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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Name of the medicinal product
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
2.
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Qualitative and quantitative composition
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Each tablet contains 2.5 mg of saxagliptin (as hydrochloride) and 1,000 mg of metformin hydrochloride.
For the full list of excipients, see section 6.1.
3.
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Pharmaceutical form
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Film-coated tablet (tablet).
Pale yellow to light yellow, biconvex, oval shaped, film-coated tablets, with "2.5/1000" printed on one side and "4247" printed on the other side, in blue ink.
4.
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Clinical particulars - Therapeutic indications
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Therapeutic indications
Komboglyze is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:
• in patients inadequately controlled on their maximally tolerated dose of metformin alone
• in combination with other medicinal products for the treatment of diabetes, including insulin, in patients inadequately controlled with metformin and these medicinal products (see sections 4.4, 4.5 and 5.1 for available data on different combinations)
• in patients already being treated with the combination of saxagliptin and metformin as separate tablets.
4.2
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Clinical particulars - Posology and method of administration
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Posology and method of administration
Posology
Adults with normal renal function (GFR ≥ 90 mL/min)
For patients inadequately controlled on maximal tolerated dose of metformin monotherapy
Patients not adequately controlled on metformin alone should receive a dose of this medicinal product equivalent to the total daily dose of saxagliptin 5 mg, dosed as 2.5 mg twice daily, plus the dose of metformin already being taken.
For patients switching from separate tablets of saxagliptin and metformin
Patients switching from separate tablets of saxagliptin and metformin should receive the doses of saxagliptin and metformin already being taken.
For patients inadequately controlled on dual combination therapy of insulin and metformin, or for patients controlled on triple combination therapy of insulin, and metformin plus saxagliptin as separate tablets
The dose of this medicinal product should provide saxagliptin 2.5 mg twice daily (5 mg total daily dose) and a dose of metformin similar to the dose already being taken. When this medicinal product is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia (see section 4.4).
For patients inadequately controlled on dual combination therapy of a sulphonylurea and metformin, or for patients switching from triple combination therapy of saxagliptin, metformin and a sulphonylurea taken as separate tablets
The dose of this medicinal product should provide saxagliptin 2.5 mg twice daily (5 mg total daily dose), and a dose of metformin similar to the dose already being taken. When this medicinal product is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be required to reduce the risk of hypoglycaemia (see section 4.4).
For patients inadequately controlled on dual combination therapy of dapagliflozin and metformin, or for patients switching from triple combination therapy of saxagliptin, metformin and dapagliflozin taken as separate tablets
The dose of this medicinal product should provide saxagliptin 2.5 mg twice daily (5 mg total daily dose), and a dose of metformin similar to the dose already being taken.
Special populations
Renal impairment
No dose adjustment is recommended for patients with mild renal impairment (GFR 60-89 mL/min).
A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months. The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis (see section 4.4) should be reviewed before considering initiation of Komboglyze in patients with GFR < 60 mL/min.
If no adequate strength of Komboglyze is available, individual monocomponents should be used instead of the fixed dose combination.
Table 1 Dosage in patients with renal impairment
GFR mL/min
Metformin
Saxagliptin
60-89
Maximum daily dose is 3000 mg.
Dose reduction may be considered in relation to declining renal function.
Maximum total daily dose is 5 mg.
45-59
Maximum daily dose is 2000 mg.
The starting dose is at most half of the maximum dose.
Maximum total daily dose is 5 mg.
30-44
Maximum daily dose is 1000 mg.
The starting dose is at most half of the maximum dose.
Maximum total daily dose is 2.5 mg.
<30
Metformin is contraindicated.
Maximum total daily dose is 2.5 mg.
Hepatic impairment
This medicinal product must not be used in patients with hepatic impairment (see sections 4.3 and 4.5).
Elderly (≥ 65 years)
As metformin and saxagliptin are excreted by the kidney, this medicinal product should be used with caution in the elderly. Monitoring of renal function is necessary to prevent metformin-associated lactic acidosis, particularly in the elderly (see sections 4.3, 4.4 and 5.2).
Paediatric population
The safety and efficacy of this medicinal product in children and adolescents from birth to < 18 years of age have not been established. No data are available.
Method of administration
Komboglyze should be given twice daily with meals to reduce the gastrointestinal adverse reactions associated with metformin.
4.3
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Clinical particulars - Contraindications
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Contraindications
- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or history of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock, and angioedema, to any dipeptidyl peptidase 4 (DPP4) inhibitor (see sections 4.4 and 4.8);
- Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis);
- Diabetic pre-coma;
- Severe renal failure (GFR < 30 mL/min) (see sections 4.2, 4.4 and 5.2);
- Acute conditions with the potential to alter renal function such as:
- dehydration,
- severe infection,
- shock;
- Acute or chronic disease which may cause tissue hypoxia such as:
- cardiac or respiratory failure,
- recent myocardial infarction,
- shock;
- Hepatic impairment (see sections 4.2 and 4.5);
- Acute alcohol intoxication, alcoholism (see section 4.5);
- Breast-feeding (see section 4.6).
4.4
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Clinical particulars - Special warnings and precautions for use
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Special warnings and precautions for use
General
Komboglyze should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Acute pancreatitis
Use of DPP4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis; persistent, severe abdominal pain. If pancreatitis is suspected, this medicinal product should be discontinued; if acute pancreatitis is confirmed, this medicinal product should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
In postmarketing experience of saxagliptin, there have been spontaneously reported adverse reactions of acute pancreatitis.
Lactic acidosis
Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.
In case of dehydration (severe diarrhoea or vomiting, fever, heat, reduced fluid intake), Komboglyze should be temporarily discontinued and contact with a health care professional is recommended.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).
Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking Komboglyze and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio.
Renal function
As metformin is excreted by the kidney, renal function should be assessed:
- Before initiation of treatment and regularly thereafter (see sections 4.2, 4.8, 5.1 and 5.2).
- For renal function with GFR levels approaching moderate renal impairment and in elderly patients, at least 2 to 4 times per year.
- In patients with moderate renal impairment that have GFR ≥ 30 to < 45 mL/min, in the absence of other conditions that may increase the risk of lactic acidosis, the dose is 2.5 mg/1000 mg or 2.5 mg/850 mg once daily. It is not recommended to initiate treatment in these patients. Treatment may be continued in the well-informed patients with close monitoring.
- Metformin is contraindicated in patients with a GFR < 30 mL/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy or when starting treatment with a NSAID.
Surgery
Komboglyze must be discontinued at the time of surgery with general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition provided that renal function has been re-evaluated and found to be stable.
Administration of iodinated contrast agents
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and increased risk of lactic acidosis. Komboglyze should be discontinued prior to, or at the time of, the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.5).
Skin disorders
Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical toxicology studies for saxagliptin (see section 5.3). Skin lesions were not observed at an increased incidence in clinical trials. Postmarketing reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an adverse event (AE) for saxagliptin (see section 4.8). Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering, ulceration or rash, is recommended.
Bullous pemphigoid
Postmarketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP4 inhibitor use, including saxagliptin. In reported cases, patients typically responded to topical or systemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. If a patient develops blisters or erosions while receiving saxagliptin and bullous pemphigoid is suspected, this medicinal product should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment (see section 4.8).
Hypersensitivity reactions
As this medicinal product contains saxagliptin, it should not be used in patients who have had any serious hypersensitivity reaction to a dipeptidyl peptidase 4 (DPP4) inhibitor.
During postmarketing experience, including spontaneous reports and clinical trials, the following adverse reactions have been reported with the use of saxagliptin: serious hypersensitivity reactions, including anaphylactic reaction, anaphylactic shock, and angioedema. If a serious hypersensitivity reaction to saxagliptin is suspected, discontinue this medicinal product, assess for other potential causes for the event, and institute alternative treatment for diabetes (see sections 4.3 and 4.8).
Change in clinical status of patients with previously controlled type 2 diabetes
As this medicinal product contains metformin, a patient with type 2 diabetes previously well controlled on Komboglyze who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, this medicinal product must be stopped immediately and other appropriate corrective measures initiated.
Cardiac failure
In the SAVOR trial a small increase in the rate for hospitalisation for heart failure was observed in the saxagliptin treated patients compared to placebo, although a causal relationship has not been established (see section 5.1). Caution is warranted if this medicinal product is used in patients who have known risk factors for hospitalisation for heart failure, such as a history of heart failure or moderate to severe renal impairment. Patients should be advised of the characteristic symptoms of heart failure, and to immediately report such symptoms.
Arthralgia
Joint pain, which may be severe, has been reported in postmarketing reports for DPP4 inhibitors (see section 4.8). Patients experienced relief of symptoms after discontinuation of the medicinal product and some experienced recurrence of symptoms with reintroduction of the same or another DPP4 inhibitor. Onset of symptoms following initiation of drug therapy may be rapid or may occur after longer periods of treatment. If a patient presents with severe joint pain, continuation of drug therapy should be individually assessed.
Immunocompromised patients
Immunocompromised patients, such as patients who have undergone organ transplantation or patients diagnosed with human immunodeficiency syndrome, have not been studied in the saxagliptin clinical program. Therefore, the efficacy and safety profile of saxagliptin in these patients has not been established.
Use with potent CYP3A4 inducers
Using CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, and rifampicin may reduce the glycaemic lowering effect of saxagliptin (see section 4.5).
Use with medicinal products known to cause hypoglycaemia
Insulin and sulphonylureas are known to cause hypoglycaemia. Therefore, a lower dose of insulin or sulphonylurea may be required to reduce the risk of hypoglycaemia when used in combination with Komboglyze.
4.5
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Clinical particulars - Interaction with other medicinal products and other forms of interaction
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Interaction with other medicinal products and other forms of interaction
Co-administration of multiple doses of saxagliptin (2.5 mg twice daily) and metformin (1,000 mg twice daily) did not meaningfully alter the pharmacokinetics of either saxagliptin or metformin in patients with type 2 diabetes.
There have been no formal interaction studies for Komboglyze. The following statements reflect the information available on the individual active substances.
Saxagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions with co-administered medicinal products is low.
The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). In in vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4. In studies conducted in healthy subjects, neither the pharmacokinetics of saxagliptin nor its major metabolite, were meaningfully altered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids or famotidine. In addition, saxagliptin did not meaningfully alter the pharmacokinetics of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, the active components of a combined oral contraceptive (ethinyl estradiol and norgestimate), diltiazem or ketoconazole.
Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem, increased the Cmax and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the corresponding values for the active metabolite were decreased by 44% and 34%, respectively.
Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole, increased the Cmax and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the corresponding values for the active metabolite were decreased by 95% and 88%, respectively.
Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin, reduced Cmax and AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the plasma DPP4 activity inhibition over a dose interval were not influenced by rifampicin (see section 4.4).
The co-administration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such as carbamazepine, dexamethasone, phenobarbital and phenytoin) have not been studied and may result in decreased plasma concentration of saxagliptin and increased concentration of its major metabolite. Glycaemic control should be carefully assessed when saxagliptin is used concomitantly with a potent CYP3A4 inducer.
The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of saxagliptin have not been specifically studied.
Metformin
Concomitant use not recommended
Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased metformin systemic exposure (AUC) by 50% and Cmax by 81%. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are co-administered.
Alcohol
Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in the case of fasting, malnutrition or hepatic impairment due to the metformin active substance of Komboglyze (see section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.
Iodinated contrast agents
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and increased risk of lactic acidosis. Komboglyze must be discontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.4).
Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes), beta-2 agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring perfomed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.
Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.
