brivaracetam has been linked to rare instances of serum aminotransferase and alkaline phosphatase elevations during treatment and is suspected of causing rare cases of clinically apparent drug induced liver disease. | Brivaracetam (briv" a ra' se tam) is a pyrrolidine derivative related in structure to levetiracetam. Its mechanism of action is not known, but it, like levetiracetam, binds to the synaptic vesicle protein 2A (SV2A) in the brain and appears to act by preventing secondary spread of focal seizure activity and decreasing simultaneous neuronal firing. Brivaracetam was approved for use in epilepsy in 2016 and current indications are as adjunctive therapy for partial onset seizures in adults and in children 16 years or older. Brivaracetam is available as tablets of 10, 25, 50, 75 and 100 mg under the brand name Briviact. Liquid oral and injectable forms are also available. The recommended initial dose in adults is 50 mg twice daily, with dose adjustment based upon tolerance and effect downward or upward to a maximum of 100 mg twice daily. Common side effects include dizziness, somnolence, fatigue, and nausea and vomiting. | Prospective studies reported that chronic brivaracetam therapy was not accompanied by significant elevations in serum aminotransferase levels and clinically apparent liver injury was not observed. Brivaracetam has had limited general use, but has not been linked to instances of clinically apparent liver injury. Levetiracetam, an anticonvulsant with similar structure and mechanism of action, has been linked to rare instances of acute liver injury, generally arising within 1 to 20 weeks and presenting with a hepatocellular pattern of injury without immunoallergic or autoimmune features. Whether similar cases will be linked to brivaracetam is not known.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | The mechanism by which brivaracetam might cause liver injury is unknown, but is likely to be hypersensitivity. Brivaracetam is metabolized by hydrolysis followed by hydroxylation that is mediated by the cytochrome P450 system, predominantly CYP 2C19. Inhibitors of CYP 2C19 (such as carbamazepine and phenytoin) may increase and CYP 2C19 inducers (such as rifampin) may decrease brivaracetam levels. | Minor serum enzyme elevations during brivaracetam therapy rarely require dose modification or discontinuation, but elevations above 5 times the ULN should lead to dose modification and search for other possible causes. Acute liver failure, chronic hepatitis and vanishing bile duct syndrome have not been reported with brivaracetam therapy, nor has anticonvulsant hypersensitivity (DRESS) syndrome, and brivaracetam may be a reasonable alternative in patients who have developed liver injury due to an aromatic anticonvulsant such as phenytoin, carbamazepine or lamotrigine.\n\nDrug Class: Anticonvulsants | Brivaracetam – Briviact® | Anticonvulsants | [
{
"cas_registry_number": "357336-20-0",
"molecular_formula": "C11-H20-N2-O2",
"name": "Brivaracetam"
},
{
"cas_registry_number": "102767-28-2",
"molecular_formula": "C8-H14-N2-O2",
"name": "Levetiracetam"
}
] |
Selexipag.nxml | Selexipag | 2016-11-10 | Selexipag is prostacyclin receptor agonist that causes vasodilation in pulmonary vasculature and is used in the therapy of pulmonary arterial hypertension (PAH). Selexipag has been associated with a low rate of serum enzyme elevations during therapy, but has yet to be implicated in cases of clinically apparent acute liver injury. | Selexipag (se lex' i pag) is a selective prostacyclin receptor agonist that is used to treat pulmonary arterial hypertension (PAH). Inhibition of the prostaglandin receptors disrupts the intracellular pathways that lead to vasoconstriction, thus causing vasodilation. Because these receptors are found in highest concentration in the lungs, selexipag primarily causes vasodilation in the pulmonary vasculature and decreases pulmonary vascular pressure. In prospective, randomized controlled trials, selexipag was effective in alleviating symptoms, improving exercise capacity and prolonging the time to clinical worsening in patients with idiopathic PAH. Selexipag was approved for use in the United States in 2015 and experience with its use is limited. The current indications are for symptomatic PAH, classified as WHO group 1 (idiopathic). Use of selexipag in other forms of PAH (due to heart failure, thromboembolic disease, or pulmonary disease) should be considered experimental as its efficacy in these forms of PAH has not been adequately shown. Selexipag is available in tablets of 200, 400, 800, 1000, 1200, 1400 and 1600 µg under the brand name Uptravi. The recommended starting dose is 200 µg twice daily, which can be increased weekly by 200 µg twice daily to the highest tolerated dose up to 1600 µg twice daily. Common side effects include headaches, diarrhea, jaw pain, nausea, vomiting, myalgia, pain in the extremities and flushing. Uncommon, but potentially severe adverse reactions include pulmonary edema and hypersensitivity reactions. | Selexipag is associated with a low rate of serum aminotransferase elevations (0% to 3%) that in clinical trials was similar to the rate among placebo recipients. These elevations were usually mild (rarely above 3 times ULN), transient and not associated with symptoms. There were no cases of serum enzyme elevations with jaundice in these preregistration clinical trials. Since licensure and more wide scale use, there have been no published reports of clinically apparent liver injury with jaundice associated with selexipag, but it has had limited general use.