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Daraprim Tablets | Pharmaceutical form | Tablet.
Each tablet is white and round with the marking GS A3A.
4. |
Daraprim Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
For the treatment of:
Toxoplasmosis, including ocular infections, proven foetal infection following maternal infection during pregnancy, and toxoplasmosis in immune-deficient patients (for the treatment of toxoplasmosis Daraprim must always be used in combination with a synergistic agent e.g. sulphadiazine).
Treatment is not normally required for asymtomatic or mild toxoplasma infection.
4.2 |
Daraprim Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Toxoplasmosis (including ocular infections)
Daraprim should be given concurrently with sulphadiazine or another appropriate antibiotic.
In the treatment of toxoplasmosis, all patients receiving Daraprim should be given a folinic acid supplement (calcium folinate) to reduce the risk of bone marrow depression (see section 4.4).
Daraprim treatment should generally be given for 3 to 6 weeks and not less than six weeks in immunosuppressed patients. If further therapy is indicated, a period of two weeks should elapse between treatments.
There have been no dose response studies of pyrimethamine in the treatment of toxoplasmosis. The following recommendations are therefore for guidance only.
Adults
A loading dose of Daraprim 100 mg should be given for the first 1 to 2 days, followed by 25 mg to 50 mg daily. This should be given together with 2 g to 4 g of sulphadiazine daily in divided doses.
β’ Foetal toxoplasmosis during pregnancy
Daraprim 50 mg every 12 hours for 2 days, followed by 50 mg daily. This should be given together with an initial dose of sulfadiazine 75 mg/kg, followed by 50 mg/kg every 12 hours (to a maximum of 4 g daily) (see section 4.4 and section 4.6).
Immune-deficient adults and adolescents
Guidelines for the treatment of opportunistic infections in HIV-infected adults and adolescents consider pyrimethamine plus sulfadiazine to be the initial therapy of choice for Toxoplasma gondii encephalitis and recommend the following doses, based on body-weight, be given for at least 6 weeks:
- less than 60 kg - pyrimethamine 200 mg orally, followed by 50 mg daily plus sulfadiazine 1 g orally every 6 hours
- 60 kg or more - pyrimethamine 200 mg orally, followed by 75 mg daily plus sulfadiazine 1.5 g orally every 6 hours.
Paediatric Population
Children over 6 years
A loading dose of Daraprim 100 mg should be given for the first 1 to 2 days, followed by 25 mg to 50 mg daily. This should be given together with 2 g to 4 g of sulphadiazine daily in divided doses.
Children aged 5 to 6 years
An initial dose of Daraprim 2 mg/kg bodyweight (to a maximum of 50 mg) followed by 1 mg/kg bodyweight/day (to a maximum of 25 mg); combined with sulphadiazine 150 mg/kg bodyweight (maximum 2 g) daily in four divided doses.
Immune-deficient children
Dosage regimens for immune-deficient children are not defined.
Children under 5 years
There is insufficient data to provide specific dose recommendations in children. This formulation is not suitable for children under 5 years.
Elderly
There is no definitive information on the effect of Daraprim on elderly individuals. It is theoretically possible that elderly patients might be more susceptible to folate depression associated with the daily administration of Daraprim in the treatment of toxoplasmosis, and supplementation of folinic acid is therefore essential (see section 4.2).
Patients with renal impairment
Daraprim should be given with caution to patients with renal impairment. Since Daraprim is co-administered with a sulphonamide care should be taken to avoid accumulation of the sulphonamide in patients with renal impairment (see section 4.4).
Patients with hepatic impairment
Daraprim should be given with caution to patients with hepatic impairment. There are no general recommendations for dosage reductions for liver-impaired states but consideration should be given to dose adjustments for individual cases (see section 4.4).
Method of administration
For oral administration.
4.3 |
Daraprim Tablets | Clinical particulars - Contraindications | Contraindications
Daraprim is contraindicated in:
Hypersensitivity to pyrimethamine or to any of the excipients of this medicinal product.
Daraprim should not generally be used during the first trimester of pregnancy (see section 4.6).
Since Daraprim is to be taken in conjunction with another drug for the indications listed, the relevant prescribing information for the synergistic agent should also be considered.
Breast-feeding should be avoided during toxoplasmosis treatment. (See section 4.6).
4.4 |
Daraprim Tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Depression of haematopoesis
Daily therapeutic doses of Daraprim have been shown to depress haematopoesis in 25% to 50% of patients. The likelihood of inducing leucopenia, anaemia or thrombocytopenia is reduced by concurrent administration of calcium folinate. Pancytopenia, responsive to folate, has been reported in patients with probable pre-existing folate deficiency. Fatalities have occurred in the absence of folate treatment.
Prevention of haematological toxicity
During pregnancy and in other conditions predisposing to folate deficiency, a folate supplement should be given. The co-administration of a folate supplement is necessary for treatment of toxoplasmosis (see section 4.2). Full blood counts should be carried out weekly during therapy and for a further two weeks after treatment is stopped. In immunosuppressed patients, full blood counts should be carried out twice weekly. Should signs of folate deficiency develop, treatment must be discontinued and high doses of calcium folinate administered. Calcium folinate should be used because folic acid does not correct folate deficiency due to dihydrofolate reductase inhibitors.
Daraprim may exacerbate folate deficiency in subjects predisposed to this condition through disease or malnutrition. Accordingly, a calcium folinate supplement should be given to such individuals. In patients with megaloblastic anaemia due to folate deficiency the risks versus benefits of administering Daraprim require careful consideration.
Seizures
Caution should be exercised in administering Daraprim to patients with a history of seizures; large loading doses should be avoided in such patients (see section 4.8).
Risk of crystalluria
When a sulphonamide is given an adequate fluid intake should be ensured to minimise the risk of crystalluria.
Precautions applicable to sulphonamides
Since Daraprim is administered with a sulphonamide for the conditions indicated the general precautions applicable to sulphonamides should be observed.
Renal impairment
The kidney is not the major route of excretion of pyrimethamine and excretion is not significantly altered in patients with renal failure. There are, however, no substantial data on the use of Daraprim in patients with renal impairment, therefore Daraprim should be given with caution. Since Daraprim is co-administered with a sulphonamide, care should be taken to avoid accumulation of the sulphonamide in renally impaired patients.
Hepatic impairment
The liver is the main route for metabolism of pyrimethamine. Data on the use of Daraprim in patients with liver disease are limited. Daraprim should be given with caution to patients with hepatic impairment. There are no general recommendations for dosage reductions for liver-impaired states but consideration should be given to dose adjustment for individual cases.
Lactose
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
4.5 |
Daraprim Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Folate inhibitors, agents associated with myelosuppression
Daraprim, by its mode of action, may further depress folate metabolism in patients receiving treatment with other folate inhibitors, or agents associated with myelosuppression, including cotrimoxazole, trimethoprim, proguanil, zidovudine, or cytostatic agents (e.g. methotrexate).
Cases of fatal bone marrow aplasia have been associated with the administration of daunorubicin, cytosine arabinoside and pyrimethamine to individuals suffering from acute myeloid leukaemia.
Megaloblastic anaemia has been reported occasionally in individuals who took pyrimethamine concurrently with a trimethoprim/sulphonamide combination.
Methotrexate
Convulsions have occurred after concurrent administration of methotrexate and pyrimethamine to children with central nervous system leukaemia.
Other antimalarial drugs
Seizures have occasionally been reported when pyrimethamine was used in combination with other antimalarial drugs.
Lorazepam
The concurrent administration of lorazepam and Daraprim may induce hepatotoxicity.
Antacid salts, kaolin
In vitro data suggest that antacid salts and the anti-diarrhoeal agent kaolin reduce the absorption of pyrimethamine.
Highly protein bound compounds
The high protein binding exhibited by pyrimethamine may prevent protein binding by other compounds (eg. quinine or warfarin). This could affect the efficacy or toxicity of the concomitant drug depending on the levels of unbound drug.
4.6 |
Daraprim Tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
Daraprim should not be used during the first trimester of pregnancy unless the benefits outweigh the risk. Daraprim has been shown to be teratogenic in animal studies. The risks associated with the administration of Daraprim must be balanced against the dangers of abortion or foetal malformation due to the infection.
Treatment with Daraprim and sulfadiazine during pregnancy is indicated in the presence of confirmed placental or foetal infection or when the mother is at risk of serious sequelae. However, in view of the theoretical risk of foetal abnormality arising from the use of Daraprim in early pregnancy, its use in combination therapy should be restricted to the second and third trimesters.
Pregnant women receiving Daraprim must be given a concurrent folinic acid supplement.
Breastfeeding
Pyrimethamine enters human breast milk. It has been estimated that over a 9-day period an average weight infant would receive about 45% of the dose ingested by the mother. In view of the high doses of pyrimethamine and concurrent sulphonamides needed in toxoplasmosis treatment, breast feeding should be avoided for the duration of treatment.
Fertility
There are no relevant data available
4.7 |
Daraprim Tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. Some patients may experience dizziness or convulsions, therefore, caution is recommended (see section 4.8).
4.8 |
Daraprim Tablets | Clinical particulars - Undesirable effects | Undesirable effects
Since a concurrent sulphonamide is to be taken with pyrimethamine for the indications listed, the relevant prescribing information for the sulphonamide should be consulted for sulphonamide-associated adverse events.
It is important to note that the frequency categories assigned for each adverse event below are only estimates as suitable data for accurately calculating incidence were not available. Adverse events may vary in their incidence according to the indication and the possible contribution of concomitant sulphonamides to the occurrence of these events is unknown. In addition some events may be related to the underlying disease.
Adverse drug reactions (ADRs) are listed below by MedDRA system organ class and by frequency.
Frequencies are defined as:
very common β₯1/10,
common β₯1/100 and <1/10,
uncommon β₯1/1000 and <1/100,
rare β₯1/10,000 and <1/1000,
very rare <1/10,000.
Blood and lymphatic system disorders
Very common:
Anaemia
Common:
Leucopenia, thromboctopenia
Very rare:
Pancytopenia
Nervous system disorders
Very common:
Headache
Common:
Dizziness
Very rare:
Convulsions (see section 4.4 and section 4.7)
Respiratory, thoracic and mediastinal Disorders
Very rare:
Pneumonia with cellular and eosinophilic pulmonary infiltration (observed when pyrimethamine was administered once weekly in association with sulfadoxine)
Gastrointestinal disorders
Very common:
Vomiting, nausea, diarrhoea
Very rare:
Colic, buccal ulceration
Skin and subcutaneous tissue disorders
Very common:
Rash
Uncommon:
Abnormal skin pigmentation
Very rare:
Dermatitis
General disorders and administrative site conditions
Uncommon:
Fever
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 by searching for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Daraprim Tablets | Clinical particulars - Overdose | Overdose
Symptoms
Vomiting and convulsions occur in cases of severe, acute overdoses. Ataxia, tremor and respiratory depression can also occur. There have been isolated cases with fatal outcomes following acute overdose of pyrimethamine.
Chronic excess doses can result in bone marrow depression (e.g. megaloblastic anaemia, leucopenia, thrombocytopenia) resulting from folic acid deficiency.
Management
Routine supportive treatment, including maintenance of a clear airway and control of convulsions.
Adequate fluids should be given to ensure optimal diuresis.
To counteract possible folate deficiency, calcium folinate should be given until signs of toxicity have subsided. There may a delay of 7 to 10 days before the full leucopenic side effects become evident, therefore calcium folinate therapy should be continued for the period at risk.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
5. Pharmacological properties
5.1 |
Daraprim Tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
Pyrimethamine is almost completely absorbed from the gastrointestinal tract. Peak plasma concentrations generally occur 2 to 4 hours after a dose and can vary widely between individuals; concentrations ranging from 260 to 1411 ng/ml after daily oral doses of 25 mg.
Distribution
The volume of distribution for pyrimethamine is approximately 2L/kg. In patients with HIV infection, population pharmacokinetic analysis has indicated that the mean volume of distribution (corrected for bioavailability) is 246+/-64L.
About 80 to 90% of the pyrimethamine is bound to plasma proteins.
Pyrimethamine is mainly concentrated in the kidneys, lungs, liver, and spleen. In AIDS patients given daily dose of pyrimethamine, concentrations of about one-fifth of those in the serum occur in cerebrospinal fluid.
Pyrimethamine crosses the placenta. It is distributed into breast milk
Elimination
Pyrimethamine is predominantly metabolised by the liver. The mean elimination half-life is 85 hours. Pyrimethamine is slowly excreted in urine. In AIDS patients, the total clearance is 1.28+/-0.41L/h resulting in an elimination half life of 139+/-34h. Data are lacking on the nature of the metabolites of pyrimethamine, their route/rate of formation and elimination in man and any pharmacological activity, particularly after prolonged daily dosing.
Multiple dose studies indicate that steady state is achieved in 12 to 20 days with daily dosing. It is theoretically possible that metabolic pathways might be saturable, leading to excessive accumulation of the drug in some patients. However, it has been demonstrated that plasma levels are approximately proportional to dose at steady state so this appears unlikely. Genetic variation in the exposure to pyrimethamine has been reported but these data are unsubstantiated.
Some studies in patients with AIDS have indicated shorter half lives than those noted above: these are very likely to be a consequence of inappropriate sampling and analytical techniques. However, if there are patients in whom the half-life is particularly short, steady state therapeutic levels might be inadequate.
5.3 |
Daraprim Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Mutagenicity
In microbial tests, pyrimethamine was found to be non-mutagenic in the Ames Salmonella assay whereas DNA damage was seen in the Escherichia coli repair assay. Further in vitro data indicate that pyrimethamine induces mutagenic activity in mouse lymphoma cells in the absence, but not in the presence of metabolic activation.
Pyrimethamine also showed clastogenic activity in mammalian lymphocytes in the absence of metabolic activation.
Following intraperitoneal administration, pyrimethamine has been shown to induce chromosomal damage in male rodent germ cells although studies in somatic cells (micronucleus tests) are either negative or inconclusive. Studies following oral administration of pyrimethamine in rodents showed negative results in female germ cells and in male and female bone marrow/peripheral blood cells.
Carcinogenicity
A study in mice (dosed with either 500 or 1000 ppm pyrimethamine in the diet for 5 days per week, for 78 weeks) showed no evidence of carcinogenicity in females. Survival in the male mice did not allow for an assessment of carcinogenicity in this sex.
A similar study in rats dosed at 200 or 400 ppm pyrimethamine showed no evidence of carcinogenicity.
Teratogenicity
No changes in early development were seen in embryos from 15 mice given a single intra-gastric dose of pyrimethamine (50 mg/kg bodyweight) on the first day of gestation. However development of mouse and rat embryos in culture was severely hindered by pyrimethamine in a dose-dependent manner.
Pyrimethamine was teratogenic in rodents and in the Gottingen minipig in a dose-dependent manner.
Other studies in rats dosed at either 1 mg/kg or 10 mg/kg bodyweight showed some inhibition of developmental processes but no teratological effects.
Pyrimethamine was not teratogenic in rabbits at dose levels up to 100 mg/kg bodyweight/day administered on days 6 to 18 of pregnancy. Pyrimethamine markedly reduced early stage cell division in rabbit embryos but implantation and foetal development were normal.
Fertility
A study in rats dosed with 5 mg/kg bodyweight/day for 6 weeks resulted in reduced sperm concentrations and testis weights, but there were no effects on fertility. Reversible arrest of spermatogenesis was shown in a study on mice dosed with 200 mg/kg/day for 50 days. However, this dose is far in excess of human therapeutic doses.
6. |
Daraprim Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Lactose Monohydrate
Maize Starch
Hydrolysed Starch
Docusate sodium
Magnesium stearate
6.2 |
Daraprim Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Daraprim Tablets | Pharmaceutical particulars - Shelf life | Shelf life
5 years
6.4 |
Daraprim Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store below 30Β°C.
Store in the original container.
6.5 |
Daraprim Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
PVC/PVdC/aluminium foil blister pack or PVC/PVdC/child-resistant aluminium foil blister pack
Pack size: 30 tablets
6.6 |
Daraprim Tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Not applicable
7. |
Daraprim Tablets | Marketing authorisation holder | The Wellcome Foundation Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
Trading as:
GlaxoSmithKline UK
8. Marketing authorisation number(s)
PL 00003/5026R
9. |
Daraprim Tablets | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 25 September 1986
Date of latest renewal: 19 February 2011
10. |
Daraprim Tablets | Date of revision of the text | 07 February 2023 |
Darunavir 400 mg film-coated tablets | Name of the medicinal product | Darunavir 400 mg film-coated tablets
2. |
Darunavir 400 mg film-coated tablets | Qualitative and quantitative composition | Each film-coated tablet contains 400 mg of darunavir.
For the full list of excipients, see section 6.1.
3. |
Darunavir 400 mg film-coated tablets | Pharmaceutical form | Film-coated tablet.
Yellow, oval shaped (15.78 mm (L) X 7.94 mm (W)), biconvex, film-coated tablets de-bossed with 'V' on one side and '4' on the other side.
4. |
Darunavir 400 mg film-coated tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Darunavir, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.
Darunavir, co-administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adults and adolescents (aged 12 years and older, weighing at least 40 kg) (see section 4.2).
Darunavir 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are:
β’ antiretroviral therapy (ART)-naΓ―ve (see section 4.2).
β’ ART-experienced with no darunavir resistance associated mutations (DRV- RAMs) and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L. In deciding to initiate treatment with Darunavir in such ART-experienced patients, genotypic testing should guide the use of Darunavir (see sections 4.2, 4.3, 4.4 and 5.1).
4.2 |
Darunavir 400 mg film-coated tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Therapy should be initiated by a healthcare provider experienced in the management of HIV infection. After therapy with Darunavir has been initiated, patients should be advised not to alter the dosage, dose form or discontinue therapy without discussing with their healthcare provider.
The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer. Darunavir may therefore have different contraindications and recommendations for concomitant medications depending on whether the compound is boosted with ritonavir or cobicistat (see sections 4.3, 4.4 and 4.5).
Posology
Darunavir must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with Darunavir. Cobicistat is not indicated for use in twice daily regimens or for use in the paediatric population less than 12 years of age weighing less than 40 kg.
Darunavir is also available as an oral suspension for use in patients who are unable to swallow Darunavir tablets (please refer to the Summary of Product Characteristics for Darunavir oral suspension).
ART-naΓ―ve adult patients
The recommended dose regimen is 800 mg once daily taken with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food. Darunavir 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.
ART-experienced adult patients
The recommended dose regimens are as follows:
β’ In ART-experienced patients with no darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L (see section 4.1) a regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food may be used. Darunavir 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.
β’ In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food. See the Summary of Product Characteristics for Darunavir 600 mg tablets.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
ART-naΓ―ve paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken with food or 800 mg once daily with cobicistat 150 mg once daily taken with food (in adolescent patients 12 years of age or older). Darunavir 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen. The dose of cobicistat to be used with Darunavir in children less than 12 years of age has not been established.
ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The dose of cobicistat to be used with Darunavir in children less than 12 years of age has not been established.
The recommended dose regimens are as follows:
In ART-experienced patients without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L (see section 4.1) a regimen of 800 mg once daily with ritonavir 100 mg once daily taken with food or 800 mg once daily with cobicistat 150 mg once daily taken with food (in adolescent patients 12 years of age or older) may be used. Darunavir 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen. The dose of cobicistat to be used with Darunavir in children less than 12 years of age has not been established.
β’ In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen is described in the Summary of Product Characteristics for Darunavir 400 mg and 600 mg tablets.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
Advice on missed doses
If a once daily dose of Darunavir and/or cobicistat or ritonavir is missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of Darunavir and cobicistat or ritonavir with food as soon as possible. If this is noticed later than 12 hours after the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.
This guidance is based on the half-life of darunavir in the presence of cobicistat or ritonavir and the recommended dosing interval of approximately 24 hours.
If a patient vomits within 4 hours of taking the medicine, another dose of Darunavir with cobicistat or ritonavir should be taken with food as soon as possible. If a patient vomits more than 4 hours after taking the medicine, the patient does not need to take another dose of Darunavir with cobicistat or ritonavir until the next regularly scheduled time.
Special populations
Elderly
Limited information is available in this population, and therefore, Darunavir should be used with caution in this age group (see sections 4.4 and 5.2).
Hepatic impairment
Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, Darunavir should be used with caution in these patients. No pharmacokinetic data are available in patients with severe hepatic impairment. Severe hepatic impairment could result in an increase of darunavir exposure and a worsening of its safety profile. Therefore, Darunavir must not be used in patients with severe hepatic impairment (Child-Pugh Class C) (see sections 4.3, 4.4 and 5.2).
Renal impairment
No dose adjustment is required for darunavir/ritonavir in patients with renal impairment (see sections 4.4 and 5.2). Cobicistat has not been studied in patients receiving dialysis, and, therefore, no recommendation can be made for the use of darunavir/cobicistat in these patients.
Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum creatinine and modest declines in creatinine clearance. Hence, the use of creatinine clearance as an estimate of renal elimination capacity may be misleading. Cobicistat as a pharmacokinetic enhancer of darunavir should, therefore, not be initiated in patients with creatine clearance less than 70 ml/min if any co- administered agent requires dose adjustment based on creatinine clearance: e.g. emtricitabine, lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate) or adefovir dipovoxil.
For information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Paediatric population
Darunavir should not be used in children
- below 3 years of age, because of safety concerns (see sections 4.4 and 5.3), or,
- less than 15 kg body weight, as the dose for this population has not been established in a sufficient number of patients (see section 5.1).
Darunavir taken with cobicistat should not be used in children aged 3 to 11 years of age weighing < 40 kg as the dose of cobicistat to be used in these children has not been established (see sections 4.4 and 5.3).
Darunavir 400 and 800 mg tablets are not suitable for this patient population. Other formulations are available, see the Summary of Product Characteristics for Darunavir 75 mg, 150 mg, 600 mg tablets and 100 mg/ml oral suspension.
Pregnancy and postpartum
No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk (see sections 4.4, 4.6 and 5.2).
Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure (see sections 4.4 and 5.2). Therefore, therapy with Darunavir/cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with Darunavir/cobicistat should be switched to an alternative regimen (see sections 4.4 and 4.6). Darunavir/ritonavir may be considered as an alternative.
Method of administration
Patients should be instructed to take Darunavir with cobicistat or low dose ritonavir within 30 minutes after completion of a meal. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5 and 5.2).
4.3 |
Darunavir 400 mg film-coated tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with severe (Child-Pugh Class C) hepatic impairment.
Concomitant treatment with any of the following medicinal products given the expected decrease in plasma concentrations of darunavir, ritonavir and cobicistat and the potential for loss of therapeutic effect (see sections 4.4 and 4.5).
Applicable to darunavir boosted with either ritonavir or cobicistat:
- The combination product lopinavir/ritonavir (see section 4.5).
- Strong CYP3A inducers such as rifampicin and herbal preparations containing St John's Wort (Hypericum perforatum). Co-administration is expected to reduce plasma concentrations of darunavir, ritonavir and cobicistat, which could lead to loss of therapeutic effect and possible development of resistance (see sections 4.4 and 4.5).
Applicable to darunavir boosted with cobicistat, not when boosted with ritonavir:
- Darunavir boosted with cobicistat is more sensitive for CYP3A induction than darunavir boosted with ritonavir. Concomitant use with strong CYP3A inducers is contraindicated, since these may reduce the exposure to cobicistat and darunavir leading to loss of therapeutic effect. Strong CYP3A inducers include e.g. carbamazepine, phenobarbital and phenytoin (see sections 4.4 and 4.5).
Darunavir boosted with either ritonavir or cobicistat inhibits the elimination of active substances that are highly dependent on CYP3A for clearance, which results in increased exposure to the co-administered medicinal product. Therefore, concomitant treatment with such medicinal products for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated (applies to darunavir boosted with either ritonavir or cobicistat).
These active substances include e.g.:
- alfuzosin
- amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
- astemizole, terfenadine
- colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)
- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
- elbasvir/grazoprevir
- cisapride
- dapoxetine
- domperidone
- naloxegol
- lurasidone, pimozide, quetiapine, sertindole (see section 4.5)
- triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5)
- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil
- simvastatin, lovastatin and lomitapide (see section 4.5)
- ticagrelor (see section 4.5).
4.4 |
Darunavir 400 mg film-coated tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Regular assessment of virological response is advised. In the setting of lack or loss of virological response, resistance testing should be performed.
Darunavir 400 mg or 800 mg must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products (see section 5.2). The Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with darunavir.
Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect darunavir concentrations. It is not recommended to alter the dose of cobicistat or ritonavir.
Darunavir binds predominantly to Ξ±1-acid glycoprotein. This protein binding is concentration-dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products highly bound to Ξ±1-acid glycoprotein cannot be ruled out (see section 4.5).
ART-experienced patients β once daily dosing
Darunavir used in combination with cobicistat or low dose ritonavir once daily in ART-experienced patients should not be used in patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA β₯ 100,000 copies/ml or CD4+ cell count < 100 cells x 106/L (see section 4.2). Combinations with optimised background regimen (OBRs) other than β₯ 2 NRTIs have not been studied in this population. Limited data are available in patients with HIV-1 clades other than B (see section 5.1).
Paediatric population
Darunavir is not recommended for use in paediatric patients below 3 years of age or less than 15 kg body weight (see sections 4.2 and 5.3).
Pregnancy
Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk. Caution should be used in pregnant women with concomitant medications which may further decrease darunavir exposure (see sections 4.5 and 5.2).
Treatment with darunavir/cobicistat 800/150 mg once daily during the second and third trimester has been shown to result in low darunavir exposure, with a reduction of around 90% in Cmin levels (see section 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in darunavir exposure may result in virological failure and an increased risk of mother to child transmission of HIV infection. Therefore, therapy with darunavir/cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with darunavir/cobicistat should be switched to an alternative regimen (see sections 4.2 and 4.6).
Darunavir given with low dose ritonavir may be considered as an alternative.
Elderly
As limited information is available on the use of darunavir in patients aged 65 and over, caution should be exercised in the administration of darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2 and 5.2).
Severe skin reactions
During the darunavir/ritonavir clinical development program (N=3,063), severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported. darunavir should be discontinued immediately if signs or symptoms of severe skin reactions develop. These can include, but are not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
Rash occurred more commonly in treatment-experienced patients receiving regimens containing darunavir/ritonavir + raltegravir compared to patients receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir (see section 4.8).
Darunavir contains a sulphonamide moiety. Darunavir should be used with caution in patients with a known sulphonamide allergy.
Hepatotoxicity
Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with darunavir. During the darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.
Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir used in combination with cobicistat or low dose ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of darunavir used in combination with cobicistat or low dose ritonavir treatment.