4.6
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Clinical particulars - Fertility, pregnancy and lactation
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Fertility, pregnancy and lactation
Pregnancy
The use of Komboglyze or saxagliptin has not been studied in pregnant women. Studies in animals have shown reproductive toxicity at high doses of saxagliptin alone or in combination with metformin (see section 5.3). The potential risk for humans is unknown. A limited amount of data suggest the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development (see section 5.3). This medicinal product should not be used during pregnancy. If the patient wishes to become pregnant, or if a pregnancy occurs, treatment with this medicinal product should be discontinued and switched to insulin treatment as soon as possible.
Breast-feeding
Studies in animals have shown excretion of both saxagliptin and/or metabolite and metformin in milk. It is unknown whether saxagliptin is excreted in human milk, but metformin is excreted in human milk in small amounts. This medicinal product must therefore not be used in women who are breast-feeding (see section 4.3).
Fertility
The effect of saxagliptin on fertility in humans has not been studied. Effects on fertility were observed in male and female rats at high doses producing overt signs of toxicity (see section 5.3). For metformin, studies in animals have not shown reproductive toxicity (see section 5.3).
4.7
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Clinical particulars - Effects on ability to drive and use machines
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Effects on ability to drive and use machines
Saxagliptin or metformin has a negligible influence on the ability to drive and use machines. When driving or using machines, it should be taken into account that dizziness has been reported in studies with saxagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when Komboglyze is used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. insulin, sulphonylureas).
4.8
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Clinical particulars - Undesirable effects
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Undesirable effects
There have been no therapeutic clinical trials conducted with Komboglyze tablets, however, bioequivalence of Komboglyze with co-administered saxagliptin and metformin has been demonstrated (see section 5.2).
Saxagliptin
Summary of the safety profile
There were 4,148 patients with type 2 diabetes, including 3,021 patients treated with saxagliptin, randomised in six double-blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control. In randomised, controlled, double-blind clinical trials (including developmental and postmarketing experience), over 17,000 patients with type 2 diabetes have been treated with saxagliptin.
In a pooled analysis of 1,681 patients with type 2 diabetes including 882 patients treated with saxagliptin 5 mg, randomised in five double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control, the overall incidence of AEs in patients treated with saxagliptin 5 mg was similar to placebo. Discontinuation of therapy due to AEs was higher in patients who received saxagliptin 5 mg as compared to placebo (3.3% as compared to 1.8%).
Tabulated list of adverse reactions
Adverse reactions reported in ≥ 5% of patients treated with saxagliptin 5 mg and more commonly than in patients treated with placebo or that were reported in ≥ 2% of patients treated with saxagliptin 5 mg and ≥ 1% more frequently compared to placebo are shown in Table 2.
The adverse reactions are listed by system organ class and absolute frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to 1/100), rare (≥ 1/10,000 to 1/1,000), or very rare (< 1/10,000), not known (cannot be estimated from the available data).
Table 2 Frequency of adverse reactions by system organ class
System organ class
Adverse reaction
Frequency of adverse reactions by treatment regimen
Saxagliptin with metformin1
Infections and infestations
Upper respiratory infection
Common
Urinary tract infection
Common
Gastroenteritis
Common
Sinusitis
Common
Nasopharyngitis
Common2
Nervous system disorders
Headache
Common
Gastrointestinal disorders
Vomiting
Common
1Includes saxagliptin in add-on to metformin and initial combination with metformin.
2Only in the initial combination therapy.
Postmarketing experience from clinical trials and spontaneous reports
Table 3 shows additional adverse reactions which have been reported in postmarketing experience with saxagliptin. The frequencies are based on the experience from clinical trials.
Table 3 Frequency of additional adverse reactions by system organ class
System organ class
Adverse Reaction
Frequency of adverse reactions1
Gastrointestinal disorders
Nausea
Common
Pancreatitis
Uncommon
Constipation
Not known
Immune system disorders
Hypersensitivity reactions2 (see sections 4.3 and 4.4)
Uncommon
Anaphylactic reactions including anaphylactic shock (see sections 4.3 and 4.4)
Rare
Skin and subcutaneous tissue disorders
Angioedema (see sections 4.3 and 4.4)
Rare
Dermatitis
Uncommon
Pruritus
Uncommon
Rash2
Common
Urticaria
Uncommon
Bullous pemphigoid
Not known
1 Frequency estimates are based on the pooled analysis of the saxagliptin monotherapy, add-on to metformin and initial combination with metformin, add-on to sulphonylurea and add-on to thiazolidinedione clinical trials.
2 These reactions were also identified in the pre-approval clinical trials, but do not meet the criteria for Table 2.
SAVOR trial results
The SAVOR trial included 8240 patients treated with saxagliptin 5 mg or 2.5 mg once daily and 8173 patients on placebo. The overall incidence of AEs in patients treated with saxagliptin in this trial was similar to placebo (72.5% versus 72.2%, respectively).
The incidence of adjudicated pancreatitis events was 0.3% in both saxagliptin-treated patients and placebo-treated patients in the intent-to-treat population.
The incidence of hypersensitivity reactions was 1.1% in both saxagliptin-treated patients and placebo-treated patients.
The overall incidence of reported hypoglycaemia (recorded in daily patient diaries) was 17.1% in subjects treated with saxagliptin and 14.8% among patients treated with placebo. The percent of subjects with reported on-treatment events of major hypoglycaemia (defined as an event that required assistance of another person) was higher in the saxagliptin group than in the placebo group (2.1% and 1.6%, respectively). The increased risk of overall hypoglycaemia and major hypoglycaemia observed in the saxagliptin-treated group occurred primarily in subjects treated with SU at baseline and not in subjects on insulin or metformin monotherapy at baseline. The increased risk of overall and major hypoglycaemia was primarily observed in subjects with A1C < 7% at baseline.
Decreased lymphocyte counts were reported in 0.5% of saxagliptin-treated patients and 0.4% of placebo-treated patients.
Hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominal statistical significance favouring placebo [HR = 1.27; 95% CI 1.07, 1.51); P = 0.007]. See also section 5.1.
Description of selected adverse reactions
AEs, considered by the investigator to be at least possibly drug-related and reported in at least two more patients treated with saxagliptin 5 mg compared to control, are described below by treatment regimen.
As monotherapy: dizziness (common) and fatigue (common).
As add-on to metformin: dyspepsia (common) and myalgia (common).
As initial combination with metformin: gastritis (common), arthralgia* (uncommon), myalgia (uncommon), and erectile dysfunction (uncommon).
As add-on to metformin and a sulphonylurea: dizziness (common), fatigue (common) and flatulence (common).
*Arthralgia has also been reported during postmarketing surveillance (see section 4.4).
Hypoglycaemia
Adverse reactions of hypoglycaemia were based on all reports of hypoglycaemia; a concurrent glucose measurement was not required. The incidence of reported hypoglycaemia for saxagliptin 5 mg versus placebo given as add-on therapy to metformin was 5.8% versus 5%. The incidence of reported hypoglycaemia was 3.4% in treatment-naive patients given saxagliptin 5 mg plus metformin and 4.0% in patients given metformin alone. When used as add-on to insulin (with or without metformin), the overall incidence of reported hypoglycaemia was 18.4% for saxagliptin 5 mg and 19.9% for placebo.
When used as add-on to metformin plus a sulphonylurea, the overall incidence of reported hypoglycaemia was 10.1 % for saxagliptin 5 mg and 6.3% for placebo.
Investigations
Across clinical studies, the incidence of laboratory AEs was similar in patients treated with saxagliptin 5 mg compared to patients treated with placebo. A small decrease in absolute lymphocyte count was observed. From a baseline mean absolute lymphocyte count of approximately 2,200 cells/μL, a mean decrease of approximately 100 cells/μL relative to placebo was observed in the placebo-controlled pooled analysis. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The clinical significance of this decrease in lymphocyte count relative to placebo is not known.
Metformin
Clinical trial data and postmarketing data
Table 4 presents adverse reactions by system organ class and by frequency category. Frequency categories are based on information available from metformin Summary of Product Characteristics available in the European Union.
Table 4 The frequency of metformin adverse reactions identified from clinical trial and postmarketing data
System organ class
Adverse reaction
Frequency
Metabolism and nutrition disorders
Lactic acidosis
Very rare
Vitamin B12 deficiency1
Very rare
Nervous system disorders
Metallic taste
Common
Gastrointestinal disorders
Gastrointestinal symptoms2
Very common
Hepatobiliary disorders
Liver function disorders, hepatitis
Very rare
Skin and subcutaneous tissue disorders
Urticaria, erythema, pruritus
Very rare
1 Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic anaemia).
2 Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Clinical particulars - Overdose
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Overdose
No data are available with regard to overdose of Komboglyze.
Saxagliptin
Saxagliptin has been shown to be well-tolerated with no clinically meaningful effect on QTc interval or heart rate at oral doses up to 400 mg daily for 2 weeks (80 times the recommended dose). In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. Saxagliptin and its major metabolite can be removed by haemodialysis (23% of dose over 4 hours).
Metformin
High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis.
5. Pharmacological properties
5.1
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Komboglyze 2.5 mg/1,000 mg film-coated tablets
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Pharmacodynamic properties - Pharmacodynamic properties
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Pharmacokinetic properties
The results of bioequivalence studies in healthy subjects demonstrated that Komboglyze combination tablets are bioequivalent to co-administration of corresponding doses of saxagliptin and metformin hydrochloride as individual tablets.
The following statements reflect the pharmacokinetic properties of the individual active substances of Komboglyze.
Saxagliptin
The pharmacokinetics of saxagliptin and its major metabolite were similar in healthy subjects and in patients with type 2 diabetes.
Absorption
Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and 4 hours (Tmax), respectively. The Cmax and AUC values of saxagliptin and its major metabolite increased proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its major metabolite were 78 ng·h/mL and 214 ng·h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The intra-subject coefficients of variation for saxagliptin Cmax and AUC were less than 12%.
The inhibition of plasma DPP4 activity by saxagliptin for at least 24 hours after oral administration of saxagliptin is due to high potency, high affinity, and extended binding to the active site.
Interaction with food
Food had relatively modest effects on the pharmacokinetics of saxagliptin in healthy subjects. Administration with food (a high-fat meal) resulted in no change in saxagliptin Cmax and a 27% increase in AUC compared with the fasted state. The time for saxagliptin to reach Cmax (Tmax) was increased by approximately 0.5 hours with food compared with the fasted state. These changes were not considered to be clinically meaningful.
Distribution
The in vitro protein binding of saxagliptin and its major metabolite in human serum is negligible. Thus, changes in blood protein levels in various disease states (e.g. renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.
Biotransformation
The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a selective, reversible, competitive DPP4 inhibitor, half as potent as saxagliptin.
Elimination
The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metabolite are 2.5 hours and 3.1 hours respectively, and the mean t1/2 value for plasma DPP4 inhibition was 26.9 hours. Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its major metabolite, and total radioactivity respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. For the major metabolite, renal clearance values were comparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivity was recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed medicinal product from the gastrointestinal tract.
Linearity
The Cmax and AUC of saxagliptin and its major metabolite increased proportionally to the saxagliptin dose. No appreciable accumulation of either saxagliptin or its major metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence was observed in the clearance of saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg.
Special populations
Renal impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a 10 mg oral dose of saxagliptin in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (approximately GFR ≥ 45 to < 90 mL/min), moderate (approximately GFR ≥ 30 to < 45 mL/min), or severe (approximately GFR < 30mL/min) renal impairment. The exposures to saxagliptin were 1.2-, 1.4- and 2.1-fold higher, respectively, and the exposures to BMS-510849 were 1.7-, 2.9-, and 4.5-fold higher, respectively, than those observed in subjects with normal renal function.