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | The mechanism by which selexipag might cause liver injury is not known. Selexipag is metabolized by the cytochrome P450 system (CYP 2C9 and 3A4), which may lead to production of a toxic intermediate and can also cause drug-drug interactions, particularly with cyclosporine A. One reason for its lack of hepatotoxicity may be that selexipag is administered in relatively low doses of 0.4 to 3.2 mg daily. | The serum enzyme elevations associated with selexipag use have been mild-to-moderate and self-limited in course, often resolving despite drug continuation. There is no reason to believe that there is cross sensitivity to liver injury among the various therapies for PAH.\n\nDrug Class: Pulmonary Arterial Hypertension Agents\n\nOther Drugs in the Class: Ambrisentan, Bosentan, Riociguat, Macitentan; Prostacyclin Analogs, Epoprostenol, Iloprost, Treprostinil | Selexipag – Uptravi® | Pulmonary Arterial Hypertension Agents | null |
EndothelinRcptAntag.nxml | Endothelin Receptor Antagonists | 2017-09-30 | null | null | null | null | null | null | null | null |
Cimetidine.nxml | Cimetidine | 2018-01-25 | Cimetidine is a histamine type 2 receptor antagonist (H2 blocker) which is widely used for treatment of acid-peptic disease and heartburn. Cimetidine has been linked to rare instances of clinically apparent acute liver injury. | Cimetidine (sye met' i deen) was the first H2 blocker introduced into clinical practice in the United States and remains a commonly used agent for treatment of duodenal and gastric ulcer and gastroesophageal reflux disease. The H2 blockers are specific antagonists of the histamine type 2 receptor, which is found on the basolateral (antiluminal) membrane of gastric parietal cells. The binding of cimetidine to the H2 receptor results in inhibition of acid production and secretion, and improvement in symptoms and signs of acid-peptic disease. The H2 blockers inhibit an early, “upstream” step in gastric acid production and are less potent that the proton pump inhibitors, which inhibit the final common step in acid secretion. Nevertheless, the H2 blockers inhibit 24 hour gastric acid production by about 70% and are most effective in blocking basal and nocturnal acid production. Cimetidine was first approved for use in the United States in 1977 and is still used widely both by prescription and in over-the-counter forms. The listed indications for cimetidine include duodenal and gastric ulcer disease, gastroesophageal reflux and prevention of stress ulcers. Cimetidine is available by prescription in tablets of 200, 300, 400 and 800 mg in several generic forms and in both oral and parenteral forms under the brand name Tagamet. Over-the-counter preparations are usually tablets of 200 mg. The typical recommended dose of cimetidine for peptic ulcer disease in adults is 300 to 400 mg twice daily or 800 mg at night for up to 8 weeks, and maintenance doses of 400 mg once daily. Lower chronic or intermittent doses are commonly used to treat heartburn and indigestion. Side effects are uncommon, usually minor, and include diarrhea, constipation, fatigue, drowsiness, headache and muscle aches. Cimetidine is metabolized by and can inhibit several isoforms of the hepatic cytochrome P450 system (CYP 1A2, 2C9 and 2D6), which can result in significant drug-drug interactions if administered with agents that rely upon their metabolism by these microsomal enzymes (such as digoxin, warfarin, oral contraceptives, isoniazid and phenytoin). | Chronic therapy with cimetidine has been associated with minor elevations in serum aminotransferase levels in 1% to 4% of patients, but similar rates were reported in placebo recipients. The ALT elevations were usually asymptomatic and transient and usually resolved even without dose modification. Several instances of clinically apparent liver injury have been reported in patients receiving cimetidine, but the time to onset and pattern of injury has varied greatly. Onset can be as short as a few days to as long as 7 months, and the serum enzyme pattern varies from hepatocellular to cholestatic, most cases having a “mixed” hepatocellular-cholestatic pattern of injury (Cases 1 and 2). The injury is rarely severe and resolves within 4 to 12 weeks of stopping cimetidine. Liver biopsy histology often shows prominent centrolobular necrosis. Immunoallergic features (rash, fever, eosinophilia) are uncommon, as is autoantibody formation.