If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients using darunavir used in combination with cobicistat or low dose ritonavir, interruption or discontinuation of treatment should be considered promptly.
Patients with coexisting conditions
Hepatic impairment
The safety and efficacy of darunavir have not been established in patients with severe underlying liver disorders and darunavir is therefore contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, darunavir should be used with caution in patients with mild or moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).
Renal impairment
No special precautions or dose adjustments for darunavir/ritonavir are required in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these patients (see sections 4.2 and 5.2). Cobicistat has not been studied in patients receiving dialysis, therefore, no recommendation can be made for the use of darunavir/cobicistat in these patients (see section 4.2).
Cobicistat decreases the estimated creatinine clearance due to inhibition of tubular secretion of creatinine. This should be taken into consideration if darunavir with cobicistat is administered to patients in whom the estimated creatinine clearance is used to adjust doses of co-administered medicinal products (see section 4.2 and cobicistat SmPC).
There are currently inadequate data to determine whether co-administration of tenofovir disoproxil and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil without cobicistat.
Haemophiliac patients
There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding.
Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with darunavir co-administered with low dose ritonavir.
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).
Interactions with medicinal products
Several of the interaction studies have been performed with darunavir at lower than recommended doses. The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated. For full information on interactions with other medicinal products see section 4.5.
Pharmacokinetic enhancer and concomitant medications
Darunavir has different interaction profiles depending on whether the compound is boosted with ritonavir or cobicistat:
- Darunavir boosted with cobicistat is more sensitive for CYP3A induction: concomitant use of darunavir/cobicistat and strong CYP3A inducers is therefore contraindicated (see section 4.3), and concomitant use with weak to moderate CYP3A inducers is not recommended (see section 4.5). Concomitant use of darunavir/ritonavir and darunavir/cobicistat with strong CYP3A inducers such as lopinavir/ritonavir, rifampicin and herbal products containing St John's Wort, Hypericum perforatum, is contraindicated (see section 4.5).
- Unlike ritonavir, cobicistat does not have inducing effects on enzymes or transport proteins (see section 4.5). If switching the pharmacoenhancer from ritonavir to cobicistat, caution is required during the first two weeks of treatment with darunavir/cobicistat, particularly if doses of any concomitantly administered medicinal products have been titrated or adjusted during use of ritonavir as a pharmacoenhancer. A dose reduction of the co-administered drug may be needed in these cases.
Efavirenz in combination with boosted darunavir may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used. See the Summary of Product Characteristics for darunavir 600 mg tablets (see section 4.5).
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-glycoprotein (P-gp; see sections 4.3 and 4.5).
4.5 |
Darunavir 400 mg film-coated tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
The interaction profile of darunavir may differ depending on whether ritonavir or cobicistat is used as pharmacoenhancer. The recommendations given for concomitant use of darunavir and other medicinal products may therefore differ depending on whether darunavir is boosted with ritonavir or cobicistat (see sections 4.3 and 4.4), and caution is also required during the first time of treatment if switching the pharmacoenhancer from ritonavir to cobicistat (see section 4.4).
Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer)
Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of these compounds and consequently that of darunavir, leading to loss of therapeutic effect and possible development of resistance (see sections 4.3 and 4.4). CYP3A inducers that are contraindicated include rifampicin, St John's Wort and lopinavir.
Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrations of darunavir and ritonavir. Co- administration with strong CYP3A4 inhibitors is not recommended and caution is warranted, these interactions are described in the interaction table below (e.g. indinavir, azole antifungals like clotrimazole).
Medicinal products that affect darunavir exposure (cobicistat as pharmacoenhancer)
Darunavir and cobicistat are metabolised by CYP3A, and co-administration with CYP3A inducers may therefore result in subtherapeutic plasma exposure to darunavir. Darunavir boosted with cobicistat is more sensitive to CYP3A induction than ritonavir-boosted darunavir: co-administration of darunavir/cobicistat with medicinal products that are strong inducers of CYP3A (e.g. St John's Wort, rifampicin, carbamazepine, phenobarbital, and phenytoin) is contraindicated (see section 4.3).
Co-administration of darunavir/cobicistat with weak to moderate CYP3A inducers (e.g. efavirenz, etravirine, nevirapine, fluticasone, and bosentan) is not recommended (see interaction table below).
For co-administration with strong CYP3A4 inhibitors, the same recommendations apply independent of whether darunavir is boosted with ritonavir or with cobicistat (see section above).
Medicinal products that may be affected by darunavir boosted with ritonavir
Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co- administration of darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or transported by P-gp may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.
Darunavir co-administered with low dose ritonavir must not be combined with medicinal products that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) (see section 4.3).
Co-administration of boosted darunavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see the Interaction table below).
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily. Therefore, darunavir must only be used in combination with a pharmacokinetic enhancer (see sections 4.4 and 5.2).
A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to the presence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions. Co- administration of darunavir and ritonavir with medicinal products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone, repaglinide) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration with substrates of these transporters can result in increased plasma concentrations of these compounds (e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).
Medicinal products that may be affected by darunavir boosted with cobicistat
The recommendations for darunavir boosted with ritonavir are similar to the recommendations for darunavir boosted with cobicistat with regard to substrates of CYP3A4, CYP2D6, P-glycoprotein, OATP1B1 and OATP1B3 (see contraindications and recommendations presented in the section above). Cobicistat 150 mg given with darunavir 800 mg once daily enhances darunavir pharmacokinetic parameters in a comparable way to ritonavir (see section 5.2).
Unlike ritonavir, cobicistat does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. For further information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Interaction table
Interaction studies have only been performed in adults.
Several of the interaction studies (indicated by# in the table below) have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated.
The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer. Darunavir may therefore have different recommendations for concomitant medications depending on whether the compound is boosted with ritonavir or cobicistat. No interaction studies presented in the table have been performed with darunavir boosted with cobicistat. The same recommendations apply, unless specifically indicated. For further information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products are listed in the table below. The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (β), below (β) or above (β) the 80-125% range (not determined as βNDβ).
In the table below the specific pharmacokinetic enhancer is specified when recommendations differ. When the recommendation is the same for darunavir when co-administered with a low dose ritonavir or cobicistat, the term βboosted darunavirβ is used.
The below list of examples of drug-drug interactions is not comprehensive and therefore the label of each drug that is co-administered with darunavir should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.
INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal product examples by therapeutic area
Interaction Geometric mean change (%)
Recommendations concerning co- administration
HIV ANTIRETROVIRALS
Integrase strand transfer inhibitors
Dolutegravir
dolutegravir AUC β 22%
dolutegravir C24h β 38%
dolutegravir Cmax β 11%
darunavir β*
* Using cross-study comparisons to historical pharmacokinetic data
Boosted darunavir and dolutegravir can be used without dose adjustment.
Raltegravir
Some clinical studies suggest raltegravir may cause a modest decrease in darunavir plasma concentrations.
At present the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically relevant.
Boosted darunavir and raltegravir can be used without dose adjustments.
Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine 400 mg once daily
didanosine AUC β 9%
didanosine Cmin ND
didanosine Cmax β 16%
darunavir AUC β
darunavir Cmin β
darunavir Cmax β
Boosted darunavir and didanosine can be used without dose adjustments.
Didanosine is to be administered on an empty stomach, thus it should be administered 1 hour before or 2 hours after boosted darunavir given with food.
Tenofovir disoproxil 245 mg once dailyβ‘
tenofovir AUC β 22%
tenofovir Cmin β 37%
tenofovir Cmax β 24%
#darunavir AUC β 21%
#darunavir Cmin β 24%
#darunavir Cmax β 16%
(β tenofovir from effect on MDR-1 transport in the renal tubules)
Monitoring of renal function may be indicated when boosted darunavir is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.
Darunavir co-administered with cobicistat lowers the creatinine clearance. Refer to section 4.4 if creatinine clearance is used for dose adjustment of tenofovir disoproxil.
Emtricitabine/tenofovir alafenamide
Tenofovir alafenamide β
Tenofovir β
The recommended dose of emtricitabine/tenofovir alafenamide is 200/10 mg once daily when used with boosted darunavir.
Abacavir
Emtricitabine
Lamivudine
Stavudine
Zidovudine
Not studied. Based on the different elimination pathways of the other NRTIs zidovudine, emtricitabine, stavudine, lamivudine, that are primarily renally excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and boosted darunavir.
Boosted darunavir can be used with these NRTIs without dose adjustment.
Darunavir co-administered with cobicistat lowers the creatinine clearance. Refer to section 4.4 if creatinine clearance is used for dose adjustment of emtricitabine or lamivudine.
Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz 600 mg once daily
efavirenz AUC β 21%
efavirenz Cmin β 17%
efavirenz Cmax β 15%
#darunavir AUC β 13%
#darunavir Cmin β 31%
#darunavir Cmax β 15%
(β efavirenz from CYP3A inhibition)
(β darunavir from CYP3A induction)
Clinical monitoring for central nervous system toxicity associated with increased exposure to efavirenz may be indicated when darunavir co- administered with low dose ritonavir is given in combination with efavirenz.
Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in sub- optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used (see section 4.4).
Co-administration with darunavir co-administered with cobicistat is not recommended (see section 4.4).
Etravirine 100 mg twice daily
etravirine AUC β 37%
etravirine Cmin β 49%
etravirine Cmax β 32%
darunavir AUC β 15%
darunavir Cmin β
darunavir Cmax β
darunavir co-administered with low dose ritonavir and etravirine 200 mg twice daily can be used without dose adjustments.
Co-administration with darunavir co-administered with cobicistat is not recommended (see section 4.4).
Nevirapine 200 mg twice daily
nevirapine AUC β 27%
nevirapine Cmin β 47%
nevirapine Cmax β 18%
#darunavir: concentrations were consistent with historical data (β nevirapine from CYP3A inhibition)
Darunavir co-administered with low dose ritonavir and nevirapine can be used without dose adjustments.
Co-administration with darunavir co-administered with cobicistat is not recommended (see section 4.4).
Rilpivirine 150 mg once daily
rilpivirine AUC β 130%
rilpivirine Cmin β 178%
rilpivirine Cmax β 79%
darunavir AUC β
darunavir Cmin β 11%
darunavir Cmax β
Boosted darunavir and rilpivirine can be used without dose adjustments.
HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavirβ
Atazanavir 300 mg once daily
atazanavir AUC β
atazanavir Cmin β 52%
atazanavir Cmax β 11%
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Atazanavir: comparison of atazanavir/ritonavir 300/100 mg once daily vs. atazanavir 300 mg once daily in combination with darunavir/ritonavir 400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg twice daily in combination with atazanavir 300 mg once daily.
Darunavir co-administered with low dose ritonavir and atazanavir can be used without dose adjustments.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).
Indinavir 800 mg twice daily
indinavir AUC β 23%
indinavir Cmin β 125%
indinavir Cmax β
#darunavir AUC β 24%
#darunavir Cmin β 44%
#darunavir Cmax β 11%
Indinavir: comparison of indinavir/ritonavir 800/100 mg twice daily vs. indinavir/darunavir/ritonavir 800/400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with indinavir 800 mg twice daily.
When used in combination with darunavir co-administered with low dose ritonavir, dose adjustment of indinavir from 800 mg twice daily to 600 mg twice daily may be warranted in case of intolerance.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).
Saquinavir 1,000 mg twice daily
#darunavir AUC β 26%
#darunavir Cmin β 42%
#darunavir Cmax β 17%
saquinavir AUC β 6%
saquinavir Cmin β 18%
saquinavir Cmax β 6%
Saquinavir: comparison of saquinavir/ritonavir 1,000/100 mg twice daily vs. saquinavir/darunavir/ritonavir 1,000/400/100 mg twice daily
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with saquinavir 1,000 mg twice daily.
It is not recommended to combine darunavir co- administered with low dose ritonavir with saquinavir.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).
HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavirβ
Lopinavir/ritonavir 400/100 mg twice daily
Β
Β
Β
Β
Lopinavir/ritonavir 533/133.3 mg twice daily
lopinavir AUC β 9%
lopinavir Cmin β 23%
lopinavir Cmax β 2%
darunavir AUC β 38%β‘
darunavir Cmin β 51%β‘
darunavir Cmax β 21%β‘
lopinavir AUC β
lopinavir Cmin β 13%
lopinavir Cmax β 11%
darunavir AUC β 41%
darunavir Cmin β 55%
darunavir Cmax β 21%
β‘ based upon non dose normalised values
Due to a decrease in the exposure (AUC) of darunavir by 40%, appropriate doses of the combination have not been established. Hence, concomitant use of boosted darunavir and the combination product lopinavir/ritonavir is contraindicated (see section 4.3).
CCR5 ANTAGONIST
Maraviroc 150 mg twice daily
maraviroc AUC β 305%
maraviroc Cmin ND
maraviroc Cmax β 129%
darunavir, ritonavir concentrations were consistent with historical data
The maraviroc dose should be 150 mg twice daily when co- administered with boosted darunavir.
Ξ±1-ADRENORECEPTOR ANTAGONIST
Alfuzosin
Based on theoretical considerations darunavir is expected to increase alfuzosin plasma concentrations. (CYP3A inhibition)
Co-administration of boosted darunavir and alfuzosin is contraindicated (see section 4.3).
ANAESTHETIC
Alfentanil
Not studied. The metabolism of alfentanil is mediated via CYP3A, and may as such be inhibited by boosted darunavir.
The concomitant use with boosted darunavir may require to lower the dose of alfentanil and requires monitoring for risks of prolonged or delayed respiratory depression.
ANTIANGINA/ANTIARRHYTHMIC
Disopyramide
Flecainide
Lidocaine (systemic)
Mexiletine
Propafenone
Amiodarone
Bepridil
Dronedarone
Ivabradine
Quinidine
Ranolazine
Not studied. Boosted darunavir is expected to increase these antiarrhythmic plasma concentrations.
(CYP3A and/or CYP2D6 inhibition)
Caution is warranted and therapeutic concentration monitoring, if available, is recommended for these antiarrhythmics when co- administered with boosted darunavir.
Co-administration of boosted darunavir and amiodarone, bepridil, dronedarone, ivabradine, quinidine, or ranolazine is contraindicated (see section 4.3).
Digoxin 0.4 mg single dose
digoxin AUC β 61%
digoxin Cmin ND
digoxin Cmax β 29%
(β digoxin from probable inhibition of P-gp)
Given that digoxin has a narrow therapeutic index, it is recommended that the lowest possible dose of digoxin should initially be prescribed in case digoxin is given to patients on boosted darunavir therapy. The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.
ANTIBIOTIC
Clarithromycin 500 mg twice daily
clarithromycin AUC β 57%
clarithromycin Cmin β 174%
clarithromycin Cmax β 26%
#darunavir AUC β 13%
#darunavir Cmin β 1%
#darunavir Cmax β17%
14-OH-clarithromycin concentrations were not detectable when combined with darunavir/ritonavir.
(β clarithromycin from CYP3A inhibition and possible P-gp inhibition)
Caution should be exercised when clarithromycin is combined with boosted darunavir.
For patients with renal impairment the Summary of Product Characteristics for clarithromycin should be consulted for the recommended dose.
ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban
Rivaroxaban
Not studied. Co-administration of boosted darunavir with these anticoagulants may increase concentrations of the anticoagulant. (CYP3A and/or P-gp inhibition)
The use of boosted darunavir with a direct oral anticoagulant (DOAC) that is metabolised by CYP3A4 and transported by P-gp is not recommended as this may lead to an increased bleeding risk.
Dabigatran etexilate
Edoxaban
Β
Β
Β
Β
Β
Β
Β
Β
Β
Β
Β
Β
Ticagrelor
Β
Β
Β
Clopidogrel
dabigatran etexilate (150 mg):
darunavir/ritonavir 800/100 mg single dose:
dabigatran AUC β 72%
dabigatran Cmax β 64%
darunavir/ritonavir 800/100 mg once daily:
dabigatran AUC β 18%
dabigatran Cmax β 22%
darunavir/cobicistat 800/150 mg single dose:
dabigatran AUC β 164%
dabigatran Cmax β 164%
darunavir/cobicistat 800/150 mg once daily:
dabigatran AUC β 88%
dabigatran Cmax β 99%
Based on theoretical considerations, co-administration of boosted darunavir with ticagrelor may increase concentrations of ticagrelor (CYP3A and/or P-glycoprotein inhibition).
Not studied. Co-administration of clopidogrel with boosted darunavir is expected to decrease clopidogrel active metabolite plasma concentration, which may reduce the antiplatelet activity of clopidogrel
Darunavir/ritonavir:
Clinical monitoring and/or dose reduction of the DOAC should be considered when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with Darunavir/rtv.
Darunavir/cobicistat:
Clinical monitoring and dose reduction is required when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with Darunavir/cobi.
Β
Β
Β
Concomitant administration of boosted darunavir with ticagrelor is contraindicated (see section 4.3).
Β
Co-administration of clopidogrel with boosted darunavir is not recommended. Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended.
Warfarin
Not studied. Warfarin concentrations may be affected when co-administered with boosted darunavir.
It is recommended that the international normalised ratio (INR) be monitored when warfarin is combined with boosted darunavir.
ANTICONVULSANTS
Phenobarbital
Phenytoin
Not studied. Phenobarbital and phenytoin are expected to decrease plasma concentrations of darunavir and its pharmacoenhancer. (induction of CYP450 enzymes)
Darunavir co-administered with low dose ritonavir should not be used in combination with these medicines.
The use of these medicines with darunavir/cobicistat is contraindicated (see section 4.3).
Carbamazepine 200 mg twice daily
carbamazepine AUC β 45%
carbamazepine Cmin β 54%
carbamazepine Cmax β 43%
darunavir AUC β
darunavir Cmin β 15%
darunavir Cmax β
No dose adjustment for darunavir/ritonavir is recommended. If there is a need to combine darunavir/ritonavir and carbamazepine, patients should be monitored for potential carbamazepine-related adverse events. Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response.
Based upon the findings, the carbamazepine dose may need to be reduced by 25% to 50% in the presence of darunavir/ritonavir.
The use of carbamazepine with darunavir co- administered with cobicistat is contraindicated (see section 4.3).
Clonazepam
Not studied. Co-administration of boosted darunavir with clonazepam may increase concentrations of clonazepam. (CYP3A inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir with clonazepam.
ANTIDEPRESSANTS
Paroxetine 20 mg once daily
Β
Β
Β
Β
Sertraline 50 mg once daily
Β
Β
Β
Β
Β
Β
Β
Β
Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone
paroxetine AUC β 39%
paroxetine Cmin β 37%
paroxetine Cmax β 36%
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
sertraline AUC β 49%
sertraline Cmin β 49%
sertraline Cmax β 44%
#darunavir AUC β
#darunavir Cmin β 6%
#darunavir Cmax β
In contrast to these data with darunavir/ritonavir, darunavir/cobicistat may increase these antidepressant plasma concentrations (CYP2D6 and/or CYP3A inhibition).
Concomitant use of boosted darunavir and these antidepressants may increase concentrations of the antidepressant.
(CYP2D6 and/or CYP3A inhibition)
If antidepressants are co- administered with boosted darunavir, the recommended approach is a dose titration of the antidepressant based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of these antidepressants who start treatment with boosted darunavir should be monitored for antidepressant response.
Β
Β
Β
Β
Β
Β
Β
Β
Β
Clinical monitoring is recommended when co- administering boosted darunavir with these antidepressants and a dose adjustment of the antidepressant may be needed.
ANTI-DIABETICS
Metformin
Not studied. Based on theoretical considerations darunavir co- administered with cobicistat is expected to increase metformin plasma concentrations.
(MATE1 inhibition)
Careful patient monitoring and dose adjustment of metformin is recommended in patients who are taking darunavir co- administered with cobicistat. (not applicable for darunavir co-administered with ritonavir)
ANTIEMETICS
Domperidone
Not studied.
Co-administration of domperidone with boosted darunavir is contraindicated.
ANTIFUNGALS
Voriconazole
Not studied. Ritonavir may decrease plasma concentrations of voriconazole.
(induction of CYP450 enzymes)
Concentrations of voriconazole may increase or decrease when co- administered with darunavir co- administered with cobicistat.
(inhibition of CYP450 enzymes)
Voriconazole should not be combined with boosted darunavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Fluconazole
Isavuconazole
Itraconazole
Posaconazole
Clotrimazole
Not studied. Boosted darunavir may increase antifungal plasma concentrations and posaconazole, isavuconazole, itraconazole or fluconazole may increase darunavir concentrations. (CYP3A and/or P-gp inhibition)
Not studied. Concomitant systemic use of clotrimazole and boosted darunavir may increase plasma concentrations of darunavir and/or clotrimazole.
Darunavir AUC24h β 33% (based on population pharmacokinetic model)
Caution is warranted and clinical monitoring is recommended.
When co-administration is required the daily dose of itraconazole should not exceed 200 mg.
ANTIGOUT MEDICINES
Colchicine
Not studied. Concomitant use of colchicine and boosted darunavir may increase the exposure to colchicine.
(CYP3A and/ or P-gp inhibition)
A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with boosted darunavir is required. For patients with renal or hepatic impairment colchicine with boosted darunavir is contraindicated (see sections 4.3 and 4.4).
ANTIMALARIALS
Artemether/Lumefantrine 80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours
artemether AUC β 16%
artemether Cmin β
artemether Cmax β 18%
dihydroartemisinin AUC β 18%
dihydroartemisinin Cmin β
dihydroartemisinin Cmax β 18%
lumefantrine AUC β 175%
lumefantrine Cmin β 126%
lumefantrine Cmax β 65%
darunavir AUC β
darunavir Cmin β 13%
darunavir Cmax β
The combination of boosted darunavir and artemether/lumefantrine can be used without dose adjustments; however, due to the increase in lumefantrine exposure, the combination should be used with caution.
ANTIMYCOBACTERIALS
Rifampicin
Rifapentine
Not studied. Rifapentine and rifampicin are strong CYP3A inducers and have been shown to cause profound decreases in concentrations of other protease inhibitors, which can result in virological failure and resistance development (CYP450 enzyme induction). During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with low dose ritonavir, a high frequency of liver reactions was seen with rifampicin.
The combination of rifapentine and boosted darunavir is not recommended.
The combination of rifampicin and boosted darunavir is contraindicated (see section 4.3).
Rifabutin 150 mg once every other day
rifabutin AUC** β 55%
rifabutin Cmin** β ND
rifabutin Cmax** β
darunavir AUC β 53%
darunavir Cmin β 68%
darunavir Cmax β 39%
** sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite)
The interaction trial showed a comparable daily systemic exposure for rifabutin between treatment at 300 mg once daily alone and 150 mg once every other day in combination with darunavir/ritonavir (600/100 mg twice daily) with an about 10-fold increase in the daily exposure to the active metabolite 25-O- desacetylrifabutin.
Furthermore, AUC of the sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite) was increased 1.6-fold, while Cmax remained comparable.
Data on comparison with a 150 mg once daily reference dose is lacking.
(Rifabutin is an inducer and substrate of CYP3A.) An increase of systemic exposure to darunavir was observed when darunavir co- administered with 100 mg ritonavir was co-administered with rifabutin (150 mg once every other day).
A dosage reduction of rifabutin by 75% of the usual dose of 300 mg/day (i.e. rifabutin 150 mg once every other day) and increased monitoring for rifabutin related adverse events is warranted in patients receiving the combination with darunavir co-administered with ritonavir. In case of safety issues, a further increase of the dosing interval for rifabutin and/or monitoring of rifabutin levels should be considered.
Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV infected patients.
Based upon the safety profile of darunavir/ritonavir, the increase in darunavir exposure in the presence of rifabutin does not warrant a dose adjustment for darunavir/ritonavir.
Based on pharmacokinetic modeling, this dosage reduction of 75% is also applicable if patients receive rifabutin at doses other than 300 mg/day.
Co-administration of darunavir co-administered with cobicistat and rifabutin is not recommended.
ANTINEOPLASTICS
Dasatinib
Nilotinib
Vinblastine
Vincristine
Β
Β
Β
Everolimus
Irinotecan
Not studied. Boosted darunavir is expected to increase these antineoplastic plasma concentrations.
(CYP3A inhibition)
Concentrations of these medicinal products may be increased when co- administered with boosted darunavir resulting in the potential for increased adverse events usually associated with these agents.
Caution should be exercised when combining one of these antineoplastic agents with boosted darunavir.
Concomitant use of everolimus or irinotecan and boosted darunavir is not recommended.
ANTIPSYCHOTICS/NEUROLEPTICS
Quetiapine
Not studied. Boosted darunavir is expected to increase these antipsychotic plasma concentrations.
(CYP3A inhibition)
Concomitant administration of boosted darunavir and quetiapine is contraindicated as it may increase quetiapine-related toxicity. Increased concentrations of quetiapine may lead to coma (see section 4.3).
Perphenazine
Risperidone
Thioridazine
Lurasidone
Pimozide
Sertindole
Not studied. Boosted darunavir is expected to increase these antipsychotic plasma concentrations.
(CYP3A, CYP2D6 and/or P-gp inhibition)
A dose decrease may be needed for these drugs when co-administered with boosted darunavir.
Concomitant administration of boosted darunavir and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).
Ξ²-BLOCKERS
Carvedilol
Metoprolol
Timolol
Not studied. Boosted darunavir is expected to increase these Ξ²- blocker plasma concentrations. (CYP2D6 inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir with Ξ²-blockers. A lower dose of the Ξ²-blocker should be considered.
CALCIUM CHANNEL BLOCKERS
Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil
Not studied. Boosted darunavir can be expected to increase the plasma concentrations of calcium channel blockers.
(CYP3A and/or CYP2D6 inhibition)
Clinical monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with boosted darunavir.
CORTICOSTEROIDS
Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone)
Fluticasone: in a clinical study where ritonavir 100 mg capsules twice daily were co-administered with 50 ΞΌg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82- 89%). Greater effects may be expected when fluticasone is inhaled.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone. The effects of high fluticasone systemic exposure on ritonavir plasma levels are unknown.
Other corticosteroids: interaction not studied. Plasma concentrations of these medicinal products may be increased when co-administered with boosted darunavir, resulting in reduced serum cortisol concentrations.
Concomitant use of boosted darunavir and corticosteroids (all routes of administration) that are metabolised by CYP3A may increase the risk of development of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.
Co-administration with CYP3A- metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects.
Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone should be considered, particularly for long term use.
Dexamethasone (systemic)
Not studied. Dexamethasone may decrease plasma concentrations of darunavir.