Hepatic impairment
In subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment the exposures to saxagliptin were 1.1-, 1.4- and 1.8-fold higher, respectively, and the exposures to BMS-510849 were 22%, 7%, and 33% lower, respectively, than those observed in healthy subjects.
Elderly (≥ 65 years)
Elderly patients (65-80 years) had about 60% higher saxagliptin AUC than young patients (18-40 years). This is not considered clinically meaningful, therefore, no dose adjustment for this medicinal product is recommended on the basis of age alone.
Metformin
Absorption
After an oral dose of metformin, tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady-state plasma concentrations are reached within 24-48 h and are generally less than 1 μg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 μg/mL, even at maximum doses.
Interaction with food
Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min prolongation of time to peak plasma concentration was observed. The clinical relevance of this decrease is unknown.
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean Vd ranged between 63-276 L.
Biotransformation
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination
Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
5.3
|
Komboglyze 2.5 mg/1,000 mg film-coated tablets
|
Pharmacodynamic properties - Pharmacokinetic properties
|
Preclinical safety data
Co-administration of saxagliptin and metformin
A 3-month dog study and embryo-foetal development studies in rats and rabbits have been conducted with the combination of saxagliptin and metformin.
Co-administration of saxagliptin and metformin, to pregnant rats and rabbits during the period of organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses yielding systemic exposures (AUC) up to 100 and 10 times the maximum recommended human doses (RHD; 5 mg saxagliptin and 2000 mg metformin), respectively, in rats; and 249 and 1.1 times the RHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of delayed ossification (“wavy ribs”); associated maternal toxicity was limited to weight decrements of 5-6% over the course of gestation days 13 through 18, and related reductions in maternal food consumption. In rabbits, co-administration was poorly tolerated in many mothers, resulting in death, moribundity or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29; and associated developmental toxicity in these litters was limited to foetal body weight decrements of 7%, and a low incidence of delayed ossification of the foetal hyoid.
A 3-month dog study was conducted with the combination of saxagliptin and metformin. No combination toxicity was observed at AUC exposures 68 and 1.5 times the RHDs for saxagliptin and metformin, respectively.
No animal studies have been conducted with the combination of products in Komboglyze to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings in the studies with saxagliptin and metformin individually.
Saxagliptin
In cynomolgus monkeys saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) in extremities (tail, digits, scrotum and/or nose) at doses ≥ 3 mg/kg/day. The no effect level (NOEL) for the lesions is 1 and 2 times the human exposure of saxagliptin and the major metabolite respectively, at the recommended human dose (RHD) of 5 mg/day.
The clinical relevance of the skin lesions is not known, however, clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.
Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes and bone marrow with no adverse sequelae have been reported in all species tested at exposures starting from 7 times the RHD.
Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces and enteropathy at higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and the major metabolite, respectively, at RHD.
Saxagliptin was not genotoxic in a conventional battery of genotoxicity studies in vitro and in vivo. No carcinogenic potential was observed in two-year carcinogenicity assays with mice and rats.
Effects on fertility were observed in male and female rats at high doses producing overt signs of toxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats, saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis and decreased foetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the human exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects of saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL 158 and 224 times the human exposure for saxagliptin and the major metabolite, respectively at RHD). In a pre- and post-natal developmental study in rats, saxagliptin caused decreased pup weight at maternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and the major metabolite, respectively at RHD. The effect on offspring body weights were noted until postnatal day 92 and 120 in females and males, respectively.
Metformin
Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
6.
|
Komboglyze 2.5 mg/1,000 mg film-coated tablets
|
Pharmaceutical particulars - List of excipients
|
List of excipients
Tablet core
Povidone K30
Magnesium stearate
Film coating
Polyvinyl alcohol
Macrogol 3350
Titanium dioxide (E171)
Talc (E553b)
Iron oxide yellow (E172)
Printing ink
Shellac
Indigo carmine aluminium lake (E132)
6.2
|
Komboglyze 2.5 mg/1,000 mg film-coated tablets
|
Pharmaceutical particulars - Incompatibilities
|
Incompatibilities
Not applicable.
6.3
|
Komboglyze 2.5 mg/1,000 mg film-coated tablets
|
Pharmaceutical particulars - Shelf life
|
Shelf life
3 years
6.4
|
Komboglyze 2.5 mg/1,000 mg film-coated tablets
|
Pharmaceutical particulars - Special precautions for storage
|
Special precautions for storage
Store below 25°C.
6.5
|
Komboglyze 2.5 mg/1,000 mg film-coated tablets
|
Pharmaceutical particulars - Nature and contents of container
|
Nature and contents of container
Alu/Alu blister.
Pack-sizes of 14, 28, 56 and 60 film-coated tablets in non-perforated blisters.
Multipacks containing 112 (2 packs of 56) and 196 (7 packs of 28) film-coated tablets in non-perforated blisters.
60x1 film-coated tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.
6.6
|
Komboglyze 2.5 mg/1,000 mg film-coated tablets
|
Pharmaceutical particulars - Special precautions for disposal and other handling
|
Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.
|
Komboglyze 2.5 mg/1,000 mg film-coated tablets
|
Marketing authorisation holder
|
AstraZeneca UK Limited
1 Francis Crick Avenue,
Cambridge,
CB2 0AA,
UK.
8. Marketing authorisation number(s)
PLGB 17901/0329
9.
|
Komboglyze 2.5 mg/1,000 mg film-coated tablets
|
Date of first authorisation/renewal of the authorisation
|
1st January 2021
10.
|
Komboglyze 2.5 mg/1,000 mg film-coated tablets
|
Date of revision of the text
|
02 February 2023
|
Konakion MM 10 mg/ml
|
Name of the medicinal product
|
Konakion MM Ampoules 10 mg/ml solution for injection
Phytomenadione 10 mg/1 ml solution for injection
2.
|
Konakion MM 10 mg/ml
|
Qualitative and quantitative composition
|
Each ampoule contains 10 mg vitamin K1 (phytomenadione) in 1 ml.
3.
|
Konakion MM 10 mg/ml
|
Pharmaceutical form
|
Solution for injection.
Amber glass ampoules containing 10 mg phytomenadione in 1 ml. The ampoule solution is clear to slightly opalescent, pale yellow in colour and contains the active constituent in a mixed micelles vehicle of glycocholic acid and lecithin.
4.
|
Konakion MM 10 mg/ml
|
Clinical particulars - Therapeutic indications
|
Therapeutic indications
Konakion MM/Phytomenadione 10 mg/1 ml is indicated as an antidote to anticoagulant drugs of the coumarin type in the treatment of haemorrhage or threatened haemorrhage, associated with a low blood level of prothrombin or factor VII.
4.2
|
Konakion MM 10 mg/ml
|
Clinical particulars - Posology and method of administration
|
Posology and method of administration
Konakion MM/Phytomenadione 10 mg/1 ml is for intravenous injection.
Adults
Severe or life-threatening haemorrhage, e.g. during anticoagulant therapy:
The coumarin anticoagulant should be withdrawn and an intravenous injection of Konakion MM/Phytomenadione 10 mg/1 ml given slowly (over at least 30 seconds) at a dose of 5-10 mg together with prothrombin complex concentrate (PCC). Fresh frozen plasma (FFP) may be used if PCC is not available. The patient's INR should be estimated three hours later and, if the response has been inadequate, the dose should be repeated. Not more than 40 mg of Konakion MM/Phytomenadione 10 mg/1 ml should be given intravenously in 24 hours. Coagulation profiles must be monitored on a daily basis until these have returned to acceptable levels; in severe cases more frequent monitoring is necessary.
Dose recommendations for vitamin K1 therapy in patients with major and life-threatening bleeding:
Anticoagulant
Condition
Intravenous vitamin K1
Concomitant therapy
Warfarin
Major bleeding
5.0 mg
PCC1
Life-threatening bleeding
5.0 to 10.0 mg
PCC1
PCC, prothrombin complex concentrate
1 Fresh frozen plasma (FFP) may be used if PCC is not available
Less severe haemorrhage:
Treatment of asymptomatic patients with elevated INR values depends on factors such as the underlying indication for anticoagulation, INR value, length of time spent outside the therapeutic INR range, patient characteristics (e.g. age, comorbidity, concomitant medication), and the associated risk of major bleeding. The following dose recommendations are provided for therapeutic guidance only:
Dose recommendations for vitamin K1 therapy in patients with asymptomatic high International Normalised ratio (INR) with or without mild haemorrhage:
Anticoagulant
INR
Intravenous vitamin K1
Warfarin
5-9
0.5 to 1.0 mg
>9
1.0 mg
For small doses one or more ampoules of Konakion MM Paediatric/ Phytomenadione 2 mg/0.2 ml solution for injection (same solution) can be used.
Reversal of anticoagulation prior to surgery
Patients who require emergency surgery that can be delayed for 6-12 hours can be given 5 mg intravenous vitamin K1 to reverse the anticoagulant effect. If surgery cannot be delayed, PCC can be given in addition to intravenous vitamin K1 and the INR checked before surgery.
Use with anticoagulants other than warfarin
The dosing recommendations above apply to patients taking warfarin. There are limited data regarding reversal of the effects of other anticoagulants, such as acenocoumarol or phenprocoumon. The half-lives of these anticoagulants are different to warfarin and different doses of vitamin K1 may be required.
Special dosage instructions
Elderly
Elderly patients tend to be more sensitive to reversal of anticoagulation with Konakion MM/Phytomenadione 10 mg/1 ml. The dosage for this patient group should therefore be at the lower end of the ranges recommended.
Instructions for infusion in adults
This medicine is for intravenous injection and should be diluted with 55 ml of 5% glucose before slowly infusing the product. The solution should be freshly prepared and protected from light. Konakion MM/Phytomenadione 10 mg/1 ml solution should not be diluted or mixed with other injectables, but may be injected into the lower part of an infusion apparatus.
Children aged 1 to 18 years
It is advisable that a haematologist is consulted about appropriate investigation and treatment in any child in whom Konakion MM/Phytomenadione 10 mg/1 ml is being considered.
Likely indications for using vitamin K in children are limited and may include:
1. Children with disorders that interfere with absorption of vitamin K (chronic diarrhoea, cystic fibrosis, biliary atresia, hepatitis, coeliac disease).
2. Children with poor nutrition who are receiving broad spectrum antibiotics.
3. Liver disease.
4. Patients receiving anticoagulant therapy with warfarin in whom the INR is increased outside the therapeutic range and therefore are at risk of, or are bleeding, and those with an INR in the therapeutic range who are bleeding.
For patients on warfarin therapy, therapeutic intervention must take into consideration the reason for the child being on warfarin and whether or not anticoagulant therapy has to be continued (e.g. in a child with mechanical heart valve or repeated thromboembolic complications) as vitamin K administration is likely to interfere with anticoagulation with warfarin for 2-3 weeks.
It should be noted that the earliest effect seen with vitamin K treatment is at 4-6 hours and therefore in patients with severe haemorrhage replacement with coagulation factors may be indicated (discuss with haematologist).
Dose of vitamin K
There are few data available regarding use of this medicine in children over 1 year. There have been no dose ranging studies in children with haemorrhage. The optimal dose should therefore be decided by the treating physician according to the indication, clinical situation and weight of the patient. Suggested dosages based on clinical experience are as follows:
Children with major and life-threatening bleeding
A dose of 5 mg vitamin K1 IV is suggested (together with PCC if appropriate, or FFP if PCC is not available).
Children with asymptomatic high International Normalised Ratio (INR) with or without mild haemorrhage
Intravenous vitamin K1 at doses of 30 micrograms/kg have been reported to be effective in reversing asymptomatic high (>8) INR in clinically well children.