\n\nLikelihood score: B (highly likely cause of clinically apparent liver injury). | Cimetidine is metabolized by and inhibits the function of the microsomal P450 drug metabolizing enzymes, and injury may be the result of its activation to a toxic intermediate. Rapid recurrence with rechallenge is typical, but features of hypersensitivity are uncommon. | The hepatic injury caused by cimetidine is usually rapidly reversible with stopping the medication (Case 1). Cimetidine has not been definitively linked to cases of acute liver failure, but there has been at least one case of prolonged cholestasis with probable vanishing bile duct syndrome after an episode of cholestatic hepatitis attributed to cimetidine. Rechallenge usually causes recurrence which can be more severe than the initial episode. There appears to be little cross susceptibility to hepatic injury between ranitidine and cimetidine, but instances have been reported of recurrence after famotidine (Case 2). If acid suppression is required, use of an unrelated proton pump inhibitor is probably prudent for patients with clinically apparent cimetidine induced liver injury.\n\nThe H2 receptor blockers include cimetidine, famotidine, nizatidine, and ranitidine. General references on all four agents are given together after the overview section on H2 Blockers, while specific references are given with the description of each drug. See also the Proton Pump Inhibitors.\n\nDrug Class: Antiulcer Agents\n\nOther Drugs in the Subclass, Histamine Type 2 Receptor Antagonists/H2 Blockers: Famotidine, Nizatidine, Ranitidine | Cimetidine – Generic, Tagamet® | Antiulcer Agents | null |
Anifrolumab.nxml | Anifrolumab | 2023-09-20 | Anifrolumab is a human monoclonal antibody to the type 1 interferon receptor which is used in the therapy of moderate-to-severe systemic lupus erythematous. Anifrolumab has been linked to a low incidence of transient serum enzyme elevations during therapy and has not been linked to instances of clinically apparent liver injury. | Anifrolumab (an” i frol’ ue mab) is a human monoclonal IgG1 antibody to the type 1 interferon (IFN) receptor subunit 1 which is used to treat adults with moderate-to-severe systemic lupus erythematosus (SLE). Anifrolumab binds to type 1 interferon receptors blocking their activation and induction of interferon related genes. This monoclonal antibody has been shown to be effective in reducing disease activity in patients with systemic lupus erythematosus, a disease marked by elevated levels of soluble interferon gene induced proteins with immune dysregulation and production of pathogenic autoantibodies and immune complexes. Anifrolumab was approved for use in the United States in 2021 and current indications are for treatment of adult patients with active, autoantibody positive systemic lupus erythematosus (SLE) who are receiving standard therapy. Its beneficial effects have not been demonstrated in patients with severe lupus nephritis or central nervous system involvement. Anifrolumab is available under the brand name Saphnelo in single dose vials of 300 mg in 2 mL. The recommended dose is 300 mg given as an intravenous infusion (over 30 minutes) every 4 weeks. Adverse effects include infusion reactions, upper respiratory symptoms and infections, bronchitis, cough, and herpes zoster. Rare but potentially serious side effects include severe hypersensitivity reactions (angioedema or anaphylaxis), severe infections, and possibly malignancies. The potential of reactivation of latent infections such as tuberculosis and hepatitis B from anifrolumab is not clear. Patients receiving anifrolumab should not receive live viral vaccines. | In preregistration controlled trials, elevations in serum aminotransferase levels were uncommon (less than 1%) and no more frequent during anifrolumab than with placebo therapy. Elevations in aminotransferase levels above 5 times the ULN were less common on anifrolumab than placebo therapy, and there were no reports of clinically apparent liver injury attributed to anifrolumab. Since its approval and more widescale use, there have been no case reports of liver injury with jaundice linked to anifrolumab therapy. Reactivation of hepatitis B as well as immune-mediated hepatitis can occur with use of immunosuppressive monoclonal antibodies such as infliximab and adalimumab, but instances have not been reported with anifrolumab.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury). | There is little evidence that anifrolumab is a cause of liver injury, and mechanisms by which it occurs is not clear but might result from immune modulation. | The serum aminotransferase elevations that have been reported during anifrolumab therapy were generally transient, mild and asymptomatic and did not require dose modification or delay in therapy. Elevations above 5 times the upper limit of normal should lead to more careful monitoring and suspension of further infusions, at least until levels return to normal or near normal levels. There is no evidence of cross sensitivity to hepatic reactions among the various monoclonal antibodies.\n\nDrug Class: Monoclonal Antibodies, Immunosuppressive Agents\n\nOther Drugs for Systemic Lupus Erythematosus: Belimumab | Anifrolumab – Saphnelo® | Immunosuppressive Agents | null |
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