(CYP3A induction)
Systemic dexamethasone should be used with caution when combined with boosted darunavir.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan
Not studied. Concomitant use of bosentan and boosted darunavir may increase plasma concentrations of bosentan.
Bosentan is expected to decrease plasma concentrations of darunavir and/or its pharmacoenhancer. (CYP3A induction)
When administered concomitantly with darunavir and low dose ritonavir, the patient's tolerability of bosentan should be monitored.
Co-administration of darunavir co-administered with cobicistat and bosentan is not recommended.
HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A protease inhibitors
Elbasvir/grazoprevir
Boosted darunavir may increase the exposure to grazoprevir. (CYP3A and OATP1B inhibition)
Concomitant use of boosted darunavir and elbasvir/grazoprevir is contraindicated (see section 4.3).
Glecaprevir/pibrentasvir
Based on theoretical considerations boosted darunavir may increase the exposure to glecaprevir and pibrentasvir. (P- gp, BCRP and/or OATP1B1/3 inhibition)
It is not recommended to co- administer boosted darunavir with glecaprevir/pibrentasvir.
HERBAL PRODUCTS
St John's Wort (Hypericum perforatum)
Not studied. St John's Wort is expected to decrease the plasma concentrations of darunavir or its pharmacoenhancers. (CYP450 induction)
Boosted darunavir must not be used concomitantly with products containing St John's Wort (Hypericum perforatum) (see section 4.3). If a patient is already taking St John's Wort, stop St John's Wort and if possible check viral levels.
Darunavir exposure (and also ritonavir exposure) may increase on stopping St John's Wort. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's Wort.
HMG CO-A REDUCTASE INHIBITORS
Lovastatin
Simvastatin
Not studied. Lovastatin and simvastatin are expected to have markedly increased plasma concentrations when co- administered with boosted darunavir.
(CYP3A inhibition)
Increased plasma concentrations of lovastatin or simvastatin may cause myopathy, including rhabdomyolysis. Concomitant use of boosted darunavir with lovastatin and simvastatin is therefore contraindicated (see section 4.3).
Atorvastatin 10 mg once daily
atorvastatin AUC β 3-4 fold
atorvastatin Cmin β β5.5-10 fold
atorvastatin Cmax β β2 fold
#darunavir/ritonavir
atorvastatin AUC β 290% Ξ©
atorvastatin Cmax β 319% Ξ©
atorvastatin Cmin ND Ξ©
Ξ© with darunavir/cobicistat 800/150 mg
When administration of atorvastatin and boosted darunavir is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily. A gradual dose increase of atorvastatin may be tailored to the clinical response.
Pravastatin 40 mg single dose
pravastatin AUC β 81%ΒΆ
pravastatin Cmin ND
pravastatin Cmax β 63%
ΒΆ an up to five-fold increase was seen in a limited subset of subjects
When administration of pravastatin and boosted darunavir is required, it is recommended to start with the lowest possible dose of pravastatin and titrate up to the desired clinical effect while monitoring for safety.
Rosuvastatin 10 mg once daily
rosuvastatin AUC β 48%β
rosuvastatin Cmax β 144%β
β based on published data with darunavir/ritonavir
rosuvastatin AUC β 93%Β§
rosuvastatin Cmax β 277%Β§
rosuvastatin Cmin ND§
Β§ with darunavir/cobicistat 800/150 mg
When administration of rosuvastatin and boosted darunavir is required, it is recommended to start with the lowest possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for safety.
OTHER LIPID MODIFYING AGENTS
Lomitapide
Based on theoretical considerations boosted darunavir is expected to increase the exposure of lomitapide when co-administered.
(CYP3A inhibition)
Co-administration is contraindicated (see section 4.3).
H2-RECEPTOR ANTAGONISTS
Ranitidine 150 mg twice daily
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Boosted darunavir can be co-administered with H2- receptor antagonists without dose adjustments.
IMMUNOSUPPRESSANTS
Ciclosporin
Sirolimus
Tacrolimus
Everolimus
Not studied. Exposure to these immunosuppressants will be increased when co-administered with boosted darunavir.
(CYP3A inhibition)
Therapeutic drug monitoring of the immunosuppressive agent must be done when co- administration occurs.
Concomitant use of everolimus and boosted darunavir is not recommended.
INHALED BETA AGONISTS
Salmeterol
Not studied. Concomitant use of salmeterol and boosted darunavir may increase plasma concentrations of salmeterol.
Concomitant use of salmeterol and boosted darunavir is not recommended. The combination may result in increased risk of cardiovascular adverse event with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE
Methadone individual dose ranging from 55 mg to 150 mg once daily
R(-) methadone AUC β 16% R(-)
methadone Cmin β 15% R(-)
methadone Cmax β 24%
Darunavir/cobicistat may, in contrast, increase methadone plasma concentrations (see cobicistat SmPC).
No adjustment of methadone dosage is required when initiating co-administration with boosted darunavir.
However, adjustment of the methadone dose may be necessary when concomitantly administered for a longer period of time. Therefore, clinical monitoring is recommended, as maintenance therapy may need to be adjusted in some patients.
Buprenorphine/naloxone 8/2 mgβ16/4 mg once daily
buprenorphine AUC β 11%
buprenorphine Cmin β
buprenorphine Cmax β 8%
norbuprenorphine AUC β 46%
norbuprenorphine Cmin β 71%
norbuprenorphine Cmax β 36%
naloxone AUC β
naloxone Cmin ND
naloxone Cmax β
The clinical relevance of the increase in norbuprenorphine pharmacokinetic parameters has not been established. Dose adjustment for buprenorphine may not be necessary when co-administered with boosted darunavir but a careful clinical monitoring for signs of opiate toxicity is recommended.
Fentanyl
Oxycodone
Tramadol
Based on theoretical considerations boosted darunavir may increase plasma concentrations of these analgesics.
(CYP2D6 and/or CYP3A inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir with these analgesics.
OESTROGEN-BASED CONTRACEPTIVES
Drospirenone
Ethinylestradiol (3 mg/0.02 mg once daily)
Β
Β
Β
Β
Ethinylestradiol
Norethindrone 35 ΞΌg/1 mg once daily
drospirenone AUC β 58%β¬
drospirenone Cmin NDβ¬
drospirenone Cmax β 15%β¬
ethinylestradiol AUC β 30%β¬
ethinylestradiol Cmin NDβ¬
ethinylestradiol Cmax β14%β¬
β¬ with darunavir/cobicistat
ethinylestradiol AUC β 44%Ξ²
ethinylestradiol Cmin β 62%Ξ²
ethinylestradiol Cmax β 32%Ξ²
norethindrone AUC β 14%Ξ²
norethindrone Cmin β 30%Ξ²
norethindrone Cmax βΞ²
Ξ²with darunavir/ritonavir
When Darunavir is co-administered with a drospirenone-containing product, clinical monitoring is recommended due to the potential for hyperkalaemia.
Β
Β
Β
Β
Alternative or additional contraceptive measures are recommended when oestrogen-based contraceptives are co-administered with boosted darunavir. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.
OPIOID ANTAGONIST
Naloxegol
Not studied.
Co-administration of boosted darunavir and naloxegol is contraindicated.
PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of erectile dysfunction
Avanafil
Sildenafil
Tadalafil
Vardenafil
In an interaction study #, a comparable systemic exposure to sildenafil was observed for a single intake of 100 mg sildenafil alone and a single intake of 25 mg sildenafil co-administered with darunavir and low dose ritonavir.
The combination of avanafil and boosted darunavir is contraindicated (see section 4.3). Concomitant use of other PDE-5 inhibitors for the treatment of erectile dysfunction with boosted darunavir should be done with caution. If concomitant use of boosted darunavir with sildenafil, vardenafil or tadalafil is indicated, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours or tadalafil at a single dose not exceeding 10 mg in 72 hours is recommended.
For the treatment of pulmonary arterial hypertension
Sildenafil
Tadalafil
Not studied. Concomitant use of sildenafil or tadalafil for the treatment of pulmonary arterial hypertension and boosted darunavir may increase plasma concentrations of sildenafil or tadalafil.
(CYP3A inhibition)
A safe and effective dose of sildenafil for the treatment of pulmonary arterial hypertension co-administered with boosted darunavir has not been established. There is an increased potential for sildenafil-associated adverse events (including visual disturbances, hypotension, prolonged erection and syncope). Therefore, co-administration of boosted darunavir and sildenafil when used for the treatment of pulmonary arterial hypertension is contraindicated (see section 4.3).
Co-administration of tadalafil for the treatment of pulmonary arterial hypertension with boosted darunavir is not recommended.
PROTON PUMP INHIBITORS
Omeprazole 20 mg once daily
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Boosted darunavir can be co-administered with proton pump inhibitors without dose adjustments.
SEDATIVES/HYPNOTICS
Buspirone
Clorazepate
Diazepam
Estazolam
Flurazepam
Midazolam (parenteral)
Zolpidem
Β
Β
Β
Β
Β
Midazolam (oral)
Triazolam
Not studied. Sedative/hypnotics are extensively metabolised by CYP3A. Co-administration with boosted darunavir may cause a large increase in the concentration of these medicines.
If parenteral midazolam is co-administered with boosted darunavir it may cause a large increase in the concentration of this benzodiazepine.
Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.
Clinical monitoring is recommended when co- administering boosted darunavir with these sedatives/hypnotics and a lower dose of the sedatives/hypnotics should be considered.
If parenteral midazolam is co- administered with boosted darunavir, it should be done in an intensive care unit (ICU) or similar setting, which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Boosted darunavir with triazolam or oral midazolam is contraindicated (see section 4.3).
TREATMENT FOR PREMATURE EJACULATION
Dapoxetine
Not studied.
Co-administration of boosted darunavir with dapoxetine is contraindicated.
UROLOGICAL DRUGS
Fesoterodine
Solifenacin
Not studied.
Use with caution. Monitor for fesoterodine or solifenacin adverse reactions, dose reduction of fesoterodine or solifenacin may be necessary.
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology).
β The efficacy and safety of the use of darunavir with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavir and tipranavir) has not been established in HIV patients. According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.
β‘ Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.
4.6 |
Darunavir 400 mg film-coated tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.
There are no adequate and well controlled studies on pregnancy outcome with darunavir in pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
Darunavir co-administered with low dose ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk.
Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure (see section 5.2), which may be associated with an increased risk of treatment failure and an increased risk of HIV transmission to the child. Therapy with darunavir/cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with darunavir/cobicistat should be switched to an alternative regimen (see sections 4.2 and 4.4).
Breast-feeding
It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted in toxicity of the offspring.
Because of both the potential for HIV transmission and the potential for adverse reactions in breast-fed infants, women should be instructed not to breast-feed if they are receiving darunavir.
In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed.
Fertility
No human data on the effect of darunavir on fertility are available. There was no effect on mating or fertility with darunavir treatment in rats (see section 5.3).
4.7 |
Darunavir 400 mg film-coated tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Darunavir in combination with cobicistat or ritonavir has no or negligible influence on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing darunavir co-administered with cobicistat or low dose ritonavir and should be borne in mind when considering a patient's ability to drive or operate machinery (see section 4.8).
4.8 |
Darunavir 400 mg film-coated tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
During the clinical development program (N=2,613 treatment-experienced subjects who initiated therapy with darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent adverse reactions reported in clinical trials and as spontaneous reports are diarrhoea, nausea, rash, headache and vomiting. The most frequent serious reactions are acute renal failure, myocardial infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis and pyrexia.
In the 96 week analysis, the safety profile of darunavir/ritonavir 800/100 mg once daily in treatment-naΓ―ve subjects was similar to that seen with darunavir/ritonavir 600/100 mg twice daily in treatment-experienced subjects except for nausea which was observed more frequently in treatment-naΓ―ve subjects. This was driven by mild intensity nausea. No new safety findings were identified in the 192 week analysis of the treatment-naΓ―ve subjects in which the mean treatment duration of darunavir/ritonavir 800/100 mg once daily was 162.5 weeks.
During the Phase III clinical trial GS-US-216-130 with darunavir/cobicistat (N=313 treatment-naΓ―ve and treatment-experienced subjects), 66.5% of subjects experienced at least one adverse reaction. The mean treatment duration was 58.4 weeks. The most frequent adverse reactions reported were diarrhoea (28%), nausea (23%), and rash (16%). Serious adverse reactions are diabetes mellitus, (drug) hypersensitivity, immune reconstitution inflammatory syndrome, rash and vomiting.
For information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Tabulated list of adverse reactions
Adverse reactions are listed by system organ class (SOC) and frequency category. Within each frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as follows: very common (β₯ 1/10), common (β₯ 1/100 to < 1/10), uncommon (β₯ 1/1,000 to < 1/100), rare (β₯ 1/10,000 to < 1/1,000) and not known (frequency cannot be estimated from the available data).
Adverse reactions observed with darunavir/ritonavir in clinical trials and post- marketing
MedDRA system organ class
Frequency category
Adverse reaction
Infections and infestations
uncommon
herpes simplex
Blood and lymphatic system disorders
uncommon
rare
thrombocytopenia, neutropenia, anaemia, leukopenia
increased eosinophil count
Immune system disorders
uncommon
immune reconstitution inflammatory syndrome, (drug) hypersensitivity
Endocrine disorders
uncommon
hypothyroidism, increased blood thyroid stimulating hormone
Metabolism and nutrition disorders
common
Β
uncommon
diabetes mellitus, hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia
gout, anorexia, decreased appetite, decreased weight, increased weight, hyperglycaemia, insulin resistance, decreased high density lipoprotein, increased appetite, polydipsia, increased blood lactate dehydrogenase
Psychiatric disorders
common
uncommon
rare
insomnia
depression, disorientation, anxiety, sleep disorder, abnormal dreams, nightmare, decreased libido
confusional state, altered mood, restlessness
Nervous system disorders
common
uncommon
rare
headache, peripheral neuropathy, dizziness
lethargy, paraesthesia, hypoaesthesia, dysgeusia, disturbance in attention, memory impairment, somnolence
syncope, convulsion, ageusia, sleep phase rhythm disturbance
Eye disorders
uncommon
rare
conjunctival hyperaemia, dry eye
visual disturbance
Ear and labyrinth disorders
uncommon
vertigo
Cardiac disorders
uncommon
rare
myocardial infarction, angina pectoris, prolonged electrocardiogram QT, tachycardia
acute myocardial infarction, sinus bradycardia, palpitations
Vascular disorders
uncommon
hypertension, flushing
Respiratory, thoracic and mediastinal disorders
uncommon
rare
dyspnoea, cough, epistaxis, throat irritation
rhinorrhoea
Gastrointestinal disorders
very common
common
uncommon
rare
diarrhoea
vomiting, nausea, abdominal pain, increased blood amylase, dyspepsia, abdominal distension, flatulence
pancreatitis, gastritis, gastrooesophageal reflux disease, aphthous stomatitis, retching, dry mouth, abdominal discomfort, constipation, increased lipase, eructation, oral dysaesthesia
stomatitis, haematemesis, cheilitis, dry lip, coated tongue
Hepatobiliary disorders
common
uncommon
increased alanine aminotransferase
hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased transaminase, increased aspartate aminotransferase, increased blood bilirubin, increased blood alkaline phosphatase, increased gamma-glutamyltransferase
Skin and subcutaneous tissue disorders
common
Β
uncommon
Β
rare
Β
not known
rash (including macular, maculopapular, papular, erythematous and pruritic rash), pruritus
angioedema, generalised rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, nail pigmentation
DRESS, Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrhoeic dermatitis, skin lesion, xeroderma
toxic epidermal necrolysis, acute generalised exanthematous pustulosis
Musculoskeletal and connective tissue disorders
uncommon
Β
rare
myalgia, osteonecrosis, muscle spasms, muscular weakness, arthralgia, pain in extremity, osteoporosis, increased blood creatine phosphokinase
musculoskeletal stiffness, arthritis, joint stiffness
Renal and urinary disorders
uncommon
Β
rare
rare
acute renal failure, renal failure, nephrolithiasis, increased blood creatinine, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria
decreased creatinine renal clearance
crystal nephropathy§
Reproductive system and breast disorders
uncommon
erectile dysfunction, gynaecomastia
General disorders and administration site conditions
common
uncommon
rare
asthenia, fatigue
pyrexia, chest pain, peripheral oedema, malaise, feeling hot, irritability, pain
chills, abnormal feeling, xerosis
Β§
adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics (Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determined using the "Rule of 3".
Adverse reactions observed with darunavir/cobicistat in adult patients
MedDRA system organ class Frequency category
Adverse reaction
Immune system disorders
common
uncommon
(drug) hypersensitivity
immune reconstitution inflammatory syndrome
Metabolism and nutrition disorders
common
anorexia, diabetes mellitus, hypercholesterolaemia, hypertriglyceridaemia, hyperlipidaemia
Psychiatric disorders
common
abnormal dreams
Nervous system disorders
very common
headache
Gastrointestinal disorders
very common
common
uncommon
diarrhoea, nausea
vomiting, abdominal pain, abdominal distension, dyspepsia, flatulence, pancreatic enzymes increased
pancreatitis acute
Hepatobiliary disorders
common
uncommon
hepatic enzyme increased
hepatitis*, cytolytic hepatitis*
Skin and subcutaneous tissue disorders
very common
common
rare
not known
rash (including macular, maculopapular, papular, erythematous, pruritic rash, generalised rash, and allergic dermatitis)
angioedema, pruritus, urticaria
drug reaction with eosinophilia and systemic symptoms*, Stevens-Johnson syndrome*
toxic epidermal necrolysis*, acute generalised exanthematous pustulosis*
Musculoskeletal and connective tissue disorders
common
uncommon
myalgia
osteonecrosis*
Renal and urinary disorders
rare
crystal nephropathy*Β§
Reproductive system and breast disorders
uncommon
gynaecomastia*
General disorders and administration site conditions
common
uncommon
fatigue
asthenia
Investigations
common
increased blood creatinine
* these adverse drug reactions have not been reported in clinical trial experience with darunavir/cobicistat but have been noted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.
Β§
adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics (Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determined using the "Rule of 3".
Description of selected adverse reactions
Rash
In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in section 4.4. In a single arm trial investigating darunavir 800 mg once daily in combination with cobicistat 150 mg once daily and other antiretrovirals 2.2% of patients discontinued treatment due to rash.
During the clinical development program of raltegravir in treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing darunavir/ritonavir + raltegravir compared to those containing darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4).
Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).
Musculoskeletal abnormalities
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of protease inhibitors, particularly in combination with NRTIs.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).
Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).
Bleeding in haemophiliac patients
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors (see section 4.4).
Paediatric population
The safety assessment of darunavir with ritonavir in paediatric patients is based on the 48-week analysis of safety data from three Phase II trials. The following patient populations were evaluated (see section 5.1):
β’ 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at least 20 kg who received darunavir tablets with low dose ritonavir twice daily in combination with other antiretroviral agents.
β’ 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received darunavir oral suspension with low dose ritonavir twice daily in combination with other antiretroviral agents.
β’ 12 ART-naΓ―ve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 40 kg who received darunavir tablets with low dose ritonavir once daily in combination with other antiretroviral agents (see section 5.1).
Overall, the safety profile in these paediatric patients was similar to that observed in the adult population.
The safety assessment of darunavir with cobicistat in paediatric patients was evaluated in adolescents aged 12 to less than 18 years, weighing at least 40 kg through the clinical trial GS-US-216-0128 (treatment-experienced, virologically suppressed, N=7). Safety analyses of this study in adolescent subjects did not identify new safety concerns compared to the known safety profile of darunavir and cobicistat in adult subjects.
Other special populations
Patients co-infected with hepatitis B and/or hepatitis C virus
Among 1,968 treatment-experienced patients receiving darunavir co-administered with ritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis (see section 4.4).
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: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Darunavir 400 mg film-coated tablets | Clinical particulars - Overdose | Overdose
Human experience of acute overdose with darunavir co-administered with cobicistat or low dose ritonavir is limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
There is no specific antidote for overdose with Darunavir. Treatment of overdose with darunavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
5. Pharmacological properties
5.1 |
Darunavir 400 mg film-coated tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
The pharmacokinetic properties of darunavir, co-administered with cobicistat or ritonavir, have been evaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infected patients compared to healthy subjects may be explained by the higher concentrations of Ξ±1- acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG and, therefore, higher plasma concentrations.
Darunavir is primarily metabolised by CYP3A. Cobicistat and ritonavir inhibit CYP3A, thereby increasing the plasma concentrations of darunavir considerably.
For information on cobicistat pharmacokinetic properties, consult the cobicistat Summary of Product Characteristics.
Absorption
Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.
The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily (see section 4.4).
When administered without food, the relative bioavailability of darunavir in the presence of cobicistat or low dose ritonavir is lower as compared to intake with food. Therefore, darunavir tablets should be taken with cobicistat or ritonavir and with food. The type of food does not affect exposure to darunavir.
Distribution
Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma Ξ±1-acid glycoprotein.
Following intravenous administration, the volume of distribution of darunavir alone was 88.1 Β± 59.0 l (Mean Β± SD) and increased to 131 Β± 49.9 l (Mean Β± SD) in the presence of 100 mg twice-daily ritonavir.
Biotransformation
In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due to the parent active substance. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild type HIV.
Elimination
After a 400/100 mg 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.
The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 l/h and 5.9 l/h, respectively.
Special populations
Paediatric population
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 74 treatment-experienced paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that the administered weight-based doses of Darunavir/ritonavir resulted in darunavir exposure comparable to that in adults receiving Darunavir/ritonavir 600/100 mg twice daily (see section 4.2).
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 14 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to < 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving Darunavir/ritonavir 600/100 mg twice daily (see section 4.2).
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naΓ―ve paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that Darunavir/ritonavir 800/100 mg once daily results in darunavir exposure that was comparable to that achieved in adults receiving Darunavir/ritonavir 800/100 mg once daily. Therefore the same once daily dosage may be used in treatment- experienced adolescents aged 12 to < 18 years and weighing at least 40 kg without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to < 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving Darunavir/ritonavir 800/100 mg once daily (see section 4.2). In addition, pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed the identification of weight-based Darunavir/ritonavir once daily dosing regimens for paediatric patients weighing at least 15 kg that are either ART-naΓ―ve or treatment- experienced paediatric patients without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
The pharmacokinetics of darunavir 800 mg co-administered with cobicistat 150 mg in paediatric patients have been studied in 7 adolescents aged 12 to less than 18 years, weighing at least 40 kg in Study GS-US-216-0128. The geometric mean adolescent exposure (AUCtau) was similar for darunavir and increased 19% for cobicistat compared to exposures achieved in adults who received darunavir 800 mg co-administered with cobicistat 150 mg in Study GS-US-216-0130. The difference observed for cobicistat was not considered clinically relevant.
Adults in Study GS-US-216-0130, week 24 (Reference)a Mean (%CV) GLSM
Adolescents in Study GS-US-216-0128, day 10 (Test)b Mean (%CV) GLSM
GLSM Ratio (90% CI)
(Test/Reference)
N
60c
7
DRV PK
Parameter
AUCtau
(h.ng/mL)d
81,646 (32.2)
77,534
80,877 (29.5)
77,217
1.00 (0.79-1.26)
Cmax (ng/mL)
7,663 (25.1)
7,422
7,506 (21.7)
7,319
0.99 (0.83-1.17)
Ctau (ng/mLd
1,311 (74.0)
947
1,087 (91.6)
676
0.71 (0.34-1.48)
COBI PK
Parameter
AUCtau
(h.ng/mL)d
7,596 (48.1)
7,022
8,741 (34.9)
8,330
1.19 (0.95-1.48)
Cmax (ng/mL)
991 (33.4)
945
1,116 (20.0)
1,095
1.16 (1.00-1.35)
Ctau (ng/mL)d
32.8 (289.4)
17.2e
28.3 (157.2)
22.0e
1.28 (0.51-3.22)
a Week 24 intensive PK data from subjects who received DRV 800 mg + COBI 150 mg.
b Day 10 intensive PK data from subjects who received DRV 800 mg + COBI 150 mg.
c N=59 for AUCtau and Ctau.
d Concentration at predose (0 hours) was used as surrogate for concentration at 24 hours for the purposes of estimating AUCtau and Ctau in Study GS-US-216-0128.
e N=57 and N=5 for GLSM of Ctau in Study GS-US-216-0130 and Study GS-US- 216-0128, respectively.
Elderly
Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (n=12, age β₯ 65) (see section 4.4). However, only limited data were available in patients above the age of 65 year.
Gender
Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV infected females compared to males. This difference is not clinically relevant.
Renal impairment
Results from a mass balance study with 14C-darunavir with ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine unchanged.
Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20) (see sections 4.2 and 4.4).
Hepatic impairment
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with darunavir co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects.
However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown therefore, darunavir should be used with caution. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see sections 4.2, 4.3 and 4.4).
Pregnancy and postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum.
Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of total darunavir
(mean Β± SD)
Second trimester of pregnancy
(n=12)a
Third trimester of pregnancy
(n=12)
Postpartum (6-12 weeks)
(n=12)
Cmax, ng/ml
4,668 Β± 1,097
5,328 Β± 1,631
6,659 Β± 2,364
AUC12h, ng.h/ml
39,370 Β± 9,597
45,880 Β± 17,360
56,890 Β± 26,340
Cmin, ng/ml
1,922 Β± 825
2,661 Β± 1,269
2,851 Β± 2,216
a n=11 for AUC12h
Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of total darunavir
(mean Β± SD)
Second trimester of pregnancy
(n=17)
Third Trimester of pregnancy
(n=15)
Postpartum (6-12 weeks)
(n=16)
Cmax, ng/ml
4,964 Β± 1,505
5,132 Β± 1,198
7,310 Β± 1,704
AUC24h, ng.h/ml
62,289 Β± 16,234
61,112 Β± 13,790
92,116 Β± 29,241
Cmin, ng/ml
1,248 Β± 542
1,075 Β± 594
1,473 Β± 1,141
In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and 26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, as compared with postpartum.
In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax,
AUC24h and Cmin were 33%, 31% and 30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared with postpartum.
Treatment with darunavir/cobicistat 800/150 mg once daily during pregnancy results in low darunavir exposure. In women receiving darunavir/cobicistat during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 49%, 56% and 92% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 37%, 50% and 89% lower, respectively, as compared with postpartum. The unbound fraction was also substantially reduced, including around 90% reductions of Cmin levels. The main cause of these low exposures is a marked reduction in cobicistat exposure as a consequence of pregnancy-associated enzyme induction (see below).