The patient's INR should be measured 2 to 6 hours later and if the response has not been adequate, the dose may be repeated. Frequent monitoring of vitamin K dependent clotting factors is essential in these patients.
Neonates and babies
Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml solution for injection should be used in these patients (see separate prescribing information).
4.3
|
Konakion MM 10 mg/ml
|
Clinical particulars - Contraindications
|
Contraindications
Use in patients with a known hypersensitivity to any of the constituents.
This medicine should not be administered intramuscularly because the IM route exhibits depot characteristics and continued release of vitamin K1 would lead to difficulties with the re-institution of anticoagulation therapy. Furthermore, IM injections given to anticoagulated subjects cause a risk of haematoma formation.
4.4
|
Konakion MM 10 mg/ml
|
Clinical particulars - Special warnings and precautions for use
|
Special warnings and precautions for use
When treating patients with severely impaired liver function, it should be borne in mind that one 1 ml ampoule of Konakion MM/Phytomenadione 10 mg/1 ml contains 54.6 mg glycocholic acid and this may have a bilirubin displacing effect. Careful monitoring of the INR is necessary after administration of this medicine in patients with severely impaired liver function.
At the time of use, the ampoule contents should be clear. Following incorrect storage, the contents may become turbid or present a phase separation. In this case the ampoule must no longer be used.
In potentially fatal and severe haemorrhage due to overdosage of coumarin anticoagulants, intravenous injections of Konakion MM/Phytomenadione 10 mg/1 ml must be administered slowly and not more than 40 mg should be given during a period of 24 hours. Konakion MM/Phytomenadione 10 mg/1 ml therapy should be accompanied by a more immediate effective treatment such as transfusion of whole blood or blood clotting factors. When patients with prosthetic heart valves are given transfusions for the treatment of severe or potentially fatal haemorrhage, fresh frozen plasma should be used. The use of vitamin K1 in patients with mechanical heart valves is generally to be avoided, unless there is major bleeding.
Large doses of Konakion MM/Phytomenadione 10 mg/1 ml (not more than 40 mg per day) should be avoided if it is intended to continue with anticoagulant therapy because there is no experience with doses above this maximum of 40 mg per day and higher doses may give rise to unexpected adverse events. Clinical studies have shown a sufficient decrease in the INR with the recommended dosage. If haemorrhage is severe, a transfusion of fresh whole blood may be necessary whilst awaiting the effect of the vitamin K1.
Vitamin K1 is not an antidote to heparin.
4.5
|
Konakion MM 10 mg/ml
|
Clinical particulars - Interaction with other medicinal products and other forms of interaction
|
Interaction with other medicinal products and other forms of interaction
No significant interactions are known other than antagonism of coumarin anticoagulants.
4.6
|
Konakion MM 10 mg/ml
|
Clinical particulars - Fertility, pregnancy and lactation
|
Fertility, pregnancy and lactation
There is no specific evidence regarding the safety of Konakion MM/Phytomenadione 10 mg/1 ml in pregnancy but, as with most drugs, the administration during pregnancy should only occur if the benefits outweigh the risks.
This medicine is not recommended for pregnant women as prophylaxis of vitamin K deficiency bleeding in the newborn.
4.7
|
Konakion MM 10 mg/ml
|
Clinical particulars - Effects on ability to drive and use machines
|
Effects on ability to drive and use machines
None
4.8
|
Konakion MM 10 mg/ml
|
Clinical particulars - Undesirable effects
|
Undesirable effects
There have been reports of anaphylactoid reactions after intravenous injections of this medicine. Very rarely, venous irritation or phlebitis has been reported in association with intravenous administration of Konakion MM/Phytomenadione 10 mg/1 ml mixed micelles solution.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9
|
Konakion MM 10 mg/ml
|
Clinical particulars - Overdose
|
Overdose
Hypervitaminosis of vitamin K1 is unknown.
Reintroduction of anti-coagulation may be affected.
5. Pharmacological properties
5.1
|
Konakion MM 10 mg/ml
|
Pharmacodynamic properties - Pharmacodynamic properties
|
Pharmacokinetic properties
In blood plasma, 90% of vitamin K1 is bound to lipoproteins. Following an intramuscular dose of 10 mg vitamin K, plasma concentrations of 10-20 mcg/l are produced (normal range 0.4-1.2 mcg/l). Systemic availability following intramuscular administration is about 50% and elimination half-life in plasma is approximately 1.5-3 hours.
5.3
|
Konakion MM 10 mg/ml
|
Pharmacodynamic properties - Pharmacokinetic properties
|
Preclinical safety data
None applicable.
6.
|
Konakion MM 10 mg/ml
|
Pharmaceutical particulars - List of excipients
|
List of excipients
Glycocholic acid
Sodium hydroxide
Lecithin (phospholipon 100)
Hydrochloric acid
Water for injection
HSE
Ph. Eur
HSE
Ph. Eur.
Ph. Eur.
6.2
|
Konakion MM 10 mg/ml
|
Pharmaceutical particulars - Incompatibilities
|
Incompatibilities
None
6.3
|
Konakion MM 10 mg/ml
|
Pharmaceutical particulars - Shelf life
|
Shelf life
The recommended shelf-life of Konakion MM/Phytomenadione 10 mg/1 ml is 36 months.
6.4
|
Konakion MM 10 mg/ml
|
Pharmaceutical particulars - Special precautions for storage
|
Special precautions for storage
The recommended maximum storage temperature is 25°C. Do not use if the solution is turbid.
6.5
|
Konakion MM 10 mg/ml
|
Pharmaceutical particulars - Nature and contents of container
|
Nature and contents of container
Konakion MM/Phytomenadione 10 mg/1 ml is supplied in amber glass ampoules containing 10 mg phytomenadione in 1 ml. The ampoule solution is clear to slightly opalescent, pale yellow in colour and contains the active constituent in a mixed micelles vehicle of glycocholic acid and lecithin.
6.6
|
Konakion MM 10 mg/ml
|
Pharmaceutical particulars - Special precautions for disposal and other handling
|
Special precautions for disposal and other handling
See Section 4.2.
7.
|
Konakion MM 10 mg/ml
|
Marketing authorisation holder
|
Neon Healthcare Limited
8 The Chase, John Tate Road,
Hertford, SG13 7NN,
United Kingdom
8. Marketing authorisation number(s)
PL 45043/0040
9.
|
Konakion MM 10 mg/ml
|
Date of first authorisation/renewal of the authorisation
|
08/04/2008
10.
|
Konakion MM 10 mg/ml
|
Date of revision of the text
|
16/11/2021
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Name of the medicinal product
|
Konakion MM Paediatric 2 mg/0.2 ml solution for injection
Phytomenadione 2 mg/0.2 ml solution for injection
2.
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Qualitative and quantitative composition
|
Each ampoule contains 2 mg phytomenadione in 0.2 ml.
For the full list of excipients, see section 6.1.
3.
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Pharmaceutical form
|
Solution for injection.
The ampoule solution is clear to slightly opalescent, pale yellow in colour and contains the active constituent in a mixed micelles vehicle of glycocholic acid and lecithin.
4.
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Clinical particulars - Therapeutic indications
|
Therapeutic indications
Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml is indicated for the prophylaxis and treatment of vitamin K deficiency bleeding (VKDB) in neonates and infants.
Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml can be used, following specialist advice from a haematologist, as an antidote to anticoagulant drugs of the coumarin type in infants and children. For use as an antidote to anticoagulant drugs of the coumarin type in adolescents and adults, refer to Konakion MM Ampoules 10 mg/ml solution for injection or Phytomenadione 10 mg/1 ml solution for injection.
4.2
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Clinical particulars - Posology and method of administration
|
Posology and method of administration
Posology
Prophylaxis of vitamin K deficiency bleeding (VKDB)
Healthy neonates of 36 weeks gestation and older:
Either:
- 1 mg administered by intramuscular injection at birth or soon after birth
or
- 2 mg orally at birth or soon after birth. The oral dose should be followed by a further dose of 2 mg at 4-7 days of age. A further 2 mg oral dose should be given at 1 month after birth. In exclusively formula fed infants the third oral dose can be omitted.
Preterm neonates of less than 36 weeks gestation weighing 2.5 kg or greater, and term neonates at special risk (e.g. prematurity, birth asphyxia, obstructive jaundice, inability to swallow, maternal use of anticoagulants or antiepileptics): 1 mg IM or IV at birth or soon after birth. The amount and frequency of further doses should be based on coagulation status.
Preterm neonates of less than 36 weeks gestation weighing less than 2.5 kg:
0.4 mg/kg (equivalent to 0.04 ml/kg) IM or IV at birth or soon after birth. This parenteral dose should not be exceeded. The amount and frequency of further doses should be based on coagulation status.
There is evidence that oral prophylaxis is insufficient in patients with underlying cholestatic liver disease and malabsorption (see section 5.1).
CAUTION: care is required when calculating and measuring the dose in relation to the baby's weight (10 times dosing errors are common).
Dosing information for preterm babies at birth for the prophylaxis of Vitamin K deficiency bleeding
Weight of the baby
Dose of vitamin K at birth
Injection volume
1 kg
0.4 mg
0.04 ml
1.5 kg
0.6 mg
0.06 ml
2 kg
0.8 mg
0.08 ml
2.5 kg
1 mg
0.1 ml
Over 2.5 kg
1 mg
0.1 ml
Further oral doses in breast-fed infants have been advised, but safety or efficacy data for these additional doses is limited (see section 5.1).
Therapy of early and/or late vitamin K deficiency bleeding (VKDB)
Initially 1 mg IV and further doses as required, depending on clinical picture and coagulation status. Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml therapy may need to be accompanied by a more immediate effective treatment, such as transfusion of blood or blood clotting factors to compensate for severe blood loss and delayed response to vitamin K1.
Antidote therapy to anticoagulant drugs of the coumarin type
There have been no dose ranging studies performed to recommend a specific dose of this medicine as an antidote to anticoagulant drugs of the coumarin type in infants and children. Suggested doses are detailed below. Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml must be administered by intravenous injection in these patients. It is advisable that a haematologist is consulted about appropriate investigation and treatment in any infant or child in whom Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml is being considered.
For patients on warfarin therapy, therapeutic intervention must consider the reason for the patient being on warfarin and whether or not anticoagulant therapy has to be continued (e.g. in a patient with mechanical heart valve or repeated thrombo-embolic complications) as vitamin K administration is likely to interfere with anticoagulation with warfarin for 2-3 weeks. For patients continuing to receive warfarin, the suggested dose for the partial reversal of anticoagulation is 30 micrograms/kg administered by IV injection. Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml is only suitable for the administration of doses of 30 micrograms/kg in children weighing over 13 kg.
The suggested dose of vitamin K for patients requiring a complete reversal of a warfarin overdose is 250-300 micrograms/kg administered by IV injection. It should be noted that the earliest effect seen with vitamin K treatment is at 4 to 6 hours and therefore, in patients with severe haemorrhage, replacement with coagulation factor concentrates may be indicated (discuss with haematologist). Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml is only suitable for the administration of doses of 250-300 micrograms/kg in children weighing over 1.6 kg. Prothrombin time should be measured 2 to 6 hours later and if the response has not been adequate, Konakion MM Paediatric/Phytomenadione 2 mg/0.2ml administration may be repeated. Frequent monitoring of vitamin K dependent clotting factors is essential in these patients.
Method of administration
This medicine can be administered by intramuscular or intravenous injection or by oral administration depending on the indication.