Pharmacokinetic results of total darunavir after administration of darunavir/cobicistat 800/150 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy, and postpartum
Pharmacokinetics of total darunavir
(mean Β± SD)
Second trimester of pregnancy
(n=7)
Third trimester of pregnancy
(n=6)
Postpartum (6-12 weeks)
(n=6)
Cmax, ng/mL
4,340 Β± 1,616
4,910 Β± 970
7,918 Β± 2,199
AUC24h, ng.h/mL
47,293 Β± 19,058
47,991 Β± 9,879
99,613 Β± 34,862
Cmin, ng/mL
168 Β± 149
184 Β± 99
1,538 Β± 1,344
The exposure to cobicistat was lower during pregnancy, potentially leading to suboptimal boosting of darunavir. During the second trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin were 50%, 63%, and 83% lower, respectively, as compared with postpartum. During the third trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin, were 27%, 49%, and 83% lower, respectively, as compared with postpartum.
5.3 |
Darunavir 400 mg film-coated tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Animal toxicology studies have been conducted at exposures up to clinical exposure levels with darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.
In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment with darunavir. In rodents the target organs identified were the haematopoietic system, the blood coagulation system, liver and thyroid. A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated partial thromboplastin time.
Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and thyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a small increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the pancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicity findings or target organs were identified up to exposures equivalent to clinical exposure at the recommended dose.
In a study conducted in rats, the number of corpora lutea and implantations were decreased in the presence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavir treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The exposure levels were lower than those with the recommended clinical dose in humans. In a pre- and postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening of eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pups that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation. These effects may be secondary to pup exposure to the active substance via the milk and/or maternal toxicity. No post weaning functions were affected with darunavir alone or in combination with ritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed with convulsions in some animals. Exposure in plasma, liver and brain was considerably higher than in adult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, the exposure was comparable to that in adult rats. The increased exposure was likely at least partly due to immaturity of the drug- metabolising enzymes in juvenile animals. No treatment related mortalities were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats.
Due to uncertainties regarding the rate of development of the human blood brain barrier and liver enzymes, darunavir with low dose ritonavir should not be used in paediatric patients below 3 years of age.
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1,000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences of hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. The observed hepatocellular and thyroid tumours in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms.
At the highest tested doses, the systemic exposures (based on AUC) to darunavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses.
After 2 years administration of darunavir at exposures at or below the human exposure, kidney changes were observed in mice (nephrosis) and rats (chronic progressive nephropathy).
Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.
6. |
Darunavir 400 mg film-coated tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Silica, colloidal anhydrous
Silicified microcrystalline cellulose
Crospovidone
Magnesium stearate
Tablet film-coat
Polyvinyl alcohol β partially hydrolysed
Macrogol 3350
Titanium dioxide (E171)
Talc
Iron oxide yellow (E172)
6.2 |
Darunavir 400 mg film-coated tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Darunavir 400 mg film-coated tablets | Pharmaceutical particulars - Shelf life | Shelf life
3 years
6.4 |
Darunavir 400 mg film-coated tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Darunavir 400 mg film-coated tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Blister pack:
OPA-Aluminium-PVC/Aluminium blister packs; pack sizes of 1x30,1x60 and 1x90 film-coated tablets.
HDPE Bottle:
White opaque high-density polyethylene (HDPE) bottle closed with white opaque child-resistant polypropylene closure. Contains a cylindrical canister filled with silica gel as desiccant. Pack sizes of 60 film-coated tablets.
Not all pack sizes may be marketed
6.6 |
Darunavir 400 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. |
Darunavir 400 mg film-coated tablets | Marketing authorisation holder | Amarox Limited
Congress House,
14 Lyon Road,
Harrow, Middlesex HA1 2EN,
United Kingdom
8. Marketing authorisation number(s)
PL 49445/0028
9. |
Darunavir 400 mg film-coated tablets | Date of first authorisation/renewal of the authorisation | 23/07/2020
10. |
Darunavir 400 mg film-coated tablets | Date of revision of the text | 10/01/2023 |
Darunavir 600 mg film-coated tablets | Name of the medicinal product | Darunavir 600 mg film-coated tablets
2. |
Darunavir 600 mg film-coated tablets | Qualitative and quantitative composition | Each film-coated tablet contains 600 mg of darunavir.
For the full list of excipients, see section 6.1.
3. |
Darunavir 600 mg film-coated tablets | Pharmaceutical form | Film-coated tablet.
Yellow, oval shaped (17.99 mm (L) X 9.04 mm (W)), biconvex, film-coated tablets de-bossed with 'V' on one side and '5' on the other side.
4. |
Darunavir 600 mg film-coated tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Darunavir, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection (see section 4.2).
Darunavir 400 mg and 800 mg tablets may be used to provide suitable dose regimens (see section 4.2):
β’ For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adult patients, including those that have been highly pre-treated.
β’ For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least 15 kg body weight.
In deciding to initiate treatment with darunavir co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of darunavir (see sections 4.2, 4.4 and 5.1).
4.2 |
Darunavir 600 mg film-coated tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Therapy should be initiated by a healthcare provider experienced in the management of HIV infection. After therapy with Darunavir has been initiated, patients should be advised not to alter the dosage, dose form or discontinue therapy without discussing with their healthcare provider.
Posology
Darunavir must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of ritonavir must, therefore, be consulted prior to initiation of therapy with Darunavir.
Darunavir is also available as an oral suspension for use in patients who are unable to swallow darunavir tablets (please refer to the Summary of Product Characteristics for darunavir oral suspension).
ART-experienced adult patients
The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food. darunavir 400 mg and 800 mg tablets can be used to construct the twice daily 600 mg regimen.
The use of 75 mg and 150 mg tablets to achieve the recommended dose is appropriate when there is a possibility of hypersensitivity to specific colouring agents, or difficulty in swallowing the 600 mg tablets.
ART-naΓ―ve adult patients
For dosage recommendations in ART-naΓ―ve patients see the Summary of Product Characteristics for darunavir 400 mg and 800 mg tablets.
ART-naΓ―ve paediatric patients (3 to 17 years of age and weighing at least 15 kg)
The weight-based dose of Darunavir and ritonavir in paediatric patients is provided in the table below.
Recommended dose for treatment-naΓ―ve paediatric patients (3 to 17 years) with darunavir tablets and ritonavira
Body weight (kg)
Dose (once daily with food)
β₯ 15 kg to < 30 kg 600 mg
Darunavir/100 mg ritonavir once daily
β₯ 30 kg to < 40 kg 675 mg
Darunavir/100 mg ritonavir once daily
β₯ 40 kg 800 mg
Darunavir/100 mg ritonavir once daily
a ritonavir oral solution: 80 mg/ml
ART-experienced paediatric patients (3 to 17 years of age and weighing at least 15 kg)
Darunavir twice daily taken with ritonavir taken with food is usually recommended.
A once daily dose regimen of darunavir taken with ritonavir taken with food may be used in patients with prior exposure to antiretroviral medicinal products but without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
The weight-based dose of darunavir and ritonavir in paediatric patients is provided in the table below. The recommended dose of darunavir with low dose ritonavir should not exceed the recommended adult dose (600/100 mg twice daily or 800/100 mg once daily).
Recommended dose for treatment-experienced paediatric patients (3 to 17 years) with Darunavir tablets and ritonavira
Body weight (kg)
Dose (once daily with food)
Dose (twice daily with food)
β₯ 15 kgβ< 30 kg
600 mg darunavir/100 mg ritonavir once daily
375 mg darunavir/50 mg ritonavir twice daily
β₯ 30 kgβ< 40 kg
675 mg darunavir/100 mg ritonavir once daily
450 mg darunavir/60 mg ritonavir twice daily
β₯ 40 kg
800 mg darunavir/100 mg ritonavir once daily
600 mg darunavir/100 mg ritonavir twice daily
a ritonavir oral solution: 80 mg/ml
For ART-experienced paediatric patients HIV genotypic testing is recommended. However, when HIV genotypic testing is not feasible, the darunavir/ritonavir once daily dosing regimen is recommended in HIV protease inhibitor-naΓ―ve paediatric patients and the twice daily dosing regimen is recommended in HIV protease inhibitor-experienced patients.
The use of only 75 mg and 150 mg tablets or the 100 mg/ml oral suspension to achieve the recommended dose of darunavir could be appropriate when there is a possibility of hypersensitivity to specific colouring agents.
Advice on missed doses
In case a dose of darunavir and/or ritonavir is missed within 6 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of Darunavir and ritonavir with food as soon as possible. If this is noticed later than 6 hours after the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.
This guidance is based on the 15 hour half-life of darunavir in the presence of ritonavir and the recommended dosing interval of approximately 12 hours.
If a patient vomits within 4 hours of taking the medicine, another dose of darunavir with ritonavir should be taken with food as soon as possible. If a patient vomits more than 4 hours after taking the medicine, the patient does not need to take another dose of darunavir with ritonavir until the next regularly scheduled time.
Special populations
Elderly
Limited information is available in this population, and therefore, darunavir should be used with caution in this age group (see sections 4.4 and 5.2).
Hepatic impairment
Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, darunavir should be used with caution in these patients. No pharmacokinetic data are available in patients with severe hepatic impairment. Severe hepatic impairment could result in an increase of darunavir exposure and a worsening of its safety profile. Therefore, darunavir must not be used in patients with severe hepatic impairment (Child-Pugh Class C) (see sections 4.3, 4.4 and 5.2).
Renal impairment
No dose adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).
Paediatric population
Darunavir/ritonavir should not be used in children with a body weight of less than 15 kg as the dose for this population has not been established in a sufficient number of patients (see section 5.1). Darunavir/ritonavir should not be used in children below 3 years of age because of safety concerns (see sections 4.4 and 5.3).
The weight-based dose regimen for darunavir and ritonavir is provided in the tables above.
Pregnancy and postpartum
No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk (see sections 4.4, 4.6 and 5.2).
Method of administration
Patients should be instructed to take darunavir with low dose ritonavir within 30 minutes after completion of a meal. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5 and 5.2).
4.3 |
Darunavir 600 mg film-coated tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with severe (Child-Pugh Class C) hepatic impairment.
Combination of strong CYP3A inducers such as rifampicin with darunavir with concomitant low dose ritonavir (see section 4.5).
Co-administration with the combination product lopinavir/ritonavir (see section 4.5).
Co-administration with herbal preparations containing St John's Wort (Hypericum perforatum) (see section 4.5).
Co-administration of darunavir with low dose ritonavir, with active substances that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These active substances include e.g.:
- alfuzosin
- amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
- astemizole, terfenadine
- colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)
- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
- elbasvir/grazoprevir
- cisapride
- dapoxetine
- domperidone
- naloxegol
- lurasidone, pimozide, quetiapine, sertindole (see section 4.5)
- triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5)
- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil
- simvastatin, lovastatin and lomitapide (see section 4.5)
- ticagrelor (see section 4.5).
4.4 |
Darunavir 600 mg film-coated tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Regular assessment of virological response is advised. In the setting of lack or loss of virological response, resistance testing should be performed.
Darunavir must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products (see section 5.2). The Summary of Product Characteristics of ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with darunavir.
Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect darunavir concentrations. It is not recommended to alter the dose of ritonavir.
Darunavir binds predominantly to Ξ±1-acid glycoprotein. This protein binding is concentration-dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products highly bound to Ξ±1-acid glycoprotein cannot be ruled out (see section 4.5).
ART-experienced patients β once daily dosing
Darunavir used in combination with cobicistat or low dose ritonavir once daily in ART-experienced patients should not be used in patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA β₯ 100,000 copies/ml or CD4+ cell count < 100 cells x 106/L (see section 4.2). Combinations with optimised background regimen (OBRs) other than β₯ 2 NRTIs have not been studied in this population. Limited data are available in patients with HIV-1 clades other than B (see section 5.1).
Paediatric population
Darunavir is not recommended for use in paediatric patients below 3 years of age or less than 15 kg body weight (see sections 4.2 and 5.3).
Pregnancy
Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk. Caution should be used in pregnant women with concomitant medications which may further decrease darunavir exposure (see sections 4.5 and 5.2).
Elderly
As limited information is available on the use of darunavir in patients aged 65 and over, caution should be exercised in the administration of darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2 and 5.2).
Severe skin reactions
During the darunavir/ritonavir clinical development program (N=3,063), severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported. darunavir should be discontinued immediately if signs or symptoms of severe skin reactions develop. These can include, but are not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
Rash occurred more commonly in treatment-experienced patients receiving regimens containing darunavir/ritonavir + raltegravir compared to patients receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir(see section 4.8).
Darunavir contains a sulphonamide moiety. Darunavir should be used with caution in patients with a known sulphonamide allergy.
Hepatotoxicity
Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with darunavir. During the darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.
Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of darunavir/ritonavir treatment.
If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients using darunavir/ritonavir, interruption or discontinuation of treatment should be considered promptly.
Patients with coexisting conditions
Hepatic impairment
The safety and efficacy of darunavir have not been established in patients with severe underlying liver disorders and darunavir is therefore contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, darunavir should be used with caution in patients with mild or moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).
Renal impairment
No special precautions or dose adjustments for darunavir/ritonavir are required in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these patients (see sections 4.2 and 5.2).
Haemophiliac patients
There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding.
Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with darunavir co-administered with low dose ritonavir.
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).
Interactions with medicinal products
Several of the interaction studies have been performed with darunavir at lower than recommended doses. The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated. For full information on interactions with other medicinal products see section 4.5.
Efavirenz in combination with boosted darunavir once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used (see section 4.5).
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-glycoprotein (P-gp; see sections 4.3 and 4.5).
4.5 |
Darunavir 600 mg film-coated tablets | 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 adults.
Medicinal products that may be affected by darunavir boosted with ritonavir
Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or transported by P-gp may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.
Co-administration of darunavir/ritonavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see the Interaction table below).
Darunavir co-administered with low dose ritonavir must not be combined with medicinal products that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) (see section 4.3).
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily. Therefore, darunavir must only be used in combination with low dose ritonavir as a pharmacokinetic enhancer (see sections 4.4 and 5.2).
A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to the presence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir with medicinal products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone, repaglinide) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration with substrates of these transporters can result in increased plasma concentrations of these compounds (e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).
Medicinal products that affect darunavir/ritonavir exposure
Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir (e.g. rifampicin, St John's Wort, lopinavir).
Co-administration of darunavir and ritonavir and other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (e.g. indinavir, azole antifungals like clotrimazole). These interactions are described in the interaction table below.
Interaction table
Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products are listed in the table below. The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (β), below (β) or above (β) the 80-125% range (not determined as βNDβ).
Several of the interaction studies (indicated by # in the table below) have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated.
The below list of examples of drug-drug interactions is not comprehensive and therefore the label of each drug that is co-administered with darunavir should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.
INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal product examples by therapeutic area
Interaction
Geometric mean change (%)
Recommendations concerning co-administration
HIV ANTIRETROVIRALS
Integrase strand transfer inhibitors
Dolutegravir
dolutegravir AUC β 22%
dolutegravir C24h β 38%
dolutegravir Cmax β 11%
darunavir β*
* Using cross-study comparisons to historical pharmacokinetic data
darunavir co-administered with low dose ritonavir and dolutegravir can be used without dose adjustment.
Raltegravir
Some clinical studies suggest raltegravir may cause a modest decrease in darunavir plasma concentrations.
At present the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically relevant. darunavir co-administered with low dose ritonavir and raltegravir can be used without dose adjustments.
Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine
400 mg once daily
didanosine AUC β 9%
didanosine Cmin ND
didanosine Cmax β 16%
darunavir AUC β
darunavir Cmin β
darunavir Cmax β
Darunavir co-administered with low dose ritonavir and didanosine can be used without dose adjustments.
Didanosine is to be administered on an empty stomach, thus it should be administered 1 hour before or 2 hours after darunavir/ritonavir given with food.
Tenofovir disoproxil 245 mg once dailyβ‘
tenofovir AUC β 22%
tenofovir Cmin β 37%
tenofovir Cmax β 24%
#darunavir AUC β 21%
#darunavir Cmin β 24%
#darunavir Cmax β 16%
(β tenofovir from effect on MDR-1 transport in the renal tubules)
Monitoring of renal function may be indicated when darunavir co-administered with low dose ritonavir is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.
Emtricitabine/tenofovir alafenamide
Tenofovir alafenamide β
Tenofovir β
The recommended dose of emtricitabine/tenofovir alafenamide is 200/10 mg once daily when used with darunavir with low dose ritonavir.
Abacavir
Emtricitabine
Lamivudine
Stavudine
Zidovudine
Not studied. Based on the different elimination pathways of the other NRTIs zidovudine, emtricitabine, stavudine, lamivudine, that are primarily renally excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and darunavir co-administered with low dose ritonavir.
darunavir co-administered with low dose ritonavir can be used with these NRTIs without dose adjustment.
Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz
600 mg once daily
efavirenz AUC β 21%
efavirenz Cmin β 17%
efavirenz Cmax β 15%
#darunavir AUC β 13%
#darunavir Cmin β 31%
#darunavir Cmax β 15%
(β efavirenz from CYP3A inhibition)
(β darunavir from CYP3A induction)
Clinical monitoring for central nervous system toxicity associated with increased exposure to efavirenz may be indicated when darunavir co-administered with low dose ritonavir is given in combination with efavirenz.
Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used (see section 4.4).
Etravirine
100 mg twice daily
etravirine AUC β 37%
etravirine Cmin β 49%
etravirine Cmax β 32%
darunavir AUC β 15%
darunavir Cmin β
darunavir Cmax β
Darunavir co-administered with low dose ritonavir and etravirine 200 mg twice daily can be used without dose adjustments.
Nevirapine
200 mg twice daily
nevirapine AUC β 27%
nevirapine Cmin β 47%
nevirapine Cmax β 18%
#darunavir: concentrations were consistent with historical data
(β nevirapine from CYP3A inhibition)
Darunavir co-administered with low dose ritonavir and nevirapine can be used without dose adjustments.
Rilpivirine
150 mg once daily
rilpivirine AUC β 130%
rilpivirine Cmin β 178%
rilpivirine Cmax β 79%
darunavir AUC β
darunavir Cmin β 11%
darunavir Cmax β
Darunavir co-administered with low dose ritonavir and rilpivirine can be used without dose adjustments.
HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavirβ
Atazanavir
300 mg once daily
atazanavir AUC β
atazanavir Cmin β 52%
atazanavir Cmax β 11%
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Atazanavir: comparison of atazanavir/ritonavir 300/100 mg once daily vs. atazanavir 300 mg once daily in combination with darunavir/ritonavir 400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg twice daily in combination with atazanavir 300 mg once daily.
Darunavir co-administered with low dose ritonavir and atazanavir can be used without dose adjustments.
Indinavir
800 mg twice daily
indinavir AUC β 23%
indinavir Cmin β 125%
indinavir Cmax β
#darunavir AUC β 24%
#darunavir Cmin β 44%
#darunavir Cmax β 11%
Indinavir: comparison of indinavir/ritonavir 800/100 mg twice daily vs. indinavir/darunavir/ritonavir 800/400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with indinavir 800 mg twice daily.
When used in combination with darunavir co-administered with low dose ritonavir, dose adjustment of indinavir from 800 mg twice daily to 600 mg twice daily may be warranted in case of intolerance.
Saquinavir
1,000 mg twice daily
#darunavir AUC β 26%
#darunavir Cmin β 42%
#darunavir Cmax β 17%
saquinavir AUC β 6%
saquinavir Cmin β 18%
saquinavir Cmax β 6%
Saquinavir: comparison of saquinavir/ritonavir 1,000/100 mg twice daily vs. saquinavir/darunavir/ritonavir 1,000/400/100 mg twice daily. Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with saquinavir 1,000 mg twice daily.
It is not recommended to combine darunavir co-administered with low dose ritonavir with saquinavir.
HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavirβ
Lopinavir/ritonavir 400/100 mg twice daily
Β
Β
Β
Β
Β
Lopinavir/ritonavir 533/133.3 mg twice daily
lopinavir AUC β 9%
lopinavir Cmin β 23%
lopinavir Cmax β 2%
darunavir AUC β 38%β‘
darunavir Cmin β 51%β‘
darunavir Cmax β 21%β‘
lopinavir AUC β
lopinavir Cmin β 13%
lopinavir Cmax β 11%
darunavir AUC β 41%
darunavir Cmin β 55%
darunavir Cmax β 21%
β‘
based upon non dose normalised values
Due to a decrease in the exposure (AUC) of darunavir by 40%, appropriate doses of the combination have not been established. Hence, concomitant use of Darunavir co-administrated with low dose ritonavir and the combination product lopinavir/ritonavir is contraindicated (see section 4.3).
CCR5 ANTAGONIST
Maraviroc
150 mg twice daily
maraviroc AUC β 305%
maraviroc Cmin ND
maraviroc Cmax β 129%
darunavir, ritonavir concentrations were consistent with historical data
The maraviroc dose should be 150 mg twice daily when co- administered with darunavir. with low dose ritonavir.
Ξ±1-ADRENORECEPTOR ANTAGONIST
Alfuzosin
Based on theoretical considerations darunavir is expected to increase alfuzosin plasma concentrations. (CYP3A inhibition)
Co-administration of darunavir with low dose ritonavir and alfuzosin is contraindicated (see section 4.3).
ANAESTHETIC
Alfentanil
Not studied. The metabolism of alfentanil is mediated via CYP3A, and may as such be inhibited by darunavir co-administered with low dose ritonavir.
The concomitant use with darunavir and low dose ritonavir may require to lower the dose of alfentanil and requires monitoring for risks of prolonged or delayed respiratory depression.
ANTIANGINA/ANTIARRHYTHMIC
Disopyramide
Flecainide
Lidocaine (systemic)
Mexiletine
Propafenone
Amiodarone
Bepridil
Dronedarone
Ivabradine
Quinidine
Ranolazine
Not studied. darunavir is expected to increase these antiarrhythmic plasma concentrations.
(CYP3A and/or CYP2D6 inhibition)
Caution is warranted and therapeutic concentration monitoring, if available, is recommended for these antiarrhythmics when co-administered with darunavir with low dose ritonavir.
Β
Β
Darunavir co-administered with low dose ritonavir and amiodarone, bepridil, dronedarone, ivabradine, quinidine, or ranolazine is contraindicated (see section 4.3).
Digoxin
0.4 mg single dose
digoxin AUC β 61%
digoxin Cmin ND
digoxin Cmax β 29%
(β digoxin from probable inhibition of P-gp)
Given that digoxin has a narrow therapeutic index, it is recommended that the lowest possible dose of digoxin should initially be prescribed in case digoxin is given to patients on darunavir/ritonavir therapy. The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.
ANTIBIOTIC
Clarithromycin
500 mg twice daily
clarithromycin AUC β 57%
clarithromycin Cmin β 174%
clarithromycin Cmax β 26%
#darunavir AUC β 13%
#darunavir Cmin β 1%
#darunavir Cmax β 17%
14-OH-clarithromycin concentrations were not detectable when combined with darunavir/ritonavir.
(β clarithromycin from CYP3A inhibition and possible P-gp inhibition)
Caution should be exercised when clarithromycin is combined with darunavir co-administered with low dose ritonavir.
For patients with renal impairment the Summary of Product Characteristics for clarithromycin should be consulted for the recommended dose.
ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban Rivaroxaban
Not studied. Co-administration of boosted darunavir with these anticoagulants may increase concentrations of the anticoagulant.
(CYP3A and/or P-gp inhibition)
The use of boosted darunavir with a direct oral anticoagulant (DOAC) that is metabolised by CYP3A4 and transported by P-gp is not recommended as this may lead to an increased bleeding risk.
Dabigatran etexilate
Edoxaban
Β
Β
Β
Β
Β
Ticagrelor
Clopidogrel
dabigatran etexilate (150 mg):
darunavir/ritonavir 800/100 mg single dose:
dabigatran AUC β 72%
dabigatran Cmax β 64%
darunavir/ritonavir 800/100 mg once daily:
dabigatran AUC β 18%
dabigatran Cmax β 22%
Based on theoretical considerations, co-administration of boosted Darunavir with ticagrelor may increase concentrations of ticagrelor (CYP3A and/or P-glycoprotein inhibition).
Not studied. Co-administration of clopidogrel with boosted darunavir is expected to decrease clopidogrel active metabolite plasma concentration, which may reduce the antiplatelet activity of clopidogrel.
Darunavir/ritonavir:
Clinical monitoring and/or dose reduction of the DOAC should be considered when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with Darunavir/rtv.
Concomitant administration of boosted darunavir with ticagrelor is contraindicated (see section 4.3).
Β
Β
Co-administration of clopidogerl with boosted darunavir is not recommended. Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended.
Warfarin
Not studied. Warfarin concentrations may be affected when co-administered with darunavir with low dose ritonavir.
It is recommended that the international normalised ratio (INR) be monitored when warfarin is combined with darunavir co-administered with low dose ritonavir.
ANTICONVULSANTS
Phenobarbital
Phenytoin
Not studied. Phenobarbital and phenytoin are expected to decrease plasma concentrations of darunavir and its pharmacoenhancer.
(induction of CYP450 enzymes)
Darunavir co-administered with low dose ritonavir should not be used in combination with these medicines.
Carbamazepine
200 mg twice daily
carbamazepine AUC β 45%
carbamazepine Cmin β 54%
carbamazepine Cmax β 43%
darunavir AUC β
darunavir Cmin β 15%
darunavir Cmax β
No dose adjustment for darunavir/ritonavir is recommended. If there is a need to combine darunavir/ritonavir and carbamazepine, patients should be monitored for potential carbamazepine-related adverse events. Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response.
Based upon the findings, the carbamazepine dose may need to be reduced by 25% to 50% in the presence of darunavir/ritonavir.
Clonazepam
Not studied. Co-administration of boosted darunavir with clonazepam may increase concentrations of clonazepam. (CYP3A inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir with clonazepam.
ANTIDEPRESSANTS
Paroxetine
20 mg once daily
Β
Β
Β
Sertraline
50 mg once daily
Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone
paroxetine AUC β 39%
paroxetine Cmin β 37%
paroxetine Cmax β 36%
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
sertraline AUC β 49%
sertraline Cmin β 49%
sertraline Cmax β 44%
#darunavir AUC β
#darunavir Cminβ 6%
#darunavir Cmax β
Concomitant use of darunavir co-administered with low dose ritonavir and these antidepressants may increase concentrations of the antidepressant.
(CYP2D6 and/or CYP3A inhibition)
If antidepressants are co-administered with darunavir with low dose ritonavir, the recommended approach is a dose titration of the antidepressant based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of these antidepressants who start treatment with darunavir with low dose ritonavir should be monitored for antidepressant response.