Parenteral use: For the administration of injection volumes of 0.04 ml (0.4 mg) to 0.1 ml (1 mg), 0.5 ml syringes with 0.01 ml graduations are recommended, see section 6.6 Special precautions for disposal and other handling.
Administration of Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml by IV infusion is not recommended because it must not be diluted or mixed with other parenteral medications. However, it may be administered by injecting the dose into the lower part of an infusion set containing 5% dextrose or 0.9% sodium chloride running at ≥ 0.7 ml/minute, see section 6.2 Incompatibilities.
Oral use: For oral administration, oral dispensers are provided in the pack. After breaking the ampoule open, 0.2 ml of solution should be withdrawn into the oral dispenser until it reaches the mark on the dispenser (0.2 ml = 2 mg vitamin K). Drop the contents of the dispenser directly into the baby's mouth by pressing the plunger.
4.3
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Clinical particulars - Contraindications
|
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Clinical particulars - Special warnings and precautions for use
|
Special warnings and precautions for use
At the time of use, the ampoule contents should be clear. Following incorrect storage, the contents may become turbid or present a phase-separation. In this case the ampoule must no longer be used.
Parenteral administration to premature babies weighing less than 2.5 kg may increase the risk for the development of kernicterus (bilirubin encephalopathy).
Infants with cholestatic disease must receive Konakion MM Paediatric/ Phytomenadione 2 mg/0.2 ml by intramuscular or intravenous injection since oral absorption is impaired in these patients.
Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml must be administered by intravenous injection when used as an antidote to anticoagulant drugs of the coumarin type, as intramuscular injections may result in significant bleeding in these patients.
4.5
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Clinical particulars - Interaction with other medicinal products and other forms of interaction
|
Interaction with other medicinal products and other forms of interaction
No significant interactions are known other than antagonism of coumarin anticoagulants.
4.6
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Clinical particulars - Fertility, pregnancy and lactation
|
Fertility, pregnancy and lactation
Not applicable
4.7
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Clinical particulars - Effects on ability to drive and use machines
|
Effects on ability to drive and use machines
Not applicable
4.8
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Clinical particulars - Undesirable effects
|
Undesirable effects
There have been reports of anaphylactoid reactions after intravenous injections of this medicine. Local irritation may occur at the injection site but is unlikely due to the small injection volume. Rarely, injection site reactions may occur which may be severe, including inflammation, atrophy and necrosis.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Clinical particulars - Overdose
|
Overdose
There is no known clinical syndrome attributable to hypervitaminosis of vitamin K1.
The following adverse events have been reported concerning overdose with use of Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml in neonates and infants: jaundice, hyperbilirubinaemia, increase GOT and GGT, abdominal pain, constipation, soft stools, malaise, agitation and cutaneous eruption. The causality of those cannot be established. The majority of these adverse events were considered non-serious and resolved without any treatment.
Treatment of suspected overdose should be aimed at alleviating symptoms.
5. Pharmacological properties
5.1
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Pharmacodynamic properties - Pharmacodynamic properties
|
Pharmacokinetic properties
In the mixed micelle solution, vitamin K1 is solubilised by means of a physiological colloidal system consisting of lecithin and a bile acid.
Following oral administration vitamin K1 is absorbed from the small intestine. The systemic availability following oral dosing is approximately 50%, with a wide range of interindividual variability. Absorption is limited in the absence of bile.
After intramuscular administration vitamin K1 release into the circulation is prolonged, i.e. the IM route acts as a depot. A single 1 mg IM dose results in comparable vitamin K1 concentrations at 1 month as two 2 mg doses (one given at birth and the other at one week).
Vitamin K1 accumulates predominantly in the liver, is up to 90% bound to lipoproteins in the plasma and is stored in the body only for short periods of time.
Vitamin K1 is transformed to more polar metabolites, such as phytomenadione-2,3- epoxide.
The half-life of vitamin K1 in plasma is approximately 72 hours in neonates and about 1.5 to 3 hours in adults. Vitamin K1 is excreted in bile and urine as the glucuronide and sulfate conjugates.
5.3
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Pharmacodynamic properties - Pharmacokinetic properties
|
Preclinical safety data
None applicable
6.
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Pharmaceutical particulars - List of excipients
|
List of excipients
Glycocholic acid, lecithin, sodium hydroxide, hydrochloric acid and water for injections.
6.2
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Pharmaceutical particulars - Incompatibilities
|
Incompatibilities
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Pharmaceutical particulars - Shelf life
|
Incompatibilities have been observed with diluted Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml solution and certain siliconised syringes, therefore, Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml must not be diluted before injection.
Do not dilute with sodium chloride containing solutions as precipitation may occur, see section 4.2 Posology and Method of Administration.
6.3
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Pharmaceutical particulars - Special precautions for storage
|
Shelf life
3 years
6.4
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Pharmaceutical particulars - Nature and contents of container
|
Special precautions for storage
This medicine should be stored below 25 °C and be protected from light. The solution should not be frozen. Do not use if the solution is turbid.
6.5
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Pharmaceutical particulars - Special precautions for disposal and other handling
|
Nature and contents of container
Amber glass ampoules containing 2 mg phytomenadione in 0.2 ml. Plastic oral dispensers. Packs of 5.
6.6
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Pharmaceutical particulars - Subsection 7
|
Special precautions for disposal and other handling
See section 4.2 Posology and method of administration, section 4.4 Special warnings and precautions for use and section 6.2
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Pharmaceutical particulars - Subsection 8
|
Incompatibilities for advice regarding the administration of this medicine.
Undiluted Konakion MM Paediatric/Phytomenadione 2 mg/0.2 ml solution for injection is compatible with 0.5 ml Omnican 50 syringes supplied by B.Braun.
7.
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Marketing authorisation holder
|
Neon Healthcare Limited
8 The Chase, John Tate Road,
Hertford, SG13 7NN,
United Kingdom
8. Marketing authorisation number(s)
PL 45043/0041
9.
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Date of first authorisation/renewal of the authorisation
|
Date of first authorisation: 20 June 1996
Date of latest renewal: 11 March 2008
10.
|
Konakion MM Paediatric 2 mg/0.2 ml
|
Date of revision of the text
|
16/11/2021
|
Koselugo 10 mg hard capsules
|
Introduction
|
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1.
|
Koselugo 10 mg hard capsules
|
Name of the medicinal product
|
Koselugo 10 mg hard capsules
2.
|
Koselugo 10 mg hard capsules
|
Qualitative and quantitative composition
|
Each hard capsule contains 10 mg of selumetinib (as hydrogen sulfate).
For the full list of excipients, see section 6.1.
3.
|
Koselugo 10 mg hard capsules
|
Pharmaceutical form
|
Hard capsule.
White to off-white, opaque, size 4 (approximately 14 mm x 5 mm), hard capsule, which has a centre band and is marked with “SEL 10” in black ink.
4.
|
Koselugo 10 mg hard capsules
|
Clinical particulars - Therapeutic indications
|
Therapeutic indications
Koselugo as monotherapy is indicated for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in paediatric patients with neurofibromatosis type 1 (NF1) aged 3 years and above.
4.2
|
Koselugo 10 mg hard capsules
|
Clinical particulars - Posology and method of administration
|
Posology and method of administration
Treatment with Koselugo should be initiated by a physician experienced in the diagnosis and the treatment of patients with NF1 related tumours.
Posology
The recommended dose of Koselugo is 25 mg/m2 of body surface area (BSA), taken orally twice daily (approximately every 12 hours).
Dosing is individualised based on BSA (mg/m2) and rounded to the nearest achievable 5 mg or 10 mg dose (up to a maximum single dose of 50 mg). Different strengths of Koselugo capsules can be combined to attain the desired dose (Table 1).
Table 1. Recommended dose based on body surface area
Body surface area (BSA) a
Recommended dose
0.55 – 0.69 m2
20 mg in the morning and 10 mg in the evening
0.70 – 0.89 m2
20 mg twice daily
0.90 – 1.09 m2
25 mg twice daily
1.10 – 1.29 m2
30 mg twice daily
1.30 – 1.49 m2
35 mg twice daily
1.50 – 1.69 m2
40 mg twice daily
1.70 – 1.89 m2
45 mg twice daily
≥ 1.90 m2
50 mg twice daily
a The recommended dose for patients with a BSA less than 0.55 m2 has not been established.
Treatment with Koselugo should continue as long as clinical benefit is observed, or until PN progression or the development of unacceptable toxicity. There is limited data in patients older than 18, therefore continued treatment into adulthood should be based on benefits and risks to the individual patient as assessed by the physician. However, start of treatment with Koselugo in adults is not appropriate.
Missed dose
If a dose of Koselugo is missed, it should only be taken if it is more than 6 hours until the next scheduled dose.
Vomiting
If vomiting occurs after Koselugo is administered, an additional dose is not to be taken. The patient should continue with the next scheduled dose.
Dose adjustments
Interruption and/or dose reduction or permanent discontinuation of selumetinib may be required based on individual safety and tolerability (see sections 4.4 and 4.8). Recommended dose reductions are given in Table 2 and may require the daily dose to be divided into two administrations of different strength or for treatment to be given as a once daily dose.
Table 2. Recommended dose reductions for adverse reactions
Body surface area (BSA)
Initial Koselugo dosea
(mg/twice daily)
First dose reduction (mg/dose)
Second dose reduction (mg/dose)b
Morning
Evening
Morning
Evening
0.55 – 0.69 m2
20 mg in the morning and 10 mg in the evening
10
10
10 once daily
0.70 – 0.89 m2
20
20
10
10
10
0.90 – 1.09 m2
25
25
10
10
10
1.10 – 1.29 m2
30
25
20
20
10
1.30 – 1.49 m2
35
25
25
25
10
1.50 – 1.69 m2
40
30
30
25
20
1.70 – 1.89 m2
45
35
30
25
20
≥ 1.90 m2
50
35
35
25
25
a Based on BSA as shown in Table 1.
b Permanently discontinue treatment in patients unable to tolerate Koselugo after two dose reductions.
Dose modifications for the management of adverse reactions associated with this medicinal product are presented in Table 3.
Table 3. Recommended dose modifications for adverse reactions
CTCAE Grade*
Recommended dose modification
Grade 1 or 2 (tolerable – can be managed with supportive care)
Continue treatment and monitor as clinically indicated
Grade 2 (intolerable – cannot be managed with supportive care) or Grade 3
Interrupt treatment until toxicity is grade 0 or 1 and reduce by one dose level when resuming therapy (see Table 2)
Grade 4
Interrupt treatment until toxicity is grade 0 or 1, reduce by one dose level when resuming therapy (see Table 2). Consider discontinuation
* Common Terminology Criteria for Adverse Events (CTCAE)
Dose modification advice for left ventricular ejection fraction (LVEF) reduction
In cases of asymptomatic LVEF reduction of ≥ 10 percentage points from baseline and below the institutional lower level of normal (LLN), selumetinib treatment should be interrupted until resolution. Once resolved, selumetinib should be reduced by one dose level when resuming therapy (see Table 2).
In patients who develop symptomatic LVEF reduction or a grade 3 or 4 LVEF reduction, selumetinib should be discontinued and a prompt cardiology referral should be carried out (see section 4.4).
Dose modification advice for ocular toxicities
Selumetinib treatment should be interrupted in patients diagnosed with retinal pigment epithelial detachment (RPED) or central serous retinopathy (CSR) with reduced visual acuity until resolution; reduce selumetinib by one dose level when resuming therapy (see Table 2). In patients diagnosed with RPED or CSR without reduced visual acuity, ophthalmic assessment should be conducted every 3 weeks until resolution. In patients who are diagnosed with retinal vein occlusion (RVO), treatment with selumetinib should be permanently discontinued (see section 4.4).