Β
Β
Β
Β
Clinical monitoring is recommended when co-administering darunavir with low dose ritonavir with these antidepressants and a dose adjustment of the antidepressant may be needed.
ANTIEMETICS
Domperidone
Not studied.
Co-administration of domperidone with boosted darunavir is contraindicated.
ANTIFUNGALS
Voriconazole
Not studied. Ritonavir may decrease plasma concentrations of voriconazole.
(induction of CYP450 enzymes)
Voriconazole should not be combined with darunavir co-administered with low dose ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Fluconazole
Isavuconazole
Itraconazole
Posaconazole
Clotrimazole
Not studied. darunavir may increase antifungal plasma concentrations and posaconazole, isavuconazole, itraconazole, or fluconazole may increase darunavir concentrations.
(CYP3A and/or P-gp inhibition)
Not studied. Concomitant systemic use of clotrimazole and darunavir co-administered with low dose ritonavir may increase plasma concentrations of darunavir and/or clotrimazole. darunavir AUC24h β 33% (based on population pharmacokinetic model)
Caution is warranted and clinical monitoring is recommended.
When co-administration is required the daily dose of itraconazole should not exceed 200 mg.
ANTIGOUT MEDICINES
Colchicine
Not studied. Concomitant use of colchicine and darunavir co-administered with low dose ritonavir may increase the exposure to colchicine.
(CYP3A and/ or P-gp inhibition)
A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with darunavir co-administered with low dose ritonavir is required. For patients with renal or hepatic impairment colchicine with darunavir co-administered with low dose ritonavir is contraindicated (see sections 4.3 and 4.4).
ANTIMALARIALS
Artemether/Lumefantrine 80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours
artemether AUC β 16%
artemether Cmin β
artemether Cmax β 18%
dihydroartemisinin AUC β 18%
dihydroartemisinin Cmin β
dihydroartemisinin Cmax β 18%
lumefantrine AUC β 175%
lumefantrine Cmin β 126%
lumefantrine Cmax β 65%
darunavir AUC β
darunavir Cmin β 13%
darunavir Cmax β
The combination of darunavir and artemether/lumefantrine can be used without dose adjustments; however, due to the increase in lumefantrine exposure, the combination should be used with caution.
ANTIMYCOBACTERIALS
Rifampicin
Rifapentine
Not studied. Rifapentine and rifampicin are strong CYP3A inducers and have been shown to cause profound decreases in concentrations of other protease inhibitors, which can result in virological failure and resistance development (CYP450 enzyme induction). During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with low dose ritonavir, a high frequency of liver reactions was seen with rifampicin.
The combination of rifapentine and darunavir with concomitant low dose ritonavir is not recommended.
The combination of rifampicin and darunavir with concomitant low dose ritonavir is contraindicated (see section 4.3).
Rifabutin
150 mg once every other day
rifabutin AUC** β 55%
rifabutin Cmin** β ND
rifabutin Cmax** β
darunavir AUC β 53%
darunavir Cmin β 68%
darunavir Cmax β 39%
** sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite)
The interaction trial showed a comparable daily systemic exposure for rifabutin between treatment at 300 mg once daily alone and 150 mg once every other day in combination with darunavir/ritonavir (600/100 mg twice daily) with an about 10-fold increase in the daily exposure to the active metabolite 25-O-desacetylrifabutin.
Furthermore, AUC of the sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite) was increased 1.6-fold, while Cmax remained comparable.
Data on comparison with a 150 mg once daily reference dose is lacking.
(Rifabutin is an inducer and substrate of CYP3A.) An increase of systemic exposure to darunavir was observed when darunavir co-administered with 100 mg ritonavir was co-administered with rifabutin (150 mg once every other day).
A dosage reduction of rifabutin by 75% of the usual dose of 300 mg/day (i.e. rifabutin 150 mg once every other day) and increased monitoring for rifabutin related adverse events is warranted in patients receiving the combination with darunavir co-administered with ritonavir. In case of safety issues, a further increase of the dosing interval for rifabutin and/or monitoring of rifabutin levels should be considered.
Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV infected patients.
Based upon the safety profile of darunavir/ritonavir, the increase in darunavir exposure in the presence of rifabutin does not warrant a dose adjustment for darunavir/ritonavir.
Based on pharmacokinetic modeling, this dosage reduction of 75% is also applicable if patients receive rifabutin at doses other than 300 mg/day.
ANTINEOPLASTICS
Dasatinib
Nilotinib
Vinblastine
Vincristine
Everolimus
Irinotecan
Not studied. Darunavir is expected to increase these antineoplastic plasma concentrations.
(CYP3A inhibition)
Concentrations of these medicinal products may be increased when co-administered with darunavir with low dose ritonavir resulting in the potential for increased adverse events usually associated with these agents.
Caution should be exercised when combining one of these antineoplastic agents with darunavir with low dose ritonavir.
Concomitant use of everolimus or irinotecan and darunavir co-administered with low dose ritonavir is not recommended.
ANTIPSYCHOTICS/NEUROLEPTICS
Quetiapine
Not studied. Darunavir is expected to increase these antipsychotic plasma concentrations.
(CYP3A inhibition)
Concomitant administration of darunavir with low dose ritonavir and quetiapine is contraindicated as it may increase quetiapine-related toxicity. Increased concentrations of quetiapine may lead to coma (see section 4.3).
Perphenazine
Risperidone
Thioridazine
Lurasidone
Pimozide
Sertindole
Not studied. Darunavir is expected to increase these antipsychotic plasma concentrations.
(CYP3A, CYP2D6 and/or P-gp inhibition)
A dose decrease may be needed for these drugs when co-administered with darunavir co-administered with low dose ritonavir.
Concomitant administration of darunavir with low dose ritonavir and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).
Ξ²-BLOCKERS
Carvedilol
Metoprolol
Timolol
Not studied. Darunavir is expected to increase these Ξ²-blocker plasma concentrations.
(CYP2D6 inhibition)
Clinical monitoring is recommended when co-administering darunavir with Ξ²-blockers. A lower dose of the Ξ²-blocker should be considered.
CALCIUM CHANNEL BLOCKERS
Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil
Not studied. Darunavir co-administered with low dose ritonavir can be expected to increase the plasma concentrations of calcium channel blockers.
(CYP3A and/or CYP2D6 inhibition)
Clinical monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with darunavir with low dose ritonavir.
CORTICOSTEROIDS
Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone)
Fluticasone: in a clinical study where ritonavir 100 mg capsules twice daily were co-administered with 50 ΞΌg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82-89%). Greater effects may be expected when fluticasone is inhaled.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone. The effects of high fluticasone systemic exposure on ritonavir plasma levels are unknown.
Other corticosteroids: interaction not studied. Plasma concentrations of these medicinal products may be increased when co-administered with darunavir with low dose ritonavir, resulting in reduced serum cortisol concentrations.
Concomitant use of darunavir with low dose ritonavir and corticosteroids (all routes of administration) that are metabolised by CYP3A may increase the risk of development of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.
Co-administration with CYP3A- metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects.
Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone should be considered, particularly for long term use.
Dexamethasone (systemic)
Not studied. Dexamethasone may decrease plasma concentrations of darunavir.
(CYP3A induction)
Systemic dexamethasone should be used with caution when combined with darunavir co-administered with low dose ritonavir.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan
Not studied. Concomitant use of bosentan and darunavir co-administered with low dose ritonavir may increase plasma concentrations of bosentan.
Bosentan is expected to decrease plasma concentrations of darunavir and/or its pharmacoenhancer.
(CYP3A induction)
When administered concomitantly with darunavir and low dose ritonavir, the patient's tolerability of bosentan should be monitored.
HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A protease inhibitors
Elbasvir/grazoprevir
Darunavir with low dose ritonavir may increase the exposure to grazoprevir.
(CYP3A and OATP1B inhibition)
Concomitant use of darunavir with low dose ritonavir and elbasvir/grazoprevir is contraindicated (see section 4.3).
Glecaprevir/pibrentasvir
Based on theoretical considerations boosted darunavir may increase the exposure to glecaprevir and pibrentasvir.
(P-gp, BCRP and/or OATP1B1/3 inhibition)
It is not recommended to co-administer boosted darunavir with glecaprevir/pibrentasvir.
HERBAL PRODUCTS
St John's Wort
(Hypericum perforatum)
Not studied. St John's Wort is expected to decrease the plasma concentrations of darunavir and ritonavir.
(CYP450 induction)
Darunavir co-administered with low dose ritonavir must not be used concomitantly with products containing St John's Wort (Hypericum perforatum) (see section 4.3). If a patient is already taking St John's Wort, stop St John's Wort and if possible check viral levels. Darunavir exposure (and also ritonavir exposure) may increase on stopping St John's Wort. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's Wort.
HMG CO-A REDUCTASE INHIBITORS
Lovastatin
Simvastatin
Not studied. Lovastatin and simvastatin are expected to have markedly increased plasma concentrations when co-administered with darunavir co-administered with low dose ritonavir.
(CYP3A inhibition)
Increased plasma concentrations of lovastatin or simvastatin may cause myopathy, including rhabdomyolysis. Concomitant use of darunavir co-administered with low dose ritonavir with lovastatin and simvastatin is therefore contraindicated (see section 4.3).
Atorvastatin
10 mg once daily
atorvastatin AUC β 3-4 fold
atorvastatin Cmin β β5.5-10 fold
atorvastatin Cmax β β2 fold
#darunavir/ritonavir
When administration of atorvastatin and darunavir co-administered with low dose ritonavir is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily. A gradual dose increase of atorvastatin may be tailored to the clinical response.
Pravastatin
40 mg single dose
pravastatin AUC β 81%ΒΆ
pravastatin Cmin ND
pravastatin Cmax β 63%
ΒΆ an up to five-fold increase was seen in a limited subset of subjects
When administration of pravastatin and darunavir co-administered with low dose ritonavir is required, it is recommended to start with the lowest possible dose of pravastatin and titrate up to the desired clinical effect while monitoring for safety.
Rosuvastatin
10 mg once daily
rosuvastatin AUC β 48%β
rosuvastatin Cmax β 144%β
βbased on published data with darunavir/ritonavir
When administration of rosuvastatin and darunavir co-administered with low dose ritonavir is required, it is recommended to start with the lowest possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for safety.
OTHER LIPID MODIFYING AGENTS
Lomitapide
Based on theoretical considerations boosted darunavir is expected to increase the exposure of lomitapide when co-administered.
(CYP3A inhibition)
Co-administration is contraindicated (see section 4.3).
H2-RECEPTOR ANTAGONISTS
Ranitidine
150 mg twice daily
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Darunavir co-administered with low dose ritonavir can be co-administered with H2-receptor antagonists without dose adjustments.
IMMUNOSUPPRESSANTS
Ciclosporin
Sirolimus
Tacrolimus
Everolimus
Not studied. Exposure to these immunosuppressants will be increased when co-administered with darunavir co-administered with low dose ritonavir.
(CYP3A inhibition)
Therapeutic drug monitoring of the immunosuppressive agent must be done when co-administration occurs.
Concomitant use of everolimus and darunavir co-administered with low dose ritonavir is not recommended.
INHALED BETA AGONISTS
Salmeterol
Not studied. Concomitant use of salmeterol and darunavir co-administered with low dose ritonavir may increase plasma concentrations of salmeterol.
Concomitant use of salmeterol and darunavir co-administered with low dose ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse event with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE
Methadone individual dose ranging from 55 mg to 150 mg once daily
R(-) methadone AUC β 16%
R(-) methadone Cmin β 15%
R(-) methadone Cmax β 24%
No adjustment of methadone dosage is required when initiating co-administration with darunavir /ritonavir. However, increased methadone dose may be necessary when concomitantly administered for a longer period of time due to induction of metabolism by ritonavir. Therefore, clinical monitoring is recommended, as maintenance therapy may need to be adjusted in some patients.
Buprenorphine/naloxone 8/2 mgβ16/4 mg once daily
buprenorphine AUC β 11%
buprenorphine Cmin β
buprenorphine Cmax β 8%
norbuprenorphine AUC β 46%
norbuprenorphine Cmin β 71%
norbuprenorphine Cmax β 36%
naloxone AUC β
naloxone Cmin ND
naloxone Cmax β
The clinical relevance of the increase in norbuprenorphine pharmacokinetic parameters has not been established. Dose adjustment for buprenorphine may not be necessary when co-administered with darunavir/ritonavir but a careful clinical monitoring for signs of opiate toxicity is recommended.
Fentanyl
Oxycodone
Tramadol
Based on theoretical considerations boosted darunavir may increase plasma concentrations of these analgesics.
(CYP2D6 and/or CYP3A inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir with these analgesics.
OESTROGEN-BASED CONTRACEPTIVES
Drospirenone
Ethinylestradiol
(3 mg/0.02 mg once daily)
Ethinylestradiol
Norethindrone 35 Β΅g/1 mg once daily
Not studied with darunavir/ritonavir.
Β
ethinylestradiol AUC β 44%Ξ²
ethinylestradiol Cmin β 62%Ξ²
ethinylestradiol Cmax β 32%Ξ²
norethindrone AUC β 14%Ξ²
norethindrone Cmin β 30%Ξ²
norethindrone Cmax βΞ²
Ξ²with darunavir/ritonavir
When darunavir is co-administered with a drospirenone-containing product, clinical monitoring is recommended due to the potential for hyperkalaemia.
Alternative or additional contraceptive measures are recommended when oestrogen-based contraceptives are co-administered with darunavir and low dose ritonavir.
Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.
OPIOID ANTAGONIST
Naloxegol
Not studied.
Co-administration of boosted darunavir and naloxegol is contraindicated.
PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of erectile dysfunction
Avanafil
Sildenafil
Tadalafil
Vardenafil
In an interaction study#, a comparable systemic exposure to sildenafil was observed for a single intake of 100 mg sildenafil alone and a single intake of 25 mg sildenafil co-administered with darunavir and low dose ritonavir.
The combination of avanafil and darunavir with low dose ritonavir is contraindicated (see section 4.3). Concomitant use of other PDE-5 inhibitors for the treatment of erectile dysfunction with darunavir co-administered with low dose ritonavir should be done with caution. If concomitant use of darunavir co-administered with low dose ritonavir with sildenafil, vardenafil or tadalafil is indicated, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours or tadalafil at a single dose not exceeding 10 mg in 72 hours is recommended.
For the treatment of pulmonary arterial hypertension
Sildenafil
Tadalafil
Not studied. Concomitant use of sildenafil or tadalafil for the treatment of pulmonary arterial hypertension and darunavir co-administered with low dose ritonavir may increase plasma concentrations of sildenafil or tadalafil.
(CYP3A inhibition)
A safe and effective dose of sildenafil for the treatment of pulmonary arterial hypertension co-administered with darunavir and low dose ritonavir has not been established. There is an increased potential for sildenafil-associated adverse events (including visual disturbances, hypotension, prolonged erection and syncope). Therefore, co-administration of darunavir with low dose ritonavir and sildenafil when used for the treatment of pulmonary arterial hypertension is contraindicated (see section 4.3).
Co-administration of tadalafil for the treatment of pulmonary arterial hypertension with darunavir and low dose ritonavir is not recommended.
PROTON PUMP INHIBITORS
Omeprazole
20 mg once daily
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Darunavir co-administered with low dose ritonavir can be co-administered with proton pump inhibitors without dose adjustments.
SEDATIVES/HYPNOTICS
Buspirone
Clorazepate
Diazepam
Estazolam
Flurazepam
Midazolam (parenteral)
Zolpidem
Midazolam (oral)
Triazolam
Not studied. Sedative/hypnotics are extensively metabolised by CYP3A. Co-administration with darunavir/ritonavir may cause a large increase in the concentration of these medicines.
If parenteral midazolam is co-administered with darunavir co-administered with low dose ritonavir it may cause a large increase in the concentration of this benzodiazepine.
Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.
Clinical monitoring is recommended when co-administering darunavir with these sedatives/hypnotics and a lower dose of the sedatives/hypnotics should be considered.
If parenteral midazolam is co-administered with darunavir with low dose ritonavir, it should be done in an intensive care unit (ICU) or similar setting, which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Darunavir with low dose ritonavir with triazolam or oral midazolam is contraindicated (see section 4.3).
TREATMENT FOR PREMATURE EJACULATION
Dapoxetine
Not studied.
Co-administration of boosted darunavir with dapoxetine is contraindicated.
UROLOGICAL DRUGS
Fesoterodine Solifenacin
Not studied.
Use with caution. Monitor for fesoterodine or solifenacin adverse reactions, dose reduction of fesoterodine or solifenacin may be necessary.
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology).
β The efficacy and safety of the use of darunavir with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavir and tipranavir) has not been established in HIV patients. According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.
β‘ Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.
4.6 |
Darunavir 600 mg film-coated tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.
There are no adequate and well controlled studies on pregnancy outcome with darunavir in pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
Darunavir co-administered with low dose ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk.
Breast-feeding
It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted in toxicity of the offspring.
Because of the potential for adverse reactions in breast-fed infants, women should be instructed not to breast-feed if they are receiving darunavir.
In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed.
Fertility
No human data on the effect of darunavir on fertility are available. There was no effect on mating or fertility with darunavir treatment in rats (see section 5.3).
4.7 |
Darunavir 600 mg film-coated tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Darunavir in combination with ritonavir has no or negligible influence on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing darunavir co-administered with low dose ritonavir and should be borne in mind when considering a patient's ability to drive or operate machinery (see section 4.8).
4.8 |
Darunavir 600 mg film-coated tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
During the clinical development program (N=2,613 treatment-experienced subjects who initiated therapy with darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent adverse reactions reported in clinical trials and as spontaneous reports are diarrhoea, nausea, rash, headache and vomiting. The most frequent serious reactions are acute renal failure, myocardial infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis and pyrexia.
In the 96 week analysis, the safety profile of darunavir/ritonavir 800/100 mg once daily in treatment-naΓ―ve subjects was similar to that seen with darunavir/ritonavir 600/100 mg twice daily in treatment-experienced subjects except for nausea which was observed more frequently in treatment-naΓ―ve subjects. This was driven by mild intensity nausea. No new safety findings were identified in the 192 week analysis of the treatment-naΓ―ve subjects in which the mean treatment duration of darunavir/ritonavir 800/100 mg once daily was 162.5 weeks.
Tabulated list of adverse reactions
Adverse reactions are listed by system organ class (SOC) and frequency category. Within each frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as follows: very common (β₯ 1/10), common (β₯ 1/100 to < 1/10), uncommon (β₯ 1/1,000 to < 1/100), rare (β₯ 1/10,000 to < 1/1,000) and not known (frequency cannot be estimated from the available data).
Adverse reactions observed with darunavir/ritonavir in clinical trials and post-marketing
MedDRA system organ class Frequency category
Adverse reaction
Infections and infestations
Uncommon
herpes simplex
Blood and lymphatic system disorders
Uncommon
Rare
thrombocytopenia, neutropenia, anaemia, leukopenia
increased eosinophil count
Immune system disorders
Uncommon
immune reconstitution inflammatory syndrome, (drug) hypersensitivity
Endocrine disorders
Uncommon
hypothyroidism, increased blood thyroid stimulating hormone
Metabolism and nutrition disorders
Common
Uncommon
diabetes mellitus, hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia
gout, anorexia, decreased appetite, decreased weight, increased weight, hyperglycaemia, insulin resistance, decreased high density lipoprotein, increased appetite, polydipsia, increased blood lactate dehydrogenase
Psychiatric disorders
Common
Uncommon
Rare
insomnia
depression, disorientation, anxiety, sleep disorder, abnormal dreams, nightmare, decreased libido
confusional state, altered mood, restlessness
Nervous system disorders
Common
Uncommon
Rare
headache, peripheral neuropathy, dizziness
lethargy, paraesthesia, hypoaesthesia, dysgeusia, disturbance in attention, memory impairment, somnolence
syncope, convulsion, ageusia, sleep phase rhythm disturbance
Eye disorders
Uncommon
Rare
conjunctival hyperaemia, dry eye
visual disturbance
Ear and labyrinth disorders
Uncommon
vertigo
Cardiac disorders
Uncommon
Rare
myocardial infarction, angina pectoris, prolonged electrocardiogram QT, tachycardia
acute myocardial infarction, sinus bradycardia, palpitations
Vascular disorders
Uncommon
hypertension, flushing
Respiratory, thoracic and mediastinal disorders
Uncommon
Rare
dyspnoea, cough, epistaxis, throat irritation
rhinorrhoea
Gastrointestinal disorders
Very common
Common
Uncommon
Rare
diarrhoea
vomiting, nausea, abdominal pain, increased blood amylase, dyspepsia, abdominal distension, flatulence
pancreatitis, gastritis, gastrooesophageal reflux disease, aphthous stomatitis, retching, dry mouth, abdominal discomfort, constipation, increased lipase, eructation, oral dysaesthesia
stomatitis, haematemesis, cheilitis, dry lip, coated tongue
Hepatobiliary disorders
Common
Uncommon
increased alanine aminotransferase
hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased transaminase, increased aspartate aminotransferase, increased blood bilirubin, increased blood alkaline phosphatase, increased gamma-glutamyltransferase
Skin and subcutaneous tissue disorders
Common
Uncommon
Rare
Not known
rash (including macular, maculopapular, papular, erythematous and pruritic rash), pruritus
angioedema, generalised rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, nail pigmentation
DRESS, Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrhoeic dermatitis, skin lesion, xeroderma
toxic epidermal necrolysis, acute generalised exanthematous pustulosis
Musculoskeletal and connective tissue disorders
Uncommon
Rare
myalgia, osteonecrosis, muscle spasms, muscular weakness, arthralgia, pain in extremity, osteoporosis, increased blood creatine phosphokinase
musculoskeletal stiffness, arthritis, joint stiffness
Renal and urinary disorders
Uncommon
Rare
Rare
acute renal failure, renal failure, nephrolithiasis, increased blood creatinine, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria
decreased creatinine renal clearance
crystal nephropathy§
Reproductive system and breast disorders
Uncommon
erectile dysfunction, gynaecomastia
General disorders and administration site conditions
Common
Uncommon
Rare
asthenia, fatigue
pyrexia, chest pain, peripheral oedema, malaise, feeling hot, irritability, pain
chills, abnormal feeling, xerosis
Β§ adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics (Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determined using the "Rule of 3".
Description of selected adverse reactions
Rash
In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in section 4.4.
During the clinical development program of raltegravir in treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing darunavir/ritonavir + raltegravir compared to those containing darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4).
Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).
Musculoskeletal abnormalities
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of protease inhibitors, particularly in combination with NRTIs.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).
Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).
Bleeding in haemophiliac patients
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors (see section 4.4).
Paediatric population
The safety assessment in paediatric patients is based on the 48-week analysis of safety data from three Phase II trials. The following patient populations were evaluated (see section 5.1):
β’ 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at least 20 kg who received darunavir tablets with low dose ritonavir twice daily in combination with other antiretroviral agents.
β’ 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received darunavir oral suspension with low dose ritonavir twice daily in combination with other antiretroviral agents.
β’ 12 ART-naΓ―ve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 40 kg who received darunavir tablets with low dose ritonavir once daily in combination with other antiretroviral agents (see section 5.1).
Overall, the safety profile in these paediatric patients was similar to that observed in the adult population.
Other special populations
Patients co-infected with hepatitis B and/or hepatitis C virus
Among 1,968 treatment-experienced patients receiving darunavir co-administered with ritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis (see section 4.4).
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: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Darunavir 600 mg film-coated tablets | Clinical particulars - Overdose | Overdose
Human experience of acute overdose with darunavir co-administered with low dose ritonavir is limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
There is no specific antidote for overdose with darunavir. Treatment of overdose with darunavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
5. Pharmacological properties
5.1 |
Darunavir 600 mg film-coated tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1infected patients compared to healthy subjects may be explained by the higher concentrations of Ξ±1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG and, therefore, higher plasma concentrations.
Darunavir is primarily metabolised by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir considerably.
Absorption
Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.
The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily (see section 4.4).
When administered without food, the relative bioavailability of darunavir in the presence of low dose ritonavir is 30% lower as compared to intake with food. Therefore, darunavir tablets should be taken with ritonavir and with food. The type of food does not affect exposure to darunavir.
Distribution
Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma Ξ±1-acid glycoprotein.
Following intravenous administration, the volume of distribution of darunavir alone was 88.1 Β± 59.0 l (Mean Β± SD) and increased to 131 Β± 49.9 l (Mean Β± SD) in the presence of 100 mg twice-daily ritonavir.
Biotransformation
In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due to the parent active substance. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild type HIV.
Elimination
After a 400/100 mg 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.
The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 l/h and 5.9 l/h, respectively.
Special populations
Paediatric population
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 74 treatment-experienced paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that the administered weight-based doses of darunavir/ritonavir resulted in darunavir exposure comparable to that in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 14 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to < 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naΓ―ve paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that darunavir/ritonavir 800/100 mg once daily results in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 800/100 mg once daily. Therefore the same once daily dosage may be used in treatment-experienced adolescents aged 12 to < 18 years and weighing at least 40 kg without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to < 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 800/100 mg once daily (see section 4.2). In addition, pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed the identification of weight-based darunavir/ritonavir once daily dosing regimens for paediatric patients weighing at least 15 kg that are either ART-naΓ―ve or treatment-experienced paediatric patients without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
Elderly
Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (n=12, age β₯ 65) (see section 4.4). However, only limited data were available in patients above the age of 65 year.
Gender
Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV infected females compared to males. This difference is not clinically relevant.
Renal impairment
Results from a mass balance study with 14C-darunavir with ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine unchanged.
Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20) (see sections 4.2 and 4.4).
Hepatic impairment
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with darunavir co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects.
However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown therefore, darunavir should be used with caution. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see sections 4.2, 4.3 and 4.4).
Pregnancy and postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum.
Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of total darunavir
(mean Β± SD)
Second trimester of pregnancy
(n=12)a
Third trimester of pregnancy
(n=12)
Postpartum (6-12 weeks)
(n=12)
Cmax, ng/ml
4,668 Β± 1,097
5,328 Β± 1,631
6,659 Β± 2,364
AUC12h, ng.h/ml
39,370 Β± 9,597
45,880 Β± 17,360
56,890 Β± 26,340
Cmin, ng/ml
1,922 Β± 825
2,661 Β± 1,269
2,851 Β± 2,216
a n=11 for AUC12h
Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of total darunavir
(mean Β± SD)
Second trimester of pregnancy
(n=17)
Third Trimester of pregnancy
(n=15)
Postpartum (6-12 weeks)
(n=16)
Cmax, ng/ml
4,964 Β± 1,505
5,132 Β± 1,198
7,310 Β± 1,704
AUC24h, ng.h/ml
62,289 Β± 16,234
61,112 Β± 13,790
92,116 Β± 29,241
Cmin, ng/ml
1,248 Β± 542
1,075 Β± 594
1,473 Β± 1,141
In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and 26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, as compared with postpartum.