Dose adjustments for co-administration with CYP3A4 or CYP2C19 inhibitors
Concomitant use of strong or moderate CYP3A4 or CYP2C19 inhibitors is not recommended and alternative agents should be considered. If a strong or moderate CYP3A4 or CYP2C19 inhibitor must be co-administered, the recommended Koselugo dose reduction is as follows: If a patient is currently taking 25 mg/m2 twice daily, dose reduce to 20 mg/m2 twice daily. If a patient is currently taking 20 mg/m2 twice daily, dose reduce to 15 mg/m2 twice daily (see Table 4 and section 4.5).
Table 4. Recommended dose to achieve 20 mg/m2 or 15 mg/m2 twice daily dose level
Body Surface Area
20 mg/m2 twice daily (mg/dose)
15 mg/m2 twice daily (mg/dose)
Morning
Evening
Morning
Evening
0.55 – 0.69 m2
10
10
10 mg once a day
0.70 – 0.89 m2
20
10
10
10
0.90 – 1.09 m2
20
20
20
10
1.10 – 1.29 m2
25
25
25
10
1.30 – 1.49 m2
30
25
25
20
1.50 – 1.69 m2
35
30
25
25
1.70 – 1.89 m2
35
35
30
25
≥ 1.90 m2
40
40
30
30
Special populations
Renal impairment
Based on clinical trials no dose adjustment is recommended in patients with mild, moderate, severe renal impairment or those with end stage renal disease (ESRD) (see section 5.2).
Hepatic impairment
Based on clinical trials, no dose adjustment is recommended in patients with mild hepatic impairment. The starting dose should be reduced in patients with moderate hepatic impairment to 20 mg/m2 BSA, twice daily (see Table 4). Koselugo is contraindicated for use in patients with severe hepatic impairment (see sections 4.3 and 5.2).
Ethnicity
Increased systemic exposure has been seen in adult Asian subjects, although there is considerable overlap with Western subjects when corrected for body weight. No specific adjustment to the starting dose is recommended for paediatric Asian patients, however these patients, should be closely monitored for adverse events (see section 5.2).
Paediatric population
The safety and efficacy of Koselugo in children less than 3 years of age has not been established. No data are available.
Method of administration
Koselugo is for oral use. It should be taken on an empty stomach with no food or drink other than water 2 hours prior to dosing and 1 hour after dosing (see sections 4.5 and 5.2).
The capsules should be swallowed whole with water. The capsules should not be chewed, dissolved, or opened, because this could impair drug release and affect the absorption of selumetinib.
Koselugo should not be administered to patients who are unable or unwilling to swallow the capsule whole. Patients should be assessed for their ability to swallow a capsule before starting treatment. Standard medicine swallowing techniques are expected to be sufficient to swallow selumetinib capsules. For patients who have difficulties swallowing the capsule, referral to an appropriate health care professional such as a speech and language therapist could be considered to identify suitable methods that can be tailored to the particular patient.
4.3
|
Koselugo 10 mg hard capsules
|
Clinical particulars - Contraindications
|
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Severe hepatic impairment (see sections 4.2 and 5.2).
4.4
|
Koselugo 10 mg hard capsules
|
Clinical particulars - Special warnings and precautions for use
|
Special warnings and precautions for use
Left ventricular ejection fraction (LVEF) reduction
Asymptomatic decreases in ejection fraction have been reported in 22% of paediatric patients in the pivotal clinical trial. Median time to initial onset of these adverse reactions was 226 days. A small number of serious reports of LVEF reduction associated with selumetinib have been reported in paediatric patients who participated in an expanded access program (see section 4.8).
Paediatric patients with a history of impaired left ventricular function or a baseline LVEF below institutional LLN have not been studied. LVEF should be evaluated by echocardiogram before initiation of treatment to establish baseline values. Prior to starting selumetinib treatment, patients should have an ejection fraction above the institutional LLN.
LVEF should be evaluated at approximately 3-month intervals, or more frequently as clinically indicated, during treatment. Reduction in LVEF can be managed using treatment interruption, dose reduction or treatment discontinuation (see section 4.2).
Ocular toxicity
Patients should be advised to report any new visual disturbances. Adverse reactions of blurred vision have been reported in paediatric patients receiving selumetinib. Isolated cases of RPED, CSR and RVO in adult patients with multiple tumour types, receiving treatment with selumetinib monotherapy and in combination with other anti-cancer agents, and in a single paediatric patient with pilocytic astrocytoma on selumetinib monotherapy, have been observed (see section 4.8).
In line with clinical practice an ophthalmological evaluation prior to treatment initiation and at any time a patient reports new visual disturbances is recommended. In patients diagnosed with RPED or CSR without reduced visual acuity, ophthalmic assessment should be conducted every 3 weeks until resolution. If RPED or CSR is diagnosed and visual acuity is affected, selumetinib therapy should be interrupted and the dose reduced when treatment is resumed (see section 4.2). If RVO is diagnosed, treatment with selumetinib should be permanently discontinued (see section 4.2).
Liver laboratory abnormalities
Liver laboratory abnormalities, specifically AST and ALT elevations, can occur with selumetinib (see section 4.8). Liver laboratory values should be monitored before initiation of selumetinib and at least monthly during the 6 first months of treatment, and thereafter as clinically indicated. Liver laboratory abnormalities should be managed with dose interruption, reduction or treatment discontinuation (see Table 2 in section 4.2).
Skin and subcutaneous disorders
Skin rash (including maculopapular rash and acneiform rash), paronychia and hair changes have been reported very commonly in the pivotal clinical study (see section 4.8). Pustular rash, hair colour changes and dry skin were seen more frequently in younger children (age 3-11 years) and acneiform rash was seen more frequently in post-pubertal children (age 12-16 years).
Vitamin E supplementation
Patients should be advised not to take any supplemental vitamin E. Koselugo 10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Koselugo 25 mg capsules contain 36 mg vitamin E as TPGS. High doses of vitamin E may increase the risk of bleeding in patients taking concomitant anticoagulant or antiplatelet medicinal products (e.g., warfarin or acetylsalicylic acid). Anticoagulant assessments, including international normalised ratio or prothrombin time, should be conducted more frequently to detect when dose adjustments of the anticoagulant or antiplatelet medicinal products are warranted (see section 4.5).
Risk of choking
Selumetinib is available as a capsule which must be swallowed whole. Some patients, in particular children < 6 years of age, may be at risk of choking on a capsule formulation due to developmental, anatomical or psychological reasons. Therefore, selumetinib should not be administered to patients who are unable or unwilling to swallow the capsule whole (see section 4.2).
Women of child bearing potential
Koselugo is not recommended in women of child bearing potential who are not using contraception (see section 4.6).
4.5
|
Koselugo 10 mg hard capsules
|
Clinical particulars - Interaction with other medicinal products and other forms of interaction
|
Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in healthy adults (aged ≥ 18 years).
Active substances that may increase selumetinib plasma concentrations
Co-administration with a strong CYP3A4 inhibitor (200 mg itraconazole twice daily for 4 days) increased selumetinib Cmax by 19% (90% CI 4, 35) and AUC by 49% (90% CI 40, 59) in healthy adult subjects.
Co-administration with a strong CYP2C19/moderate CYP3A4 inhibitor (200 mg fluconazole once daily for 4 days) increased selumetinib Cmax by 26% (90% CI 10, 43) and AUC by 53% (90% CI 44, 63) in healthy adult subjects, respectively.
Concomitant use of erythromycin (moderate CYP3A4 inhibitor) or fluoxetine (strong CYP2C19/CYP2D6 inhibitor) is predicted to increase selumetinib AUC by ~30-40% and Cmax by ~20%.
Co-administration with medicinal products that are strong inhibitors of CYP3A4 (e.g., clarithromycin, grapefruit juice, oral ketoconazole) or CYP2C19 (e.g., ticlopidine) should be avoided. Co-administration with medicinal products that are moderate inhibitors of CYP3A4 (e.g., erythromycin and fluconazole) and CYP2C19 (e.g., omeprazole) should be avoided.
If co-administration is unavoidable, patients should be carefully monitored for adverse events and the selumetinib dose should be reduced (see section 4.2 and Table 4).
Active substances that may decrease selumetinib plasma concentrations
Co-administration with a strong CYP3A4 inducer (600 mg rifampicin daily for 8 days) decreased selumetinib Cmax by -26% (90% CI -17, -34) and AUC by -51% (90% CI -47, -54).
Concomitant use of strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John's Wort) or moderate CYP3A4 inducers with Koselugo should be avoided.
Active substances whose plasma concentrations may be altered by selumetinib
In vitro, selumetinib is an inhibitor of OAT3. The potential for a clinically relevant effect on the pharmacokinetics of concomitantly administered substrates of OAT3 (e.g., methotrexate and furosemide) cannot be excluded (see section 5.2).
TPGS is a P-gp inhibitor in vitro and it cannot be excluded that it may cause clinically relevant drug interactions with substrates of P-gp (e.g. digoxin or fexofenadine).
The effect of selumetinib on the exposure of oral contraceptives has not been evaluated. Therefore, use of an additional barrier method should be recommended to women using hormonal contraceptives (see section 4.6).
Effect of gastric acid reducing agents on selumetinib
Selumetinib capsules do not exhibit pH dependent dissolution. Koselugo can be used concomitantly with gastric pH modifying agents (i.e. H2-receptor antagonists and proton pump inhibitors) without restrictions, except for omeprazole which is a CYP2C19 inhibitor.
Vitamin E
Koselugo capsules contain vitamin E as the excipient TPGS. Therefore, patients should avoid taking supplemental vitamin E and anticoagulant assessments should be performed more frequently in patients taking concomitant anticoagulant or antiplatelet medicinal products (see section 4.4).
4.6
|
Koselugo 10 mg hard capsules
|
Clinical particulars - Fertility, pregnancy and lactation
|
Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in males and females
Women of childbearing potential should be advised to avoid becoming pregnant while receiving Koselugo. It is recommended that a pregnancy test should be performed on women of childbearing potential prior to initiating treatment.
Both male and female patients (of reproductive potential) should be advised to use effective contraception during and for at least 1 week after completion of treatment with Koselugo. It cannot be excluded that selumetinib may reduce the effectiveness of oral contraceptives, therefore women using hormonal contraceptives should be recommended to add a barrier method (see section 4.5).
Pregnancy
There are no data on the use of selumetinib in pregnant women. Studies in animals have shown reproductive toxicity including embryofoetal death, structural defects and reduced foetal weights (see section 5.3). Koselugo is not recommended during pregnancy and in women of childbearing potential not using contraception (see section 4.4).
If a female patient or a female partner of a male patient receiving Koselugo becomes pregnant, she should be apprised of the potential risk to the foetus.
Breast-feeding
It is not known whether selumetinib, or its metabolites, are excreted in human milk. Selumetinib and its active metabolite are excreted in the milk of lactating mice (see section 5.3). A risk to the breast-fed child cannot be excluded, therefore breast-feeding should be discontinued during treatment with Koselugo.
Fertility
There are no data on the effect of Koselugo on human fertility. Selumetinib had no impact on fertility and mating performance in male and female mice, although a reduction in embryonic survival was observed in female mice (see section 5.3).
4.7
|
Koselugo 10 mg hard capsules
|
Clinical particulars - Effects on ability to drive and use machines
|
Effects on ability to drive and use machines
Koselugo may have a minor influence on the ability to drive and use machines. Fatigue, asthenia and visual disturbances have been reported during treatment with selumetinib and patients who experience these symptoms should observe caution when driving or using machines.
4.8
|
Koselugo 10 mg hard capsules
|
Clinical particulars - Undesirable effects
|
Undesirable effects
Summary of the safety profile
The safety profile of selumetinib monotherapy in paediatric patients with NF1 who have inoperable PN has been determined following evaluation of a combined safety population of 74 paediatric patients (20-30 mg/m2 twice daily). This paediatric 'pool' of patients comprised 50 patients in SPRINT phase II stratum I, treated with selumetinib 25 mg/m2 twice daily (the pivotal dataset) and 24 patients in SPRINT phase I treated with 20 to 30 mg/m2 selumetinib twice daily (the dose finding study). There were no clinically relevant differences in the safety profile between SPRINT phase I and SPRINT phase II stratum I. This safety profile was also substantiated by a pool of safety data from 7 AstraZeneca sponsored studies in adult patients with multiple tumour types (N = 347) who received 75 to 100 mg twice daily).
In the paediatric pool, the median total duration of selumetinib treatment in paediatric patients with NF1 who have PN was 28 months (range: < 1 to 71 months), 23% of patients were exposed to selumetinib treatment for > 48 months. Patients aged ≥ 2 to 11 years (N = 45) had a higher incidence of the following adverse drug reactions (ADRs) compared to patients aged 12 to 18 years (N = 29): hypoalbuminaemia, dry skin, pyrexia, hair colour changes.
In the paediatric pool (N = 74; comprises 50 patients from the pivotal SPRINT phase II stratum 1 dataset and 24 patients from the supportive SPRINT phase I dataset), the most common adverse reactions of any grade (incidence ≥ 45%) were vomiting (82%), rash (80%), blood creatine phosphokinase increased (76%), diarrhoea (77%), nausea (73%), asthenic events (59%), dry skin (58%), pyrexia (57%), acneiform rash (54%), hypoalbuminaemia (50%), aspartate aminotransferase increased (50%) and paronychia (45%). Dose interruptions and reductions due to adverse events were reported in 78% and 32% of patients, respectively. The most commonly reported ADRs leading to dose modification (dose interrupted or dose reduced) of selumetinib were vomiting (26%), paronychia (16%), diarrhoea (15%) and nausea (11%). Permanent discontinuation due to adverse events was reported in 12% of the patients. The following serious adverse reactions were reported: diarrhoea (3%), anaemia (3%) pyrexia (3%), blood CPK increased (3%), blood creatinine increased (1%).
Tabulated list of adverse reactions
Table 5 presents the adverse reactions identified in the paediatric population with NF1 who have inoperable PN and in adult patients (see footnote to Table 5). The frequency is determined from the paediatric pool (N = 74); comprises 50 patients from the pivotal SPRINT phase II stratum 1 dataset and 24 patients from supportive SPRINT phase I dataset. Adverse drug reactions(ADRs) are organised by MedDRA system organ class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000) and not known (cannot be estimated from available data), including isolated reports.
Table 5. Adverse drug reactions reported in the paediatric pool (pivotal SPRINT phase II stratum 1 [N = 50] and supportive SPRINT phase I [N = 24]) and in other identified clinical trials in adult patients (N = 347)††
MedDRA SOC
MedDRA Term
Overall Frequency
(All CTCAE grades)
NF1 paediatric pool‡
(N = 74)
Frequency of CTCAE grade 3 and Above†
NF1 paediatric pool‡
(N = 74)
Eye disorders
Vision blurred^
Common (9%)
-
Respiratory, thoracic & mediastinal disorders
Dyspnoea*
Common (5%)
-
Gastrointestinal disorders
Vomiting^
Very common (82%)
Common (8%)
Diarrhoea^
Very common (77%)
Very common (15%)
Nausea^
Very common (73%)
Common (1%)
Stomatitis^
Very common (38%)
Common (1%)
Dry mouth
Common (5%)
-
Skin and subcutaneous tissue disorders
Rash ^ *
Very common (80%)
Common (5%)
Dry skin
Very common (58%)
-
Rash acneiform^ *
Very common (54%)
Common (3%)
Paronychia^
Very common (45%)
Common (9%)
Hair changes^ *
Very common (39%)
-
General disorders
Asthenic events*
Very common (59%)
-
Pyrexia
Very common (57%)
Common (8%)
Peripheral oedema*
Very common (12%)
-
Facial oedema*
Common (7%)
-
Investigations
Blood CPK increased^
Very common (76%)
Common (9%)
Hypoalbuminaemia
Very common (50%)
-
AST increased
Very common (50%)
Common (1%)
Haemoglobin decreased*
Very common (45%)
Common (3%)
ALT increased
Very common (36%)
Common (3%)
Blood creatinine increased
Very common (28%)
Common (1%)
Ejection fraction decreased^
Very common (23%)
Common (1%)
Increased blood pressure*
Very common (16%)
-
Eye disorders
Retinal pigment epithelial detachment (RPED)/ Central serous retinopathy (CSR)* ††
Uncommon (0.6%)
-
Retinal vein occlusion (RVO)* ††
Uncommon (0.3%)
-
Per National Cancer Institute CTCAE version 4.03
CPK = creatine phosphokinase; AST = aspartate aminotransferase; ALT = alanine aminotransferase.
^ See Description of selected adverse reactions
†
All reactions were CTCAE grade 3, except for one CTCAE grade 4 event of blood CPK increased and one CTCAE grade 4 event of blood creatinine increased. There were no deaths.
†† Identified ADRs from other clinical trial experience in adult patients (N = 347), with multiple tumour types, receiving treatment with selumetinib (75 mg twice daily). These ADRs have not been reported in paediatric population with NF1 who have inoperable PN.
‡ Paediatric pool (N=74) percentage rounded to the nearest decimal.
*ADRs based on grouping of individual preferred terms (PT):
Asthenic events: asthenia, fatigue,
CSR/RPED: Detachment of macular retinal pigment epithelium, chorioretinopathy
Dyspnoea: dyspnoea exertional, dyspnoea, dyspnoea at rest
Facial oedema: face odema, periorbital oedema
Haemoglobin decreased: anaemia, haemoglobin decreased
Hair changes: alopecia, hair colour change
Increased blood pressure: blood pressure increased, hypertension
Peripheral oedema: oedema peripheral, oedema
Rash (acneiform): dermatitis acneiform
Rash: dermatitis acneiform, rash maculo-papular, rash papular, rash, rash erythematous, rash macular
RVO: retinal vascular disorder, retinal vein occlusion, retinal vein thrombosis
Description of selected adverse reactions
Left ventricular ejection fraction (LVEF) reduction
In SPRINT, phase II stratum 1, LVEF reduction (PT: ejection fraction decreased) was reported in 11 (22%) patients; all cases were grade 2, asymptomatic and did not lead to dose interruptions, reductions or discontinuation. Of the 11 patients, 6 patients recovered and for 5 patients the outcome was not reported. The median time to first occurrence of LVEF reduction was 226 days (median duration 78 days). The majority of LVEF reduction adverse reactions were reported as reductions from baseline (≥ 10% reduction) but were considered to remain in the normal range. Patients with LVEF lower than the institutional LLN at baseline were not included in the pivotal study. In addition, 2 serious cases of LVEF reduction associated with selumetinib have been reported in paediatric patients who participated in an expanded access program. For clinical management of LVEF reduction, see sections 4.2 and 4.4.
Ocular toxicity
In SPRINT, phase II stratum 1, grade 1 and 2 adverse reactions of blurred vision were reported in 4 (8%) patients. Two patients required dose interruption. All adverse reactions were managed without dose reduction. For clinical management of new visual disturbances, see sections 4.2 and 4.4.
In addition, a single event of RPED was reported in a paediatric patient receiving selumetinib monotherapy (25 mg/m2 twice daily) for pilocytic astrocytoma involving the optic pathway in an externally sponsored paediatric study (see sections 4.2 and 4.4).
Paronychia
In SPRINT, phase II stratum 1, paronychia was reported in 23 (46%) patients, the median time to first onset of maximum grade paronychia adverse reaction was 306 days and the median duration of adverse reactions was 96 days. The majority of these adverse reactions were grade 1 or 2 and were treated with supportive or symptomatic therapy and/or dose modification. Grade ≥ 3 events occurred in three (6%) patients. Seven patients (3 with a maximum grade 3 adverse reaction and 4 with a maximum grade 2 adverse reaction) had a selumetinib dose interruption for adverse reactions of paronychia, of whom 3 had dose interruption followed by dose reduction (2 patients required a second dose reduction). In one patient (2%) the event led to discontinuation.
Blood creatine phosphokinase (CPK) increase
Adverse reactions of blood CPK elevation occurred in 76% of patients in SPRINT phase II stratum 1. The median time to first onset of the maximum grade CPK increase was 106 days and the median duration of adverse reactions was 126 days. The majority of adverse reactions were grade 1 or 2 and resolved with no change in selumetinib dose. Grade ≥ 3 adverse reactions occurred in three (6%) patients. A grade 4 adverse reaction led to treatment interruption followed by dose reduction.
Gastrointestinal toxicities
In SPRINT, phase II stratum 1, vomiting (41 patients, 82%, median duration 3 days), diarrhoea (35 patients, 70%, median duration 5 days), nausea (33 patients, 66%, median duration 16 days), and stomatitis (25 patients, 50%, median duration 12 days) were the most commonly reported gastrointestinal (GI) reactions. The majority of these cases were grade 1 or 2 and did not require any dose interruptions or dose reductions.
Grade 3 adverse reactions were reported for diarrhoea (8 patients, 16%), nausea (1 patient, 2%), and vomiting (3 patients, 6%). For one patient diarrhoea led to dose reduction and subsequent discontinuation. No dose reduction or discontinuation was required for adverse reactions of nausea, vomiting or stomatitis.
Skin toxicities
In SPRINT, phase II stratum 1, acneiform rash was observed in 25 (50%) patients (median time to onset 13 days; median duration of 60 days for the maximum CTCAE grade event). The majority of these cases were grade 1 or 2, observed in post-pubertal patients (> 12 years) and did not require any dose interruptions or reductions. Grade 3 adverse reactions were reported for 4%.
Other (non-acneiform) rashes were observed in 35 (70%) patients in the pivotal study and were predominantly grade 1 or 2.
Hair changes
In SPRINT, phase II stratum 1, 32% of patients experienced hair changes (reported as hair lightening [PT: hair colour changes] in 11 patients (22%) and hair thinning [PT: alopecia]) in 12 patients (24%)); in 7 patients (14%) both alopecia and hair colour changes were reported during treatment. All cases were grade 1 and did not require dose interruption or dose reduction.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9
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Koselugo 10 mg hard capsules
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Clinical particulars - Overdose
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Overdose
There is no specific treatment for overdose. If overdose occurs, patients should be closely monitored for signs and symptoms of adverse reactions and treated supportively with appropriate monitoring as necessary. Dialysis is ineffective in the treatment of overdose.
5. Pharmacological properties
5.1
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Koselugo 10 mg hard capsules
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Pharmacodynamic properties - Pharmacodynamic properties
|
Pharmacokinetic properties
At the recommended dose of 25 mg/m2 twice daily in paediatric patients (3 to ≤ 18 years old), the geometric mean (coefficient of variation [CV%]) maximum plasma concentration (Cmax) was 731 (62%) ng/mL and that of the area under the plasma drug concentration curve (AUC0-12) following the first dose was 2009 (35%) ng·h/mL. Minimal accumulation of ~1.1-fold was observed at steady state upon twice daily dosing.
In paediatric patients, at a dose level of 25 mg/m2, selumetinib has an apparent oral clearance of 8.8 L/h, mean apparent volume of distribution at steady state of 78 L and mean elimination half-life of ~6.2 hours.