In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and 30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared with postpartum.
5.3 |
Darunavir 600 mg film-coated tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Animal toxicology studies have been conducted at exposures up to clinical exposure levels with darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.
In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment with darunavir. In rodents the target organs identified were the haematopoietic system, the blood coagulation system, liver and thyroid. A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated partial thromboplastin time.
Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and thyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a small increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the pancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicity findings or target organs were identified up to exposures equivalent to clinical exposure at the recommended dose.
In a study conducted in rats, the number of corpora lutea and implantations were decreased in the presence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavir treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The exposure levels were lower than those with the recommended clinical dose in humans. In a pre- and postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening of eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pups that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation. These effects may be secondary to pup exposure to the active substance via the milk and/or maternal toxicity. No post weaning functions were affected with darunavir alone or in combination with ritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed with convulsions in some animals. Exposure in plasma, liver and brain was considerably higher than in adult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, the exposure was comparable to that in adult rats. The increased exposure was likely at least partly due to immaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalities were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats.
Due to uncertainties regarding the rate of development of the human blood brain barrier and liver enzymes, darunavir with low dose ritonavir should not be used in paediatric patients below 3 years of age.
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1,000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences of hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. The observed hepatocellular and thyroid tumours in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses.
After 2 years administration of darunavir at exposures at or below the human exposure, kidney changes were observed in mice (nephrosis) and rats (chronic progressive nephropathy).
Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.
6. |
Darunavir 600 mg film-coated tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Silica, colloidal anhydrous
Silicified microcrystalline cellulose
Crospovidone
Magnesium stearate
Tablet film-coat
Polyvinyl alcohol β partially hydrolysed
Macrogol 3350
Titanium dioxide (E171)
Talc
Iron oxide yellow (E172)
6.2 |
Darunavir 600 mg film-coated tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Darunavir 600 mg film-coated tablets | Pharmaceutical particulars - Shelf life | Shelf life
3 years
6.4 |
Darunavir 600 mg film-coated tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Darunavir 600 mg film-coated tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Blister pack:
OPA-Aluminium-PVC/Aluminium blister packs; pack sizes of 1x30, 1x60 and 1x90 film-coated tablets.
HDPE Bottle:
White opaque high-density polyethylene (HDPE) bottle closed with white opaque child-resistant polypropylene closure. Contains a cylindrical canister filled with silica gel as desiccant. Pack sizes of 60 film-coated tablets.
Not all pack sizes may be marketed
6.6 |
Darunavir 600 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. |
Darunavir 600 mg film-coated tablets | Marketing authorisation holder | Amarox Limited
Congress House,
14 Lyon Road,
Harrow, Middlesex HA1 2EN,
United Kingdom
8. Marketing authorisation number(s)
PL 49445/0029
9. |
Darunavir 600 mg film-coated tablets | Date of first authorisation/renewal of the authorisation | 23/07/2020
10. |
Darunavir 600 mg film-coated tablets | Date of revision of the text | 10/01/2023 |
Darunavir 600mg Film-Coated Tablets | Name of the medicinal product | Darunavir 600 mg film-coated tablets
2. |
Darunavir 600mg Film-Coated Tablets | Qualitative and quantitative composition | Each film-coated tablet contains 600 mg of darunavir.
This medicine contains less than 1 mmol sodium (23 mg) per tablets, that is to say essentially 'sodium-free'.
For the full list of excipients, see section 6.1.
3. |
Darunavir 600mg Film-Coated Tablets | Pharmaceutical form | Film-coated tablet.
Beige coloured, oval shaped, biconvex, film-coated tablet, debossed with βDβ on one side and β600β on the other side.
4. |
Darunavir 600mg Film-Coated Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Darunavir co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection (see section 4.2).
Darunavir 600 mg tablets may be used to provide suitable dose regimens (see section 4.2)
β’ For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adult patients, including those that have been highly pre-treated.
β’ For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least 15 kg body weight.
In deciding to initiate treatment with darunavir co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of darunavir (see sections 4.2, 4.4 and 5.1).
4.2 |
Darunavir 600mg Film-Coated Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Therapy should be initiated by a health care provider experienced in the management of HIV infection. After therapy with darunavir has been initiated, patients should be advised not to alter the dosage, dose form or discontinue therapy without discussing with their health care provider.
Posology
Darunavir must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of ritonavir must, therefore, be consulted prior to initiation of therapy with darunavir.
Darunavir may also be available as an oral suspension for use in patients who are unable to swallow darunavir tablets.
ART-experienced adult patients
The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food.
ART-naΓ―ve adult patients
For dosage recommendations in ART-naΓ―ve patients see the Summary of Product Characteristics for darunavir 400 mg and 800 mg tablets.
ART-naΓ―ve paediatric patients (3 to 17 years of age and weighing at least 15 kg)
The weight-based dose of darunavir and ritonavir in paediatric patients is provided in the table below.
Recommended dose for treatment-naΓ―ve paediatric patients (3 to 17 years) with darunavir tablets and ritonavira
Body weight (kg)
Dose (once daily with food)
β₯ 15 kg to < 30 kg
600 mg darunavir/100 mg ritonavir once daily
β₯ 30 kg to < 40 kg
675 mg darunavir/100 mg ritonavir once daily
β₯ 40 kg
800 mg darunavir/100 mg ritonavir once daily
a ritonavir oral solution: 80 mg/ml
ART-experienced paediatric patients (3 to 17 years of age and weighing at least 15 kg)
Darunavir twice daily taken with ritonavir taken with food is usually recommended.
A once daily dose regimen of darunavir taken with ritonavir taken with food may be used in patients with prior exposure to antiretroviral medicinal products but without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
The weight-based dose of darunavir and ritonavir in paediatric patients is provided in the table below. The recommended dose of darunavir with low dose ritonavir should not exceed the recommended adult dose (600/100 mg twice daily or 800/100 mg once daily).
Recommended dose for treatment-experienced paediatric patients (3 to 17 years) with darunavir tablets and ritonavira
Body weight (kg)
Dose (once daily with food)
Dose (twice daily with food)
β₯ 15 kg to < 30 kg
600 mg darunavir/100 mg ritonavir once daily
375 mg darunavir/50 mg ritonavir twice daily
β₯ 30 kg to < 40 kg
675 mg darunavir/100 mg ritonavir once daily
450 mg darunavir/60 mg ritonavir twice daily
β₯ 40 kg
800 mg darunavir/100 mg ritonavir once daily
600 mg darunavir/100 mg ritonavir twice daily
a ritonavir oral solution: 80 mg/ml
For ART-experienced paediatric patients HIV genotypic testing is recommended. However, when HIV genotypic testing is not feasible, the darunavir/ritonavir once daily dosing regimen is recommended in HIV protease inhibitor-naΓ―ve paediatric patients and the twice daily dosing regimen is recommended in HIV protease inhibitor-experienced patients.
Advice on missed doses
In case a dose of darunavir and/or ritonavir is missed within 6 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of darunavir and ritonavir with food as soon as possible. If this is noticed later than 6 hours after the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.
This guidance is based on the 15-hour half-life of darunavir in the presence of ritonavir and the recommended dosing interval of approximately 12 hours.
If a patient vomits within 4 hours of taking the medicine, another dose of darunavir with ritonavir should be taken with food as soon as possible. If a patient vomits more than 4 hours after taking the medicine, the patient does not need to take another dose of darunavir with ritonavir until the next regularly scheduled time.
Special populations
Elderly
Limited information is available in this population, and therefore, darunavir should be used with caution in this age group (see sections 4.4 and 5.2).
Hepatic impairment
Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, darunavir should be used with caution in these patients. No pharmacokinetic data are available in patients with severe hepatic impairment. Severe hepatic impairment could result in an increase of darunavir exposure and a worsening of its safety profile. Therefore, darunavir must not be used in patients with severe hepatic impairment (Child-Pugh Class C) (see sections 4.3, 4.4 and 5.2).
Renal impairment
No dose adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).
Paediatric population
Darunavir/ritonavir should not be used in children with a body weight of less than 15 kg as the dose for this population has not been established in a sufficient number of patients (see section 5.1).
Darunavir/ritonavir should not be used in children below 3 years of age because of safety concerns (see sections 4.4 and 5.3).
The weight-based dose regimen for darunavir and ritonavir is provided in the tables above.
Pregnancy and postpartum
No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk (see sections 4.4, 4.6 and 5.2).
Method of administration
Patients should be instructed to take darunavir with low dose ritonavir within 30 minutes after completion of a meal. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5 and 5.2).
4.3 |
Darunavir 600mg Film-Coated Tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with severe (Child-Pugh Class C) hepatic impairment.
Combination of rifampicin with darunavir with concomitant low dose ritonavir (see section 4.5).
Co-administration with the combination product lopinavir/ritonavir (see section 4.5).
Co-administration with herbal preparations containing St John's wort (Hypericum perforatum) (see section 4.5).
Co-administration of darunavir with low dose ritonavir, with active substances that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These active substances include e.g.:
β’ alfuzosin
β’ amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
β’ astemizole, terfenadine
β’ colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)
β’ ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
β’ elbasvir/grazoprevir
β’ cisapride
β’ dapoxetine
β’ domperidone
β’ naloxegol
β’ lurasidone, pimozide, quetiapine, sertindole (see section 4.5)
β’ triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5)
β’ sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil
β’ simvastatin, lovastatin and lomitapide (see section 4.5)
β’ dabigatran, ticagrelor (see section 4.5).
4.4 |
Darunavir 600mg Film-Coated Tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Regular assessment of virological response is advised. In the setting of lack or loss of virological response, resistance testing should be performed.
Darunavir must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products (see section 5.2). The Summary of Product Characteristics of ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with darunavir.
Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect darunavir concentrations. It is not recommended to alter the dose of ritonavir.
Darunavir binds predominantly to Ξ±1-acid glycoprotein. This protein binding is concentration-dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products highly bound to Ξ±1-acid glycoprotein cannot be ruled out (see section 4.5).
ART-experienced patients β once daily dosing
Darunavir used in combination with cobicistat or low dose ritonavir once daily in ART-experienced patients should not be used in patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA β₯ 100,000 copies/ml or CD4+ cell count < 100 cells x 106/L (see section 4.2). Combinations with optimised background regimen (OBRs) other than β₯ 2 NRTIs have not been studied in this population. Limited data are available in patients with HIV-1 clades other than B (see section 5.1).
Paediatric population
Darunavir is not recommended for use in paediatric patients below 3 years of age or less than 15 kg body weight (see sections 4.2 and 5.3).
Pregnancy
Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk. Caution should be used in pregnant women with concomitant medications which may further decrease darunavir exposure (see sections 4.5 and 5.2).
Elderly
As limited information is available on the use of darunavir in patients aged 65 and over, caution should be exercised in the administration of darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2 and 5.2).
Severe skin reactions
During the darunavir/ritonavir clinical development program (N=3,063), severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported. Darunavir should be discontinued immediately if signs or symptoms of severe skin reactions develop. These can include, but are not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
Rash occurred more commonly in treatment-experienced patients receiving regimens containing darunavir/ritonavir + raltegravir compared to patients receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir (see section 4.8).
Darunavir contains a sulphonamide moiety. Darunavir should be used with caution in patients with a known sulphonamide allergy.
Hepatotoxicity
Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with darunavir. During the darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.
Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of darunavir/ritonavir treatment.
If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients using darunavir/ritonavir, interruption or discontinuation of treatment should be considered promptly.
Patients with coexisting conditions
Hepatic impairment
The safety and efficacy of darunavir have not been established in patients with severe underlying liver disorders and darunavir is therefore contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, darunavir should be used with caution in patients with mild or moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).
Renal impairment
No special precautions or dose adjustments for darunavir/ritonavir are required in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these patients (see sections 4.2 and 5.2).
Haemophiliac patients
There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding.
Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Immune reconstitution inflammatory syndromeIn HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated, and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with darunavir co-administered with low dose ritonavir.
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).
Interactions with medicinal products
Several of the interaction studies have been performed with darunavir at lower than recommended doses. The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated. For full information on interactions with other medicinal products see section 4.5.
Efavirenz in combination with boosted darunavir once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used (see section 4.5).
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-glycoprotein (P-gp; see sections 4.3 and 4.5).
4.5 |
Darunavir 600mg Film-Coated Tablets | 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 adults.
Medicinal products that may be affected by darunavir boosted with ritonavir
Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or transported by P-gp may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.
Co-administration of darunavir/ritonavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see the Interaction table below).
Darunavir co-administered with low dose ritonavir must not be combined with medicinal products that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) (see section 4.3).
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily. Therefore, darunavir must only be used in combination with low dose ritonavir as a pharmacokinetic enhancer (see sections 4.4 and 5.2).
A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to the presence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir with medicinal products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone, repaglinide) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration with substrates of these transporters can result in increased plasma concentrations of these compounds (e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).
Medicinal products that affect darunavir/ritonavir exposure
Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir (e.g. rifampicin, St John's wort, lopinavir). Co-administration of darunavir and ritonavir and other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (e.g. indinavir, azole antifungals like clotrimazole). These interactions are described in the interaction table below.
Interaction table
Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products are listed in the table below. The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (β), below (β) or above (β) the 80-125% range (not determined as βNDβ).
Several of the interaction studies (indicated by # in the table below) have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated.
The below list of examples of drug-drug interactions is not comprehensive and therefore the label of each drug that is co-administered with darunavir should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.
INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal products by therapeutic areas
Interaction Geometric mean change (%)
Recommendations concerning co-administration
HIV ANTIRETROVIRALS
Integrase strand transfer inhibitors
Dolutegravir
dolutegravir AUC β 22%
dolutegravir C24h β 38%
dolutegravir Cmax β 11%
darunavir β*
* Using cross-study comparisons to historical pharmacokinetic data
Darunavir co-administered with low dose ritonavir and dolutegravir can be used without dose adjustment.
Raltegravir
Some clinical studies suggest raltegravir may cause a modest decrease in darunavir plasma concentrations.
At present the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically relevant. Darunavir co-administered with low dose ritonavir and raltegravir can be used without dose adjustments.
Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine
400 mg once daily
didanosine AUC β 9%
didanosine Cmin ND
didanosine Cmax β 16%
darunavir AUC β
darunavir Cmin β
darunavir Cmax β
Darunavir co-administered with low dose ritonavir and didanosine can be used without dose adjustments.
Didanosine is to be administered on an empty stomach, thus it should be administered 1 hour before or 2 hours after darunavir/ritonavir given with food.
Tenofovir disoproxil
245 mg once dailyβ‘
tenofovir AUC β 22%
tenofovir Cmin β 37%
tenofovir Cmax β 24%
# darunavir AUC β 21%
# darunavir Cmin β 24%
# darunavir Cmax β 16%
(β tenofovir from effect on MDR-1 transport in the renal tubules)
Monitoring of renal function may be indicated when darunavir co-administered with low dose ritonavir is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.
Emtricitabine/tenofovir alafenamide
Tenofovir alafenamide β
Tenofovir β
The recommended dose of emtricitabine/ tenofovir alafenamide is 200/10 mg once daily when used with darunavir with low dose ritonavir.
Abacavir
Emtricitabine
Lamivudine
Stavudine
Zidovudine
Not studied. Based on the different elimination pathways of the other NRTIs zidovudine, emtricitabine, stavudine, lamivudine, that are primarily renally excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and darunavir co-administered with low dose ritonavir.
Darunavir co-administered with low dose ritonavir can be used with these NRTIs without dose adjustment.
Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz
600 mg once daily
efavirenz AUC β 21%
efavirenz Cmin β 17%
efavirenz Cmax β 15%
#darunavir AUC β 13%
#darunavir Cmin β 31%
#darunavir Cmax β 15%
(β efavirenz from CYP3A inhibition)
(β darunavir from CYP3A induction)
Clinical monitoring for central nervous system toxicity associated with increased exposure to efavirenz may be indicated when darunavir co-administered with low dose ritonavir is given in combination with efavirenz.
Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used (see section 4.4).
Etravirine
100 mg twice daily
etravirine AUC β 37%
etravirine Cmin β 49%
etravirine Cmax β 32%
darunavir AUC β 15%
darunavir Cmin β
darunavir Cmax β
Darunavir co-administered with low dose ritonavir and etravirine 200 mg twice daily can be used without dose adjustments.
Nevirapine
200 mg twice daily
nevirapine AUC β 27%
nevirapine Cmin β 47%
nevirapine Cmax β 18%
#darunavir: concentrations were consistent with historical data
(β nevirapine from CYP3A inhibition)
Darunavir co-administered with low dose ritonavir and nevirapine can be used without dose adjustments.
Rilpivirine
150 mg once daily
rilpivirine AUC β 130%
rilpivirine Cmin β 178%
rilpivirine Cmax β 79%
darunavir AUC β
darunavir Cmin β 11%
darunavir Cmax β
Darunavir co-administered with low dose ritonavir and rilpivirine can be used without dose adjustments.
HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavirβ
Atazanavir
300 mg once daily
atazanavir AUC β
atazanavir Cmin β 52%
atazanavir Cmax β 11%
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Atazanavir: comparison of atazanavir/ritonavir 300/100 mg once daily vs. atazanavir 300 mg once daily in combination with darunavir/ritonavir 400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg twice daily in combination with atazanavir 300 mg once daily.
Darunavir co-administered with low dose ritonavir and atazanavir can be used without dose adjustments.
Indinavir
800 mg twice daily
indinavir AUC β 23%
indinavir Cmin β 125%
indinavir Cmax β
#darunavir AUC β 24%
#darunavir Cmin β 44%
#darunavir Cmax β 11%
Indinavir: comparison of indinavir/ritonavir 800/100 mg twice daily vs. indinavir/darunavir/ritonavir 800/400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with indinavir 800 mg twice daily.
When used in combination with darunavir co-administered with low dose ritonavir, dose adjustment of indinavir from 800 mg twice daily to 600 mg twice daily may be warranted in case of intolerance.
Saquinavir
1,000 mg twice daily
#darunavir AUC β 26%
#darunavir Cmin β 42%
#darunavir Cmax β 17%
saquinavir AUC β 6%
saquinavir Cmin β 18%
saquinavir Cmax β 6%
Saquinavir: comparison of saquinavir/ritonavir 1,000/100 mg twice daily vs. saquinavir/darunavir/ritonavir 1,000/400/100 mg twice daily
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with saquinavir 1,000 mg twice daily.
It is not recommended to combine darunavir co-administered with low dose ritonavir with saquinavir.
HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavirβ
Lopinavir/ritonavir
400/100 mg twice daily
Lopinavir/ritonavir
533/133.3 mg twice daily
lopinavir AUC β 9%
lopinavir Cmin β 23%
lopinavir Cmax β 2%
darunavir AUC β 38%β‘
darunavir Cmin β 51%β‘
darunavir Cmax β 21%β‘
lopinavir AUC β
lopinavir Cmin β 13%
lopinavir Cmax β 11%
darunavir AUC β 41%
darunavir Cmin β 55%
darunavir Cmax β 21%
β‘ based upon non dose normalised values
Due to a decrease in the exposure (AUC) of darunavir by 40%, appropriate doses of the combination have not been established. Hence, concomitant use of darunavir co-administered with low dose ritonavir and the combination product lopinavir/ritonavir is contraindicated (see section 4.3).
CCR5 ANTAGONIST
Maraviroc
150 mg twice daily
maraviroc AUC β 305%
maraviroc Cmin ND
maraviroc Cmax β 129%
darunavir, ritonavir concentrations were consistent with historical data
The maraviroc dose should be 150 mg twice daily when co-administered with darunavir with low dose ritonavir.
Ξ±1-ADRENORECEPTOR ANTAGONIST
Alfuzosin
Based on theoretical considerations darunavir is expected to increase alfuzosin plasma concentrations.
(CYP3A inhibition)
Co-administration of darunavir with low dose ritonavir and alfuzosin is contraindicated (see section 4.3).
ANAESTHETIC
Alfentanil
Not studied. The metabolism of alfentanil is mediated via CYP3A, and may as such be inhibited by darunavir co-administered with low dose ritonavir.
The concomitant use with darunavir and low dose ritonavir may require to lower the dose of alfentanil and requires monitoring for risks of prolonged or delayed respiratory depression.
ANTIANGINA/ANTIARRHYTHMIC
Disopyramide
Flecainide
Lidocaine (systemic)
Mexiletine
Propafenone
Amiodarone
Bepridil
Dronedarone
Ivabradine
Quinidine
Ranolazine
Not studied. Darunavir is expected to increase these antiarrhythmic plasma concentrations.
(CYP3A and/or CYP2D6 inhibition)
Caution is warranted and therapeutic concentration monitoring, if available, is recommended for these antiarrhythmics when co-administered with darunavir with low dose ritonavir.
Darunavir co-administered with low dose ritonavir and amiodarone, bepridil, dronedarone, ivabradine, quinidine, or ranolazine is contraindicated (see section 4.3).
Digoxin
0.4 mg single dose
digoxin AUC β 61%
digoxin Cmin ND
digoxin Cmax β 29%
(β digoxin from probable inhibition of P-gp)
Given that digoxin has a narrow therapeutic index, it is recommended that the lowest possible dose of digoxin should initially be prescribed in case digoxin is given to patients on darunavir/ritonavir therapy. The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.
ANTIBIOTIC
Clarithromycin
500 mg twice daily
clarithromycin AUC β 57%
clarithromycin Cmin β 174%
clarithromycin Cmax β 26%
#darunavir AUC β 13%
#darunavir Cmin β 1%
#darunavir Cmax β17%
14-OH-clarithromycin concentrations were not detectable when combined with darunavir/ritonavir.
(β clarithromycin from CYP3A inhibition and possible P-gp inhibition)
Caution should be exercised when clarithromycin is combined with darunavir co-administered with low dose ritonavir.
For patients with renal impairment the Summary of Product Characteristics for clarithromycin should be consulted for the recommended dose.
ANTICOAGULANTS/PLATELET AGGREGATION INHIBITOR
Apixaban
Edoxaban
Rivaroxaban
Not studied. Co-administration of darunavir with these anticoagulants may increase concentrations of the anticoagulant, which may lead to an increased bleeding risk
(CYP3A and/or P-gp inhibition)
The use of boosted darunavir and these anticoagulants is not recommended.
Dabigatran
Ticagrelor
Clopidogrel
Not studied. Co-administration with boosted darunavir may lead to a substantial increase in exposure to dabigatran or ticagrelor.
Not studied. Co-administration of clopidogrel with boosted darunavir is expected to decrease clopidogrel active metabolite plasma concentration, which may reduce the antiplatelet activity of clopidogrel.
Concomitant administration of boosted darunavir with dabigatran or ticagrelor is contraindicated (see section 4.3).
Co-administration of clopidogrel with boosted darunavir is not recommended.
Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended.
Warfarin
Not studied. Warfarin concentrations may be affected when co-administered with darunavir with low dose ritonavir.
It is recommended that the international normalised ratio (INR) be monitored when warfarin is combined with darunavir co-administered with low dose ritonavir
ANTICONVULSANTS
Phenobarbital
Phenytoin
Not studied. Phenobarbital and phenytoin are expected to decrease plasma concentrations of darunavir and its pharmacoenhancer.
(induction of CYP450 enzymes)
Darunavir co-administered with low dose ritonavir should not be used in combination with these medicines.
Carbamazepine
200 mg twice daily
carbamazepine AUC β 45%
carbamazepine Cmin β 54%
carbamazepine Cmax β 43%
darunavir AUC β
darunavir Cmin β 15%
darunavir Cmax β
No dose adjustment for darunavir/ritonavir is recommended. If there is a need to combine darunavir/ritonavir and carbamazepine, patients should be monitored for potential carbamazepine-related adverse events. Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response. Based upon the findings, the carbamazepine dose may need to be reduced by 25% to 50% in the presence of darunavir/ritonavir.
Clonazepam
Not studied. Co-administration of boosted darunavir with clonazepam may increase concentrations of clonazepam. (CYP3A inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir with clonazepam.
ANTIDEPRESSANTS
Paroxetine
20 mg once daily
Β
Β
Β
Sertraline
50 mg once daily
Β
Β
Β
Β
Β
Β
Β
Β
Β
Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone
paroxetine AUC β 39%
paroxetine Cmin β 37%
paroxetine Cmax β 36%
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
sertraline AUC β 49%
sertraline Cmin β 49%
sertraline Cmax β 44%
#darunavir AUC β
#darunavir Cmin β 6%
#darunavir Cmax β
Concomitant use of darunavir co-administered with low dose ritonavir and these antidepressants may increase concentrations of the antidepressant.
(CYP2D6 and/or CYP3A inhibition)
If antidepressants are co-administered with darunavir with low dose ritonavir, the recommended approach is a dose titration of the antidepressant based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of these antidepressants who start treatment with darunavir with low dose ritonavir should be monitored for antidepressant response.
Β
Β
Β
Β
Β
Clinical monitoring is recommended when co-administering darunavir with low dose ritonavir with these antidepressants and a dose adjustment of the antidepressant may be needed.
ANTIEMETICS
Domperidone
Not studied.
Co-administration of domperidone with boosted darunavir is contraindicated.
ANTIFUNGALS
Voriconazole
Not studied. Ritonavir may decrease plasma concentrations of voriconazole.
(induction of CYP450 enzymes)
Voriconazole should not be combined with darunavir co-administered with low dose ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Fluconazole
Isavuconazole
Itraconazole
Posaconazole
Clotrimazole
Not studied. Darunavir may increase antifungal plasma concentrations and posaconazole, isavuconazole, itraconazole or fluconazole may increase darunavir concentrations.
(CYP3A and/or P-gp inhibition)
Not studied. Concomitant systemic use of clotrimazole and darunavir co-administered with low dose ritonavir may increase plasma concentrations of darunavir and/or clotrimazole.
Darunavir AUC24h β 33% (based on population pharmacokinetic model)
Caution is warranted, and clinical monitoring is recommended. When co-administration is required the daily dose of itraconazole should not exceed 200 mg.
ANTIGOUT MEDICINES
Colchicine
Not studied. Concomitant use of colchicine and darunavir co-administered with low dose ritonavir may increase the exposure to colchicine.
(CYP3A and/ or P-gp inhibition)
A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with darunavir co-administered with low dose ritonavir is required. For patients with renal or hepatic impairment colchicine with darunavir co-administered with low dose ritonavir is contraindicated (see sections 4.3 and 4.4).
ANTIMALARIALS
Artemether/Lumefantrine
80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours
artemether AUC β 16%
artemether Cmin β
artemether Cmax β 18%
dihydroartemisinin AUC β 18%
dihydroartemisinin Cmin β
dihydroartemisinin Cmax β 18%
lumefantrine AUC β 175%
lumefantrine Cmin β 126%
lumefantrine Cmax β 65%
darunavir AUC β
darunavir Cmin β 13%
darunavir Cmax β
The combination of darunavir and artemether/lumefantrine can be used without dose adjustments; however, due to the increase in lumefantrine exposure, the combination should be used with caution.
ANTIMYCOBACTERIALS
Rifampicin
Rifapentine
Not studied. Rifapentine and rifampicin are strong CYP3A inducers and have been shown to cause profound decreases in concentrations of other protease inhibitors, which can result in virological failure and resistance development (CYP450 enzyme induction). During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with low dose ritonavir, a high frequency of liver reactions was seen with rifampicin.
The combination of rifapentine and darunavir with concomitant low dose ritonavir is not recommended.
The combination of rifampicin and darunavir with concomitant low dose ritonavir is contraindicated (see section 4.3).
Rifabutin
150 mg once every other day
rifabutin AUC** β 55%
rifabutin Cmin ** β ND
rifabutin Cmax ** β
darunavir AUC β 53%
darunavir Cmin β 68%
darunavir Cmax β 39%
** sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite)
The interaction trial showed a comparable daily systemic exposure for rifabutin between treatment at 300 mg once daily alone and 150 mg once every other day in combination with darunavir/ritonavir (600/100 mg twice daily) with an about 10-fold increase in the daily exposure to the active metabolite 25-O-desacetylrifabutin. Furthermore, AUC of the sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite) was increased 1.6- fold, while Cmax remained comparable.
Data on comparison with a 150 mg once daily reference dose is lacking.
(Rifabutin is an inducer and substrate of CYP3A.) An increase of systemic exposure to darunavir was observed when darunavir co-administered with 100 mg ritonavir was co-administered with rifabutin (150 mg once every other day).
A dosage reduction of rifabutin by 75% of the usual dose of 300 mg/day (i.e. rifabutin 150 mg once every other day) and increased monitoring for rifabutin related adverse events is warranted in patients receiving the combination with darunavir co-administered with ritonavir. In case of safety issues, a further increase of the dosing interval for rifabutin and/or monitoring of rifabutin levels should be considered.
Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV infected patients.
Based upon the safety profile of darunavir/ritonavir, the increase in darunavir exposure in the presence of rifabutin does not warrant a dose adjustment for darunavir/ritonavir.
Based on pharmacokinetic modeling, this dosage reduction of 75% is also applicable if patients receive rifabutin at doses other than 300 mg/day.
ANTINEOPLASTICS
Dasatinib
Nilotinib
Vinblastine
Vincristine
Everolimus
Irinotecan
Not studied. Darunavir is expected to increase these antineoplastic plasma concentrations.
(CYP3A inhibition)
Concentrations of these medicinal products may be increased when co-administered with darunavir with low dose ritonavir resulting in the potential for increased adverse events usually associated with these agents.
Caution should be exercised when combining one of these antineoplastic agents with darunavir with low dose ritonavir.
Concomitant use of everolimus or irinotecan and darunavir co-administered with low dose ritonavir is not recommended.
ANTIPSYCHOTICS/NEUROLEPTICS
Quetiapine
Not studied. Darunavir is expected to increase these antipsychotic plasma concentrations.
(CYP3A inhibition)
Concomitant administration of darunavir with low dose ritonavir and quetiapine is contraindicated as it may increase quetiapine-related toxicity. Increased concentrations of quetiapine may lead to coma (see section 4.3).
Perphenazine
Risperidone
Thioridazine
Lurasidone
Pimozide
Sertindole
Not studied. Darunavir is expected to increase these antipsychotic plasma concentrations.
(CYP3A, CYP2D6 and/or P-gp inhibition)
A dose decrease may be needed for these drugs when co-administered with darunavir co-administered with low dose ritonavir.
Concomitant administration of darunavir with low dose ritonavir and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).
Ξ²-BLOCKERS
Carvedilol
Metoprolol
Timolol
Not Studied. Darunavir is expected to increase these Ξ²-blocker plasma concentrations.
(CYP2D6 inhibition)
Clinical monitoring is recommended when co-administering darunavir with Ξ²-blockers. A lower dose of the Ξ²-blocker should be considered.
CALCIUM CHANNEL BLOCKERS
Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil
Not studied. Darunavir co-administered with low dose ritonavir can be expected to increase the plasma concentrations of calcium channel blockers.
(CYP3A and/or CYP2D6 inhibition)
Clinical monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with darunavir with low dose ritonavir.
CORTICOSTEROIDS
Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone)
Fluticasone: in a clinical study where ritonavir 100 mg capsules twice daily were co-administered with 50 ΞΌg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82-89%). Greater effects may be expected when fluticasone is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone. The effects of high fluticasone systemic exposure on ritonavir plasma levels are unknown.
Other corticosteroids: interaction not studied. Plasma concentrations of these medicinal products may be increased when co-administered with darunavir with low dose ritonavir, resulting in reduced serum cortisol concentrations.
Concomitant use of darunavir with low dose ritonavir and corticosteroids that are metabolised by CYP3A (e.g. fluticasone propionate or other inhaled or nasal corticosteroids) may increase the risk of development of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.
Co-administration with CYP3A-metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects.
Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone for intranasal or inhalational use should be considered, particularly for long term use.
Dexamethasone (systemic)
Not studied. Dexamethasone may decrease plasma concentrations of darunavir.
(CYP3A induction)
Systemic dexamethasone should be used with caution when combined with darunavir co-administered with low dose ritonavir.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan
Not studied. Concomitant use of bosentan and darunavir co-administered with low dose ritonavir may increase plasma concentrations of bosentan.
Bosentan is expected to decrease plasma concentrations of darunavir and/or its pharmacoenhancer.
(CYP3A induction)
When administered concomitantly with darunavir and low dose ritonavir, the patient's tolerability of bosentan should be monitored.
HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A protease inhibitors
Elbasvir/grazoprevir
Darunavir with low dose ritonavir may increase the exposure to grazoprevir.
(CYP3A and OATP1B inhibition)
Concomitant use of darunavir with low dose ritonavir and elbasvir/grazoprevir is contraindicated (see section 4.3).
Glecaprevir/pibrentasvir
Based on theoretical considerations boosted darunavir may increase the exposure to glecaprevir and pibrentasvir.
(P-gp, BCRP and /or OATP1B1/3 inhibition
It is not recommended to co-administer boosted darunavir with glecaprevir/pibrentasvir.
HERBAL PRODUCTS
St John's wort (Hypericum perforatum)
Not studied. St John's wort is expected to decrease the plasma concentrations of darunavir and ritonavir.
(CYP450 induction)
Darunavir co-administered with low dose ritonavir must not be used concomitantly with products containing St John's wort (Hypericum perforatum) (see section 4.3). If a patient is already taking St John's wort, stop St John's wort and if possible check viral levels. Darunavir exposure (and also ritonavir exposure) may increase on stopping St John's wort. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's wort.
HMG CO-A REDUCTASE INHIBITORS
Lovastatin
Simvastatin
Not studied. Lovastatin and simvastatin are expected to have markedly increased plasma concentrations when co-administered with darunavir co-administered with low dose ritonavir.
(CYP3A inhibition)
Increased plasma concentrations of lovastatin or simvastatin may cause myopathy, including rhabdomyolysis. Concomitant use of darunavir co-administered with low dose ritonavir with lovastatin and simvastatin is therefore contraindicated (see section 4.3).
Atorvastatin
10 mg once daily
atorvastatin AUC β 3-4 fold
atorvastatin Cmin β β5.5-10 fold
atorvastatin Cmax β β2 fold
#darunavir/ritonavir
When administration of atorvastatin and darunavir co-administered with low dose ritonavir is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily. A gradual dose increase of atorvastatin may be tailored to the clinical response.
Pravastatin
40 mg single dose
pravastatin AUC β 81%ΒΆ
pravastatin Cmin ND
pravastatin Cmax β 63%
ΒΆ an up to five-fold increase was seen in a limited subset of subjects
When administration of pravastatin and darunavir co-administered with low dose ritonavir is required, it is recommended to start with the lowest possible dose of pravastatin and titrate up to the desired clinical effect while monitoring for safety.
Rosuvastatin
10 mg once daily
rosuvastatin AUC β 48%β
rosuvastatin Cmax β 144%β
β based on published data with darunavir/ritonavir
When administration of rosuvastatin and darunavir co-administered with low dose ritonavir is required, it is recommended to start with the lowest possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for safety.
OTHER LIPID MODIFYING AGENTS
Lomitapide
Based on theoretical considerations boosted darunavir is expected to increase the exposure of lomitapide when co-administered.
(CYP3A inhibition)
Co-administration is contraindicated (see section 4.3)
H2-RECEPTOR ANTAGONISTS
Ranitidine
150 mg twice daily
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Darunavir co-administered with low dose ritonavir can be co-administered with H2-receptor antagonists without dose adjustments.
IMMUNOSUPPRESSANTS
Ciclosporin
Sirolimus
Tacrolimus
Everolimus
Not studied. Exposure to these immunosuppressants will be increased when co-administered with darunavir co-administered with low dose ritonavir.
(CYP3A inhibition)
Therapeutic drug monitoring of the immunosuppressive agent must be done when co-administration occurs.
Concomitant use of everolimus and darunavir co-administered with low dose ritonavir is not recommended.
INHALED BETA AGONISTS
Salmeterol
Not studied. Concomitant use of salmeterol and darunavir co-administered with low dose ritonavir may increase plasma concentrations of salmeterol.
Concomitant use of salmeterol and darunavir co-administered with low dose ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse event with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE
Methadone
individual dose ranging from 55 mg to 150 mg once daily
R(-) methadone AUC β 16%
R(-) methadone Cmin β 15%
R(-) methadone Cmax β 24%
No adjustment of methadone dosage is required when initiating co-administration with darunavir/ritonavir. However, increased methadone dose may be necessary when concomitantly administered for a longer period of time due to induction of metabolism by ritonavir. Therefore, clinical monitoring is recommended, as maintenance therapy may need to be adjusted in some patients.
Buprenorphine/naloxone
8/2 mgβ16/4 mg once daily
buprenorphine AUC β 11%
buprenorphine Cmin β
buprenorphine Cmax β 8%
norbuprenorphine AUC β46%
norbuprenorphine Cmin β 71%
norbuprenorphine Cmax β 36%
naloxone AUC β
naloxone Cmin ND
naloxone Cmax β
The clinical relevance of the increase in norbuprenorphine pharmacokinetic parameters has not been established. Dose adjustment for buprenorphine may not be necessary when co-administered with darunavir/ritonavir but a careful clinical monitoring for signs of opiate toxicity is recommended.
Fentanyl
Oxycodone
Tramadol
Based on theoretical considerations boosted darunavir may increase plasma concentrations of these analgesics.
(CYP2D6 and/or CYP3A inhibition)
Clinical monitoring is recommended when co-administering darunavir with a low dose ritonavir with these analgesics.
OESTROGEN-BASED CONTRACEPTIVES
Drospirenone Ethinylestradiol (3 mg/0.02 mg once daily)
Β
Β
Β
Β
Ethinylestradiol
Norethindrone
35 ΞΌg/1 mg once daily
Not studied with darunavir/ritonavir
ethinylestradiol AUC β 44%Ξ²
ethinylestradiol Cmin β 62%Ξ²
ethinylestradiol Cmax β 32%Ξ²
norethindrone AUC β 14%Ξ²
norethindrone Cmin β 30%Ξ²
norethindrone Cmax β Ξ²
Ξ² with darunavir/ritonavir
When darunavir is co-administered with a drospirenone-containing product, clinical monitoring is recommended due to the potential for hyperkalaemia
Alternative or additional contraceptive measures are recommended when oestrogen-based contraceptives are co-administered with darunavir and low dose ritonavir.
Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.
OPIOID ANTAGONIST
Naloxegol
Not studied.
Co-administration of boosted darunavir and naloxegol is contraindicated.
PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of erectile dysfunction
Avanafil
Sildenafil
Tadalafil
Vardenafil
In an interaction study #, a comparable systemic exposure to sildenafil was observed for a single intake of 100 mg sildenafil alone and a single intake of 25 mg sildenafil co-administered with darunavir and low dose ritonavir.
The combination of avanafil and darunavir with low dose ritonavir is contraindicated (see section 4.3).
Concomitant use of other PDE-5 inhibitors for the treatment of erectile dysfunction with darunavir co-administered with low dose ritonavir should be done with caution. If concomitant use of darunavir co-administered with low dose ritonavir with sildenafil, vardenafil or tadalafil is indicated, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours or tadalafil at a single dose not exceeding 10 mg in 72 hours is recommended.
For the treatment of pulmonary arterial hypertension
Sildenafil
Tadalafil
Not studied. Concomitant use of sildenafil or tadalafil for the treatment of pulmonary arterial hypertension and darunavir co-administered with low dose ritonavir may increase plasma concentrations of sildenafil or tadalafil.
(CYP3A inhibition)
A safe and effective dose of sildenafil for the treatment of pulmonary arterial hypertension co-administered with darunavir and low dose ritonavir has not been established. There is an increased potential for sildenafil-associated adverse events (including visual disturbances, hypotension, prolonged erection and syncope). Therefore, co-administration of darunavir with low dose ritonavir and sildenafil when used for the treatment of pulmonary arterial hypertension is contraindicated (see section 4.3).
Co-administration of tadalafil for the treatment of pulmonary arterial hypertension with darunavir and low dose ritonavir is not recommended.
PROTON PUMP INHIBITORS
Omeprazole
20 mg once daily
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Darunavir co-administered with low dose ritonavir can be co-administered with proton pump inhibitors without dose adjustments.
SEDATIVES/HYPNOTICS
Buspirone
Clorazepate
Diazepam
Estazolam
Flurazepam
Midazolam (parenteral)
Zolpidem
Midazolam (oral)
Triazolam
Not studied. Sedative/hypnotics are extensively metabolised by CYP3A. Co-administration with darunavir/ritonavir may cause a large increase in the concentration of these medicines.
Β
If parenteral midazolam is co-administered with darunavir co-administered with low dose ritonavir, it may cause a large increase in the concentration of this benzodiazepine. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.
Clinical monitoring is recommended when co-administering darunavir with these sedatives/hypnotics and a lower dose of the sedatives/hypnotics should be considered.
Β
If parenteral midazolam is co-administered with darunavir with low dose ritonavir, it should be done in an intensive care unit (ICU) or similar setting, which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Darunavir with low dose ritonavir with triazolam or oral midazolam is contraindicated (see section 4.3)
TREATMENT FOR PREMATURE EJACULATION
Dapoxetine
Not studied.
Co-administration of boosted darunavir with dapoxetine is contraindicated.
UROLOGICAL DRUGS
Fesoterodine
Solifenacin
Not studied.
Use with caution. Monitor for fesoterodine or solifenacin adverse reactions, dose reduction of fesoterodine or solifenacin may be necessary.
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology).
β The efficacy and safety of the use of darunavir with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavir, nelfinavir and tipranavir) has not been established in HIV patients. According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.
β‘ Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.
4.6 |
Darunavir 600mg Film-Coated Tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.
There are no adequate and well controlled studies on pregnancy outcome with darunavir in pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
Darunavir co-administered with low dose ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk.
Breast-feeding
It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted in toxicity. Because of both the potential for HIV transmission and the potential for adverse reactions in breast-fed infants, mothers should be instructed not to breast-feed under any circumstances if they are receiving darunavir.
Fertility
No human data on the effect of darunavir on fertility are available. There was no effect on mating or fertility with darunavir treatment in rats (see section 5.3).
4.7 |
Darunavir 600mg Film-Coated Tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Darunavir in combination with ritonavir has no or negligible influence on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing darunavir co-administered with low dose ritonavir and should be borne in mind when considering a patient's ability to drive or operate machinery (see section 4.8)
4.8 |
Darunavir 600mg Film-Coated Tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
During the clinical development program (N=2,613 treatment-experienced subjects who initiated therapy with darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent adverse reactions reported in clinical trials and as spontaneous reports are diarrhoea, nausea, rash, headache and vomiting. The most frequent serious reactions are acute renal failure, myocardial infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis and pyrexia.
In the 96 week analysis, the safety profile of darunavir /ritonavir 800/100 mg once daily in treatment-naΓ―ve subjects was similar to that seen with darunavir /ritonavir 600/100 mg twice daily in treatment-experienced subjects except for nausea which was observed more frequently in treatment-naΓ―ve subjects. This was driven by mild intensity nausea. No new safety findings were identified in the 192 week analysis of the treatment-naΓ―ve subjects in which the mean treatment duration of darunavir /ritonavir 800/100 mg once daily was 162.5 weeks.
Tabulated list of adverse reactions
Adverse reactions are listed by system organ class (SOC) and frequency category. Within each frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as follows: very common (β₯ 1/10), common (β₯ 1/100 to < 1/10), uncommon (β₯ 1/1,000 to < 1/100), rare (β₯ 1/10,000 to < 1/1,000) and not known (frequency cannot be estimated from the available data).
Adverse reactions observed with darunavir/ritonavir in clinical trials and post-marketing
MedDRA system organ class
Frequency category
Adverse reaction
Infections and infestations
uncommon
herpes simplex
Blood and lymphatic system disorders
uncommon
thrombocytopenia, neutropenia, anaemia, leukopenia
rare
increased eosinophil count
Immune system disorders
uncommon
immune reconstitution inflammatory syndrome, (drug) hypersensitivity
Endocrine disorders
uncommon
hypothyroidism, increased blood thyroid stimulating hormone
Metabolism and nutrition disorders
common
diabetes mellitus, hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia
uncommon
gout, anorexia, decreased appetite, decreased weight, increased weight, hyperglycaemia, insulin resistance, decreased high density lipoprotein, increased appetite, polydipsia, increased blood lactate dehydrogenase
Psychiatric disorders
common
insomnia
uncommon
depression, disorientation, anxiety, sleep disorder, abnormal dreams, nightmare, decreased libido
rare
confusional state, altered mood, restlessness
Nervous system disorders
common
headache, peripheral neuropathy, dizziness
uncommon
lethargy, paraesthesia, hypoaesthesia, dysgeusia, disturbance in attention, memory impairment, somnolence
rare
syncope, convulsion, ageusia, sleep phase rhythm disturbance
Eye disorders
uncommon
conjunctival hyperaemia, dry eye
rare
visual disturbance
Ear and labyrinth disorders
uncommon
vertigo
Cardiac disorders
uncommon
myocardial infarction, angina pectoris, prolonged electrocardiogram QT, tachycardia
rare
acute myocardial infarction, sinus bradycardia, palpitations
Vascular disorders
uncommon
hypertension, flushing
Respiratory, thoracic and mediastinal disorders
uncommon
dyspnoea, cough, epistaxis, throat irritation
rare
rhinorrhoea
Gastrointestinal disorders
Very common
diarrhoea
common
vomiting, nausea, abdominal pain, increased blood amylase, dyspepsia, abdominal distension, flatulence
uncommon
pancreatitis, gastritis, gastrooesophageal reflux disease, aphthous stomatitis, retching, dry mouth, abdominal discomfort, constipation, increased lipase, eructation, oral dysaesthesia
rare
stomatitis, haematemesis, cheilitis, dry lip, coated tongue
Hepatobiliary disorders
common
increased alanine aminotransferase
uncommon
hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased transaminase, increased aspartate aminotransferase, increased blood bilirubin, increased blood alkaline phosphatase, increased gamma-glutamyltransferase
Skin and subcutaneous tissue disorders
common
rash (including macular, maculopapular, papular, erythematous and pruritic rash), pruritus
uncommon
angioedema, generalised rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, nail pigmentation
rare
DRESS, Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrhoeic dermatitis, skin lesion, xeroderma
not known
toxic epidermal necrolysis, acute generalised exanthematous pustulosis
Musculoskeletal and connective tissue disorders
uncommon
myalgia, osteonecrosis, muscle spasms, muscular weakness, arthralgia, pain in extremity, osteoporosis, increased blood creatine phosphokinase
rare
musculoskeletal stiffness, arthritis, joint stiffness
Renal and urinary disorders
uncommon
acute renal failure, renal failure, nephrolithiasis, increased blood creatinine, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria
rare
decreased creatinine renal clearance
Reproductive system and breast disorders
uncommon
erectile dysfunction, gynaecomastia
General disorders and administration site conditions
common
asthenia, fatigue
uncommon
pyrexia, chest pain, peripheral oedema, malaise, feeling hot, irritability, pain
rare
chills, abnormal feeling, xerosis
Description of selected adverse reactions
Rash
In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in section 4.4.
During the clinical development program of raltegravir in treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing darunavir /ritonavir + raltegravir compared to those containing darunavir/ ritonavir without raltegravir or raltegravir without darunavir /ritonavir. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4).
Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).
Musculoskeletal abnormalities
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of protease inhibitors, particularly in combination with NRTIs.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).
Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).
Bleeding in haemophiliac patients
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors (see section 4.4).
Paediatric population
The safety assessment in paediatric patients is based on the 48-week analysis of safety data from three Phase II trials. The following patient populations were evaluated (see section 5.1):
β’ 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at least 20 kg who received darunavir tablets with low dose ritonavir twice daily in combination with other antiretroviral agents.
β’ 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received darunavir oral suspension with low dose ritonavir twice daily in combination with other antiretroviral agents.
β’ 12 ART-naΓ―ve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 40 kg who received darunavir tablets with low dose ritonavir once daily in combination with other antiretroviral agents (see section 5.1).
Overall, the safety profile in these paediatric patients was similar to that observed in the adult population.
Other special populations
Patients co-infected with hepatitis B and/or hepatitis C virus
Among 1,968 treatment-experienced patients receiving darunavir co-administered with ritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis (see section 4.4).
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 |
Darunavir 600mg Film-Coated Tablets | Clinical particulars - Overdose | Overdose
Human experience of acute overdose with darunavir co-administered with low dose ritonavir is limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
There is no specific antidote for overdose with darunavir. Treatment of overdose with darunavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
5. Pharmacological properties
5.1 |
Darunavir 600mg Film-Coated Tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infected patients compared to healthy subjects may be explained by the higher concentrations of Ξ±1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG and, therefore, higher plasma concentrations.
Darunavir is primarily metabolised by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir considerably.
Absorption
Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.
The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily (see section 4.4).
When administered without food, the relative bioavailability of darunavir in the presence of low dose ritonavir is 30%lower as compared to intake with food. Therefore, darunavir tablets should be taken with ritonavir and with food. The type of food does not affect exposure to darunavir.
Distribution
Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma Ξ±1-acid glycoprotein.
Following intravenous administration, the volume of distribution of darunavir alone was 88.1 Β± 59.0 l (Mean Β± SD) and increased to 131 Β± 49.9 l (Mean Β± SD) in the presence of 100 mg twice-daily ritonavir.
Biotransformation
In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due to the parent active substance. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild type HIV.
Elimination
After a 400/100 mg 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.
The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 l/h and 5.9 l/h, respectively.
Special populations
Paediatric population
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 74 treatment-experienced paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that the administered weight-based doses of darunavir/ritonavir resulted in darunavir exposure comparable to that in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 14 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to < 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naΓ―ve paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that darunavir/ritonavir 800/100 mg once daily results in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 800/100 mg once daily. Therefore the same once daily dosage may be used in treatment-experienced adolescents aged 12 to < 18 years and weighing at least 40 kg without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L (see section 4.2).* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to < 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 800/100 mg once daily (see section 4.2). In addition, pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed the identification of weight-based darunavir/ritonavir once daily dosing regimens for paediatric patients weighing at least 15 kg that are either ART-naΓ―ve or treatment-experienced paediatric patients without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/l (see section 4.2).* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
Elderly
Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (n=12, age β₯ 65) (see section 4.4). However, only limited data were available in patients above the age of 65 years.
Gender
Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV infected females compared to males. This difference is not clinically relevant.
Renal impairment
Results from a mass balance study with 14C-darunavir with ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine unchanged.
Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20) (see sections 4.2 and 4.4).
Hepatic impairment
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with darunavir co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects. However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown therefore, darunavir should be used with caution. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see sections 4.2, 4.3 and 4.4).
Pregnancy and postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum.
Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of total darunavir
(mean Β± SD)
Second trimester of pregnancy
(n=12)a
Third trimester of pregnancy
(n=12)
Postpartum
(6-12 weeks)
(n=12)
Cmax, ng/ml
4,668 Β± 1,097
5,328 Β± 1,631
6,659 Β± 2,364
AUC12h, ng.h/ml
39,370 Β± 9,597
45,880 Β± 17,360
56,890 Β± 26,340
Cmin, ng/ml
1,922 Β± 825
2,661 Β± 1,269
2,851 Β± 2,216
a n=11 for AUC12h
Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of total darunavir
(mean Β± SD)
Second trimester of pregnancy
(n=17)
Third trimester of pregnancy
(n=15)
Postpartum
(6-12 weeks)
(n=16)
Cmax, ng/ml
4,964 Β± 1,505
5,132 Β± 1,198
7,310 Β± 1,704
AUC24h, ng.h/ml
62,289 Β± 16,234
61,112 Β± 13,790
92,116 Β± 29,241
Cmin, ng/ml
1,248 Β± 542
1,075 Β± 594
1,473 Β± 1,141
In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and 26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, as compared with postpartum.
In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and 30% lower, respectively as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared with postpartum.
5.3 |
Darunavir 600mg Film-Coated Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Animal toxicology studies have been conducted at exposures up to clinical exposure levels with darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.
In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment with darunavir. In rodents the target organs identified were the haematopoietic system, the blood coagulation system, liver and thyroid. A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated partial thromboplastin time.
Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and thyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a small increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the pancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicity findings or target organs were identified up to exposures equivalent to clinical exposure at the recommended dose.
In a study conducted in rats, the number of corpora lutea and implantations were decreased in the presence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavir treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The exposure levels were lower than those with the recommended clinical dose in humans. In a pre- and postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening of eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pups that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation. These effects may be secondary to pup exposure to the active substance via the milk and/or maternal toxicity. No post weaning functions were affected with darunavir alone or in combination with ritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed with convulsions in some animals. Exposure in plasma, liver and brain was considerably higher than in adult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, the exposure was comparable to that in adult rats. The increased exposure was likely at least partly due to immaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalities were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats.