Absorption
In healthy adult subjects, the mean absolute oral bioavailability of selumetinib was 62%.
Following oral dosing, selumetinib is rapidly absorbed, producing peak steady state plasma concentrations (Tmax) between 1-1.5 hours post-dose.
Effect of food
In separate clinical studies, in healthy adult subjects and in adult patients with advanced solid malignancies at a dose of 75 mg, co-administration of selumetinib with a high-fat meal resulted in a mean decrease in Cmax of 50% and 62%, respectively, compared to fasting administration. Selumetinib mean AUC was reduced by 16% and 19%, respectively, and the time to reach maximum concentration (Tmax) was delayed by approximately 1.5 to 3 hours (see section 4.2).
In healthy adult subjects at a dose of 50 mg, co-administration of selumetinib with a low-fat meal resulted in 60% lower Cmax when compared to fasting administration. Selumetinib AUC was reduced by 38%, and the time to reach maximum concentration (Tmax) was delayed by approximately 0.9 hours (see section 4.2).
Distribution
The mean apparent volume of distribution at steady state of selumetinib across 20 to 30 mg/m2 ranged from 78 to 171 L in paediatric patients, indicating moderate distribution into tissue.
In vitro plasma protein binding is 98.4% in humans. Selumetinib mostly binds to serum albumin (96.1%) than α-1 acid glycoprotein (< 35%).
Biotransformation
In vitro, selumetinib undergoes phase 1 metabolic reactions including oxidation of the side chain, N-demethylation, and loss of the side chain to form amide and acid metabolites. CYP3A4 is the predominant isoform responsible for selumetinib oxidative metabolism with CYP2C19, CYP2C9, CYP2E1 and CYP3A5 involved to a lesser extent. In vitro studies indicate that selumetinib also undergoes direct phase 2 metabolic reactions to form glucuronide conjugates principally involving the enzymes UGT1A1 and UGT1A3. Glucuronidation is a significant route of elimination for selumetinib phase 1 metabolites involving several UGT isoforms.
Following oral dosing of 14C-selumetinib to healthy male subjects, unchanged selumetinib (~40% of the radioactivity) with other metabolites including glucuronide of imidazoindazole metabolite (M2; 22%), selumetinib glucuronide (M4; 7%), N-desmethyl selumetinib (M8; 3%), and N-desmethyl carboxylic acid (M11; 4%) accounted for the majority of the circulating radioactivity in human plasma. N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma but is approximately 3 to 5 times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity.
Interactions
In vitro, selumetinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP2E1. In vitro, selumetinib is not an inducer of CYP1A2 and CYP2B6. Selumetinib is an inducer of CYP3A4 in vitro, this is however not expected to be clinically relevant.
In vitro, selumetinib inhibits UGT1A3, UGT1A4, UGT1A6 and UGT1A9 however these effects are not expected to be clinically relevant.
Interactions with transport proteins
Based on in vitro studies, selumetinib is a substrate for BCRP and P-gp transporters but is unlikely to be subjected to clinically relevant drug interactions. In vitro studies suggest that selumetinib does not inhibit the breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, MATE1 and MATE2K at the recommended paediatric dose. A clinically relevant effect on the pharmacokinetics of concomitantly administered substrates of OAT3 cannot be excluded.
Elimination
In healthy adult subjects, following a single oral 75 mg dose of radiolabelled selumetinib, 59% of the dose was recovered in faeces (19% unchanged) while 33% of the administered dose (< 1% as parent) was found in urine by 9 days of sample collection.
Special populations
Renal impairment
The exposure of 50 mg oral selumetinib was investigated in adult subjects with normal renal function (n = 11) and subjects with ESRD (n = 12). The ESRD group showed 16% and 28% lower Cmax and AUC, respectively, with the fraction of unbound selumetinib being 35% higher in ESRD subjects. As a result, the unbound Cmax and AUC ratios were 0.97 and 1.13 in the ESRD group when compared to the group with normal renal function. A small increase, approximately 20% AUC, in the N-desmethyl metabolite to parent ratio was detected in the ESRD group when compared to the normal group. As exposure in ESRD subjects was similar to those with normal renal function, investigations in mild, moderate and severe renally impaired subjects were not performed. Renal impairment is expected to have no meaningful influence on the exposure of selumetinib (see section 4.2).
Hepatic impairment
Adult subjects with normal hepatic function (n = 8) and mild hepatic impairment (Child-Pugh A, n = 8) were dosed with 50 mg selumetinib, subjects with moderate hepatic impairment (Child-Pugh B, n = 8) were administered a 50 or 25 mg dose, and subjects with severe hepatic impairment (Child-Pugh C, n = 8) were administered a 20 mg dose. Selumetinib total dose normalised AUC and unbound AUC were 86% and 69% respectively, in mild hepatic impairment patients, compared to the AUC values for subjects with normal hepatic function. Selumetinib exposure (AUC) was higher in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment; the total AUC and unbound AUC values were 159% and 141% (Child-Pugh B) and 157% and 317% (Child-Pugh C), respectively, of subjects with normal hepatic function (see section 4.2). There was a trend of lower protein binding in subjects with severe hepatic impairment although the protein binding remained > 99% (see section 4.3).
Ethnicity
Following a single-dose, selumetinib exposure appears to be higher in Japanese, non-Japanese-Asian and Indian healthy adult subjects compared to Western adult subjects, however, there is considerable overlap with Western subjects when corrected for body weight or BSA (see section 4.2).
Adult patients (> 18 years old)
The PK parameters in adult healthy subjects and adult patients with advanced solid malignancies, are similar to those in paediatric patients (3 to ≤ 18 years old) with NF1.
In adult patients, Cmax and AUC increased dose proportionally over a 25 mg to 100 mg dose range.
5.3
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Koselugo 10 mg hard capsules
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Pharmacodynamic properties - Pharmacokinetic properties
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Preclinical safety data
Genotoxicity
Selumetinib was positive in the mouse micronucleus study via an aneugenic mode of action. The free mean exposure (Cmax) at the no observed effect level (NOEL) was approximately 27-times greater than clinical free exposure at the maximum recommended human dose (MRHD) of 25 mg/m2.
Carcinogenicity
Selumetinib was not carcinogenic in rats or transgenic mice.
Repeat-dose toxicity
In repeat-dose toxicity studies in mice, rats and monkeys, the main effects seen after selumetinib exposure were in the skin, GI tract and bones. Scabs associated with microscopic erosions and ulceration at a free exposure similar to the clinical exposure (free AUC) at the MRHD were seen in rats. Inflammatory and ulcerative GI tract findings associated with secondary changes in the liver and lymphoreticular system at free exposures approximately 28 times the clinical free exposure at the MRHD were observed in mice. Growth plate (physeal) dysplasia was seen in male rats dosed for up to 3 months with selumetinib at a free exposure 11 times the clinical free exposure at the MRHD. GI findings showed evidence of reversibility following a recovery period. Reversibility for skin toxicities and physeal dysplasia was not evaluated. Vascular engorgement of the corpus cavernosum of the bulbocavernosus muscle were observed in male mice in a 26-week study at a dose of 40 mg/kg/day (28 times the free AUC in humans at the MRHD) leading to significant urinary tract obstruction as well as inflammation and luminal hemorrhage of the urethra leading to early death in male mice.
Reproductive toxicology
Developmental and reproduction toxicity studies were conducted in mice. Fertility was not affected in male mice at up to 40 mg/kg/day (corresponding to 22-fold the free AUC in humans at the MRHD). In females, mating performance and fertility were not affected at up to 75 mg/kg/day, but a reversible decrease in the number of live fetuses was observed at this dose level; the NOAEL for effects on reproductive performance was 5 mg/kg/day (approximately 3.5-fold the free AUC in humans at the MRHD). A treatment-related increase in the incidence of external malformations (open eye, cleft palate) was reported in absence of maternal toxicity in embryo-fetal development studies at > 5 mg/kg/day, and in the pre- and post-natal development study at ≥ 1 mg/kg/day (corresponding to 0.4-fold the free Cmax in humans at the MRHD). The other treatment related effects observed at non-maternotoxic dose levels in these studies consisted of embryo-lethality and decreased fetal weight at ≥ 25 mg/kg/day (corresponding to 22-fold the free AUC in humans at the MRHD), reductions in post-natal pup growth and at weaning a lower number of pups met the pupil constriction criterion at 15 mg/kg/day (corresponding to 3.6-fold the free Cmax in humans at the MRHD). Selumetinib and its active metabolite were excreted in the milk of lactating mice at concentrations approximately the same as those in plasma.
6.
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Koselugo 10 mg hard capsules
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Pharmaceutical particulars - List of excipients
|
List of excipients
Capsule content
Vitamin E polyethylene glycol succinate (D α-tocopheryl polyethylene glycol succinate).
Capsule shell
Hypromellose (E464)
Carrageenan (E407)
Potassium chloride (E508)
Titanium dioxide (E171)
Carnauba wax (E903)
Printing ink
Shellac glaze, standard (E904)
Iron oxide black (E172)
Propylene glycol (E1520)
Ammonium hydroxide (E527)
6.2
|
Koselugo 10 mg hard capsules
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Pharmaceutical particulars - Incompatibilities
|
Incompatibilities
Not applicable.
6.3
|
Koselugo 10 mg hard capsules
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Pharmaceutical particulars - Shelf life
|
Shelf life
3 years.
6.4
|
Koselugo 10 mg hard capsules
|
Pharmaceutical particulars - Special precautions for storage
|
Special precautions for storage
Do not store above 30 °C.
Store in the original bottle in order to protect from moisture and light.
Keep the bottle tightly closed.
6.5
|
Koselugo 10 mg hard capsules
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Pharmaceutical particulars - Nature and contents of container
|
Nature and contents of container
High-density polyethylene (HDPE) plastic bottle with white child-resistant polypropylene closure.
Each bottle contains 60 hard capsules and a silica gel desiccant. Each carton contains one bottle.
6.6
|
Koselugo 10 mg hard capsules
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Pharmaceutical particulars - Special precautions for disposal and other handling
|
Special precautions for disposal and other handling
Patients should be instructed not to remove the desiccant from the bottle.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.
|
Koselugo 10 mg hard capsules
|
Marketing authorisation holder
|
AstraZeneca UK Limited,
1 Francis Crick Avenue,
Cambridge,
CB2 0AA,
UK.
8. Marketing authorisation number(s)
PLGB 17901/0356
9.
|
Koselugo 10 mg hard capsules
|
Date of first authorisation/renewal of the authorisation
|
Date of first authorisation: 9th August 2021
Date of latest renewal: 10th August 2022
10.
|
Koselugo 10 mg hard capsules
|
Date of revision of the text
|
7th March 2023
|
Koselugo 25 mg hard capsules
|
Introduction
|
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1.
|
Koselugo 25 mg hard capsules
|
Name of the medicinal product
|
Koselugo 25 mg hard capsules
2.
|
Koselugo 25 mg hard capsules
|
Qualitative and quantitative composition
|
Each hard capsule contains 25 mg of selumetinib (as hydrogen sulfate).
For the full list of excipients, see section 6.1.
3.
|
Koselugo 25 mg hard capsules
|
Pharmaceutical form
|
Hard capsule.
Blue, opaque, size 4 (approximately 14 mm x 5 mm), hard capsule, which has a centre band and is marked with “SEL 25” in black ink.
4.
|
Koselugo 25 mg hard capsules
|
Clinical particulars - Therapeutic indications
|
Therapeutic indications
Koselugo as monotherapy is indicated for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in paediatric patients with neurofibromatosis type 1 (NF1) aged 3 years and above.
4.2
|
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