Due to uncertainties regarding the rate of development of the human blood brain barrier and liver enzymes, darunavir with low dose ritonavir should not be used in paediatric patients below 3 years of age.
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1,000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences of hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. The observed hepatocellular and thyroid tumours in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses.
After 2 years administration of darunavir at exposures at or below the human exposure, kidney changes were observed in mice (nephrosis) and rats (chronic progressive nephropathy).
Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.
6. |
Darunavir 600mg Film-Coated Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Silicified Microcrystalline celluloseCrospovidoneHydroxypropyl CelluloseSodium chlorideSilica Colloidal AnhydrousMagnesium stearatePolacrilin potassium
Tablet film-coat
Polyvinyl alcohol-part. Hydrolyzed
Macrogol 4000Titanium dioxide (E171)TalcIron oxide yellow (E172)Iron oxide red (E172)
6.2 |
Darunavir 600mg Film-Coated Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Darunavir 600mg Film-Coated Tablets | Pharmaceutical particulars - Shelf life | Shelf life
Unopened: 30 months
6.4 |
Darunavir 600mg Film-Coated Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Darunavir 600mg Film-Coated Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Opaque, white, high density polyethylene (HDPE) plastic bottle containing 30 tablets, fitted with polypropylene (PP) child resistant closure.
Pack size: multipacks containing 60 (2 packs of 30) film-coated tablets.
6.6 |
Darunavir 600mg 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. |
Darunavir 600mg Film-Coated Tablets | Marketing authorisation holder | Tillomed Laboratories Ltd
220 Butterfield Great Marlings
Luton LU2 8DL
United Kingdom
8. Marketing authorisation number(s)
PL 11311/0649
9. |
Darunavir 600mg Film-Coated Tablets | Date of first authorisation/renewal of the authorisation | 10/12/2019
10. |
Darunavir 600mg Film-Coated Tablets | Date of revision of the text | 15/07/2021 |
Darunavir 800 mg film-coated tablets | Name of the medicinal product | Darunavir 800 mg film-coated tablets
2. |
Darunavir 800 mg film-coated tablets | Qualitative and quantitative composition | Each film-coated tablet contains 800 mg of darunavir.
For the full list of excipients, see section 6.1.
3. |
Darunavir 800 mg film-coated tablets | Pharmaceutical form | Film-coated tablet.
Yellow, oval shaped (20.24 mm (L) X 10.20 mm (W)), biconvex, film- coated tablets de-bossed with 'V' on one side and '7' on the other side.
4. |
Darunavir 800 mg film-coated tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Darunavir, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.
Darunavir, co-administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adults and adolescents (aged 12 years and older, weighing at least 40 kg) (see section 4.2).
Darunavir 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are:
β’ antiretroviral therapy (ART)-naΓ―ve (see section 4.2).
β’ ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L. In deciding to initiate treatment with Darunavir in such ART-experienced patients, genotypic testing should guide the use of Darunavir (see sections 4.2, 4.3, 4.4 and 5.1).
4.2 |
Darunavir 800 mg film-coated tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Therapy should be initiated by a healthcare provider experienced in the management of HIV infection. After therapy with Darunavir has been initiated, patients should be advised not to alter the dosage, dose form or discontinue therapy without discussing with their healthcare provider.
The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer. Darunavir may therefore have different contraindications and recommendations for concomitant medications depending on whether the compound is boosted with ritonavir or cobicistat (see sections 4.3, 4.4 and 4.5).
Posology
Darunavir must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with Darunavir. Cobicistat is not indicated for use in twice daily regimens or for use in the paediatric population less than 12 years of age weighing less than 40 kg.
Darunavir is also available as an oral suspension for use in patients who are unable to swallow Darunavir tablets (please refer to the Summary of Product Characteristics for Darunavir oral suspension).
ART-naΓ―ve adult patients
The recommended dose regimen is 800 mg once daily taken with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food. Darunavir 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.
ART-experienced adult patients
The recommended dose regimens are as follows:
β’ In ART-experienced patients with no darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L (see section 4.1) a regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food may be used. Darunavir 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.
β’ In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food. See the Summary of Product Characteristics for Darunavir 600 mg tablets.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
ART-naΓ―ve paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken with food or 800 mg once daily with cobicistat 150 mg once daily taken with food (in adolescent patients 12 years of age or older). Darunavir 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen. The dose of cobicistat to be used with Darunavir in children less than 12 years of age has not been established.
ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The dose of cobicistat to be used with Darunavir in children less than 12 years of age has not been established.
The recommended dose regimens are as follows:
In ART-experienced patients without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count β₯ 100 cells x 106/L (see section 4.1) a regimen of 800 mg once daily with ritonavir 100 mg once daily taken with food or 800 mg once daily with cobicistat 150 mg once daily taken with food (in adolescent patients 12 years of age or older) may be used. Darunavir 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen. The dose of cobicistat to be used with Darunavir in children less than 12 years of age has not been established.
β’ In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen is described in the Summary of Product Characteristics for Darunavir 400 mg and 600 mg tablets.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
Advice on missed doses
If a once daily dose of Darunavir and/or cobicistat or ritonavir is missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of Darunavir and cobicistat or ritonavir with food as soon as possible. If this is noticed later than 12 hours after the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.
This guidance is based on the half-life of darunavir in the presence of cobicistat or ritonavir and the recommended dosing interval of approximately 24 hours.
If a patient vomits within 4 hours of taking the medicine, another dose of Darunavir with cobicistat or ritonavir should be taken with food as soon as possible. If a patient vomits more than 4 hours after taking the medicine, the patient does not need to take another dose of Darunavir with cobicistat or ritonavir until the next regularly scheduled time.
Special populations
Elderly
Limited information is available in this population, and therefore, Darunavir should be used with caution in this age group (see sections 4.4 and 5.2).
Hepatic impairment
Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, Darunavir should be used with caution in these patients. No pharmacokinetic data are available in patients with severe hepatic impairment. Severe hepatic impairment could result in an increase of darunavir exposure and a worsening of its safety profile. Therefore, Darunavir must not be used in patients with severe hepatic impairment (Child-Pugh Class C) (see sections 4.3, 4.4 and 5.2).
Renal impairment
No dose adjustment is required for darunavir/ritonavir in patients with renal impairment (see sections 4.4 and 5.2). Cobicistat has not been studied in patients receiving dialysis, and, therefore, no recommendation can be made for the use of darunavir/cobicistat in these patients.
Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum creatinine and modest declines in creatinine clearance. Hence, the use of creatinine clearance as an estimate of renal elimination capacity may be misleading. Cobicistat as a pharmacokinetic enhancer of darunavir should, therefore, not be initiated in patients with creatine clearance less than 70 ml/min if any co-administered agent requires dose adjustment based on creatinine clearance: e.g. emtricitabine, lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate) or adefovir dipovoxil.
For information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Paediatric population
Darunavir should not be used in children
- below 3 years of age, because of safety concerns (see sections 4.4 and 5.3), or,
- less than 15 kg body weight, as the dose for this population has not been established in a sufficient number of patients (see section 5.1).
Darunavir taken with cobicistat should not be used in children aged 3 to 11 years of age weighing < 40 kg as the dose of cobicistat to be used in these children has not been established (see sections 4.4 and 5.3).
Darunavir 400 and 800 mg tablets are not suitable for this patient population. Other formulations are available, see the Summary of Product Characteristics for Darunavir 75 mg, 150 mg, 600 mg tablets and 100 mg/ml oral suspension.
Pregnancy and postpartum
No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk (see sections 4.4, 4.6 and 5.2).
Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure (see sections 4.4 and 5.2). Therefore, therapy with Darunavir/cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with darunavir/cobicistat should be switched to an alternative regimen (see sections 4.4 and 4.6). Darunavir/ritonavir may be considered as an alternative.
Method of administration
Patients should be instructed to take Darunavir with cobicistat or low dose ritonavir within 30 minutes after completion of a meal. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5 and 5.2).
4.3 |
Darunavir 800 mg film-coated tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with severe (Child-Pugh Class C) hepatic impairment.
Concomitant treatment with any of the following medicinal products given the expected decrease in plasma concentrations of darunavir, ritonavir and cobicistat and the potential for loss of therapeutic effect (see sections 4.4 and 4.5).
Applicable to darunavir boosted with either ritonavir or cobicistat:
- The combination product lopinavir/ritonavir (see section 4.5).
- Strong CYP3A inducers such as rifampicin and herbal preparations containing St John's Wort (Hypericum perforatum). Co-administration is expected to reduce plasma concentrations of darunavir, ritonavir and cobicistat, which could lead to loss of therapeutic effect and possible development of resistance (see sections 4.4 and 4.5).
Applicable to darunavir boosted with cobicistat, not when boosted with ritonavir:
- Darunavir boosted with cobicistat is more sensitive for CYP3A induction than darunavir boosted with ritonavir. Concomitant use with strong CYP3A inducers is contraindicated, since these may reduce the exposure to cobicistat and darunavir leading to loss of therapeutic effect. Strong CYP3A inducers include e.g. carbamazepine, phenobarbital and phenytoin (see sections 4.4 and 4.5).
Darunavir boosted with either ritonavir or cobicistat inhibits the elimination of active substances that are highly dependent on CYP3A for clearance, which results in increased exposure to the co-administered medicinal product. Therefore, concomitant treatment with such medicinal products for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated (applies to darunavir boosted with either ritonavir or cobicistat). These active substances include e.g.:
- alfuzosin
- amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
- astemizole, terfenadine
- colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)
- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
- elbasvir/grazoprevir
- cisapride
- dapoxetine
- domperidone
- naloxegol
- lurasidone, pimozide, quetiapine, sertindole (see section 4.5)
- triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5)
- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil
- simvastatin, lovastatin and lomitapide (see section 4.5)
- ticagrelor (see section 4.5).
4.4 |
Darunavir 800 mg film-coated tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Regular assessment of virological response is advised. In the setting of lack or loss of virological response, resistance testing should be performed.
Darunavir 400 mg or 800 mg must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products (see section 5.2). The Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with darunavir.
Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect darunavir concentrations. It is not recommended to alter the dose of cobicistat or ritonavir.
Darunavir binds predominantly to Ξ±1-acid glycoprotein. This protein binding is concentration-dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products highly bound to Ξ±1-acid glycoprotein cannot be ruled out (see section 4.5).
ART-experienced patients β once daily dosing
Darunavir used in combination with cobicistat or low dose ritonavir once daily in ART-experienced patients should not be used in patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA β₯ 100,000 copies/ml or CD4+ cell count < 100 cells x 106/L (see section 4.2). Combinations with optimised background regimen (OBRs) other than β₯ 2 NRTIs have not been studied in this population. Limited data are available in patients with HIV-1 clades other than B (see section 5.1).
Paediatric population
Darunavir is not recommended for use in paediatric patients below 3 years of age or less than 15 kg body weight (see sections 4.2 and 5.3).
Pregnancy
Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk. Caution should be used in pregnant women with concomitant medications which may further decrease darunavir exposure (see sections 4.5 and 5.2).
Treatment with darunavir/cobicistat 800/150 mg once daily during the second and third trimester has been shown to result in low darunavir exposure, with a reduction of around 90% in Cmin levels (see section 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in darunavir exposure may result in virological failure and an increased risk of mother to child transmission of HIV infection. Therefore, therapy with Darunavir/cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with darunavir/cobicistat should be switched to an alternative regimen (see sections 4.2 and 4.6).
Darunavir given with low dose ritonavir may be considered as an alternative.
Elderly
As limited information is available on the use of darunavir in patients aged 65 and over, caution should be exercised in the administration of darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2 and 5.2).
Severe skin reactions
During the darunavir/ritonavir clinical development program (N=3,063), severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported. Darunavir should be discontinued immediately if signs or symptoms of severe skin reactions develop. These can include, but are not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
Rash occurred more commonly in treatment-experienced patients receiving regimens containing darunavir/ritonavir + raltegravir compared to patients receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir (see section 4.8).
Darunavir contains a sulphonamide moiety. Darunavir should be used with caution in patients with a known sulphonamide allergy.
Hepatotoxicity
Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with darunavir. During the darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.
Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir used in combination with cobicistat or low dose ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of darunavir used in combination with cobicistat or low dose ritonavir treatment.
If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients using darunavir used in combination with cobicistat or low dose ritonavir, interruption or discontinuation of treatment should be considered promptly.
Patients with coexisting conditions
Hepatic impairment
The safety and efficacy of darunavir have not been established in patients with severe underlying liver disorders and Darunavir is therefore contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, darunavir should be used with caution in patients with mild or moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).
Renal impairment
No special precautions or dose adjustments for darunavir/ritonavir are required in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these patients (see sections 4.2 and 5.2). Cobicistat has not been studied in patients receiving dialysis, therefore, no recommendation can be made for the use of darunavir/cobicistat in these patients (see section 4.2).
Cobicistat decreases the estimated creatinine clearance due to inhibition of tubular secretion of creatinine. This should be taken into consideration if darunavir with cobicistat is administered to patients in whom the estimated creatinine clearance is used to adjust doses of co-administered medicinal products (see section 4.2 and cobicistat SmPC).
There are currently inadequate data to determine whether co-administration of tenofovir disoproxil and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil without cobicistat.
Haemophiliac patients
There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding.
Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with darunavir co-administered with low dose ritonavir.
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).
Interactions with medicinal products
Several of the interaction studies have been performed with darunavir at lower than recommended doses. The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated. For full information on interactions with other medicinal products see section 4.5.
Pharmacokinetic enhancer and concomitant medications
Darunavir has different interaction profiles depending on whether the compound is boosted with ritonavir or cobicistat:
- Darunavir boosted with cobicistat is more sensitive for CYP3A induction: concomitant use of darunavir/cobicistat and strong CYP3A inducers is therefore contraindicated (see section 4.3), and concomitant use with weak to moderate CYP3A inducers is not recommended (see section 4.5). Concomitant use of darunavir/ritonavir and darunavir/cobicistat with strong CYP3A inducers such as lopinavir/ritonavir, rifampicin and herbal products containing St John's Wort, Hypericum perforatum, is contraindicated (see section 4.5).
- Unlike ritonavir, cobicistat does not have inducing effects on enzymes or transport proteins (see section 4.5). If switching the pharmacoenhancer from ritonavir to cobicistat, caution is required during the first two weeks of treatment with darunavir/cobicistat, particularly if doses of any concomitantly administered medicinal products have been titrated or adjusted during use of ritonavir as a pharmacoenhancer. A dose reduction of the co-administered drug may be needed in these cases.
Efavirenz in combination with boosted darunavir may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used. See the Summary of Product Characteristics for darunavir 600 mg tablets (see section 4.5).
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-glycoprotein (P-gp; see sections 4.3 and 4.5).
4.5 |
Darunavir 800 mg film-coated tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
The interaction profile of darunavir may differ depending on whether ritonavir or cobicistat is used as pharmacoenhancer. The recommendations given for concomitant use of darunavir and other medicinal products may therefore differ depending on whether darunavir is boosted with ritonavir or cobicistat (see sections 4.3 and 4.4), and caution is also required during the first time of treatment if switching the pharmacoenhancer from ritonavir to cobicistat (see section 4.4).
Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer)
Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of these compounds and consequently that of darunavir, leading to loss of therapeutic effect and possible development of resistance (see sections 4.3 and 4.4). CYP3A inducers that are contraindicated include rifampicin, St John's Wort and lopinavir.
Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrations of darunavir and ritonavir. Co-administration with strong CYP3A4 inhibitors is not recommended and caution is warranted, these interactions are described in the interaction table below (e.g. indinavir, azole antifungals like clotrimazole).
Medicinal products that affect darunavir exposure (cobicistat as pharmacoenhancer)
Darunavir and cobicistat are metabolised by CYP3A, and co-administration with CYP3A inducers may therefore result in subtherapeutic plasma exposure to darunavir. Darunavir boosted with cobicistat is more sensitive to CYP3A induction than ritonavir-boosted darunavir: co-administration of darunavir/cobicistat with medicinal products that are strong inducers of CYP3A (e.g. St John's Wort, rifampicin, carbamazepine, phenobarbital, and phenytoin) is contraindicated (see section 4.3).
Co-administration of darunavir/cobicistat with weak to moderate CYP3A inducers (e.g. efavirenz, etravirine, nevirapine, fluticasone, and bosentan) is not recommended (see interaction table below).
For co-administration with strong CYP3A4 inhibitors, the same recommendations apply independent of whether darunavir is boosted with ritonavir or with cobicistat (see section above).
Medicinal products that may be affected by darunavir boosted with ritonavir
Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or transported by P-gp may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.
Darunavir co-administered with low dose ritonavir must not be combined with medicinal products that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) (see section 4.3).
Co-administration of boosted darunavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see the Interaction table below).
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily. Therefore, darunavir must only be used in combination with a pharmacokinetic enhancer (see sections 4.4 and 5.2).
A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to the presence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir with medicinal products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone, repaglinide) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration with substrates of these transporters can result in increased plasma concentrations of these compounds (e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).
Medicinal products that may be affected by darunavir boosted with cobicistat
The recommendations for darunavir boosted with ritonavir are similar to the recommendations for darunavir boosted with cobicistat with regard to substrates of CYP3A4, CYP2D6, P-glycoprotein, OATP1B1 and OATP1B3 (see contraindications and recommendations presented in the section above). Cobicistat 150 mg given with darunavir 800 mg once daily enhances darunavir pharmacokinetic parameters in a comparable way to ritonavir (see section 5.2).
Unlike ritonavir, cobicistat does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. For further information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Interaction table
Interaction studies have only been performed in adults.
Several of the interaction studies (indicated by # in the table below) have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated.
The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer. Darunavir may therefore have different recommendations for concomitant medications depending on whether the compound is boosted with ritonavir or cobicistat. No interaction studies presented in the table have been performed with darunavir boosted with cobicistat. The same recommendations apply, unless specifically indicated. For further information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products are listed in the table below. The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (β), below (β) or above (β) the 80-125% range (not determined as βNDβ).
In the table below the specific pharmacokinetic enhancer is specified when recommendations differ. When the recommendation is the same for darunavir when co-administered with a low dose ritonavir or cobicistat, the term βboosted Darunavirβ is used.
The below list of examples of drug-drug interactions is not comprehensive and therefore the label of each drug that is co-administered with darunavir should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.
INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal product examples by therapeutic area
Interaction
Geometric mean change (%)
Recommendations concerning co-administration
HIV ANTIRETROVIRALS
Integrase strand transfer inhibitors
Dolutegravir
dolutegravir AUC β 22%
dolutegravir C24h β 38%
dolutegravir Cmax β 11%
darunavir β*
* Using cross-study comparisons to historical pharmacokinetic data
Boosted darunavir and dolutegravir can be used without dose adjustment.
Raltegravir
Some clinical studies suggest raltegravir may cause a modest decrease in darunavir plasma concentrations.
At present the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically relevant. Boosted darunavir and raltegravir can be used without dose adjustments.
Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine
400 mg once daily
didanosine AUC β 9%
didanosine Cmin ND
didanosine Cmax β 16%
darunavir AUC β
darunavir Cmin β
darunavir Cmax β
Boosted darunavir and didanosine can be used without dose adjustments.
Didanosine is to be administered on an empty stomach, thus it should be administered 1 hour before or 2 hours after boosted darunavir given with food.
Tenofovir disoproxil 245 mg once dailyβ‘
tenofovir AUC β 22%
tenofovir Cmin β 37%
tenofovir Cmax β 24%
#darunavir AUC β 21%
#darunavir Cmin β 24%
#darunavir Cmax β 16%
(β tenofovir from effect on MDR-1 transport in the renal tubules)
Monitoring of renal function may be indicated when boosted darunavir is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.
Darunavir co-administered with cobicistat lowers the creatinine clearance. Refer to section 4.4 if creatinine clearance is used for dose adjustment of tenofovir disoproxil.
Emtricitabine/tenofovir alafenamide
Tenofovir alafenamide β
Tenofovir β
The recommended dose of emtricitabine/tenofovir alafenamide is 200/10 mg once daily when used with boosted darunavir.
Abacavir Emtricitabine Lamivudine Stavudine Zidovudine
Not studied. Based on the different elimination pathways of the other NRTIs zidovudine, emtricitabine, stavudine, lamivudine, that are primarily renally excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and boosted darunavir.
Boosted darunavir can be used with these NRTIs without dose adjustment.
Darunavir co-administered with cobicistat lowers the creatinine clearance. Refer to section 4.4 if creatinine clearance is used for dose adjustment of emtricitabine or lamivudine.
Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz
600 mg once daily
efavirenz AUC β 21%
efavirenz Cmin β 17%
efavirenz Cmax β 15%
#darunavir AUC β 13%
#darunavir Cmin β 31%
#darunavir Cmax β 15%
(β efavirenz from CYP3A inhibition)
(β darunavir from CYP3A induction)
Clinical monitoring for central nervous system toxicity associated with increased exposure to efavirenz may be indicated when darunavir co-administered with low dose ritonavir is given in combination with efavirenz.
Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used (see section 4.4).
Co-administration with darunavir co-administered with cobicistat is not recommended (see section 4.4).
Etravirine
100 mg twice daily
etravirine AUC β 37%
etravirine Cmin β 49%
etravirine Cmax β 32%
darunavir AUC β 15%
darunavir Cmin β
darunavir Cmax β
Darunavir co-administered with low dose ritonavir and etravirine 200 mg twice daily can be used without dose adjustments.
Co-administration with darunavir co-administered with cobicistat is not recommended (see section 4.4).
Nevirapine
200 mg twice daily
nevirapine AUC β 27%
nevirapine Cmin β 47%
nevirapine Cmax β 18%
#darunavir: concentrations were consistent with historical data
(β nevirapine from CYP3A inhibition)
Darunavir co-administered with low dose ritonavir and nevirapine can be used without dose adjustments.
Co-administration with darunavir co-administered with cobicistat is not recommended (see section 4.4).
Rilpivirine
150 mg once daily
rilpivirine AUC β 130%
rilpivirine Cmin β 178%
rilpivirine Cmax β 79%
darunavir AUC β
darunavir Cmin β 11%
darunavir Cmax β
Boosted darunavir and rilpivirine can be used without dose adjustments.
HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavirβ
Atazanavir
300 mg once daily
atazanavir AUC β
atazanavir Cmin β 52%
atazanavir Cmax β 11%
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Atazanavir: comparison of atazanavir/ritonavir 300/100 mg once daily vs. atazanavir 300 mg once daily in combination with darunavir/ritonavir 400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg twice daily in combination with atazanavir 300 mg once daily.
Darunavir co-administered with low dose ritonavir and atazanavir can be used without dose adjustments.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).
Indinavir
800 mg twice daily
indinavir AUC β 23%
indinavir Cmin β 125%
indinavir Cmax β
#darunavir AUC β 24%
#darunavir Cmin β 44%
#darunavir Cmax β 11%
Indinavir: comparison of indinavir/ritonavir 800/100 mg twice daily vs. indinavir/darunavir/ritonavir 800/400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with indinavir 800 mg twice daily.
When used in combination with darunavir co-administered with low dose ritonavir, dose adjustment of indinavir from 800 mg twice daily to 600 mg twice daily may be warranted in case of intolerance.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).
Saquinavir
1,000 mg twice daily
#darunavir AUC β 26%
#darunavir Cmin β 42%
#darunavir Cmax β 17%
saquinavir AUC β 6%
saquinavir Cmin β 18%
saquinavir Cmax β 6%
Saquinavir: comparison of saquinavir/ritonavir 1,000/100 mg twice daily vs. saquinavir/darunavir/ritonavir 1,000/400/100 mg twice daily. Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with saquinavir 1,000 mg twice daily.
It is not recommended to combine darunavir co-administered with low dose ritonavir with saquinavir.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).
HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavirβ
Lopinavir/ritonavir 400/100 mg twice daily
Β
Β
Β
Lopinavir/ritonavir 533/133.3 mg twice daily
lopinavir AUC β 9%
lopinavir Cmin β 23%
lopinavir Cmax β 2%
darunavir AUC β 38%β‘
darunavir Cmin β 51%β‘
darunavir Cmax β 21%β‘
lopinavir AUC β
lopinavir Cmin β 13%
lopinavir Cmax β 11%
darunavir AUC β 41%
darunavir Cmin β 55%
darunavir Cmax β 21%
β‘ based upon non dose normalised values
Due to a decrease in the exposure (AUC) of darunavir by 40%, appropriate doses of the combination have not been established.
Hence, concomitant use of boosted darunavir and the combination product lopinavir/ritonavir is contraindicated (see section 4.3).
CCR5 ANTAGONIST
Maraviroc
150 mg twice daily
maraviroc AUC β 305%
maraviroc Cmin ND
maraviroc Cmax β 129%
darunavir, ritonavir concentrations were consistent with historical data
The maraviroc dose should be 150 mg twice daily when co- administered with boosted darunavir.
Ξ±1-ADRENORECEPTOR ANTAGONIST
Alfuzosin
Based on theoretical considerations darunavir is expected to increase alfuzosin plasma concentrations. (CYP3A inhibition)
Co-administration of boosted darunavir and alfuzosin is contraindicated (see section 4.3).
ANAESTHETIC
Alfentanil
Not studied. The metabolism of alfentanil is mediated via CYP3A, and may as such be inhibited by boosted darunavir.
The concomitant use with boosted darunavir may require to lower the dose of alfentanil and requires monitoring for risks of prolonged or delayed respiratory depression.
ANTIANGINA/ANTIARRHYTHMIC
Disopyramide Flecainide
Lidocaine (systemic) Mexiletine Propafenone
Amiodarone
Bepridil
Dronedarone
Ivabradine
Quinidine
Ranolazine
Not studied. Boosted darunavir is expected to increase these antiarrhythmic plasma concentrations.
(CYP3A and/or CYP2D6 inhibition)
Caution is warranted and therapeutic concentration monitoring, if available, is recommended for these antiarrhythmics when co-administered with boosted darunavir.
Co-administration of boosted darunavir and amiodarone, bepridil, dronedarone, ivabradine, quinidine, or ranolazine is contraindicated (see section 4.3).
Digoxin
0.4 mg single dose
digoxin AUC β 61%
digoxin Cmin ND
digoxin Cmax β 29%
(β digoxin from probable inhibition of P-gp)
Given that digoxin has a narrow therapeutic index, it is recommended that the lowest possible dose of digoxin should initially be prescribed in case digoxin is given to patients on boosted darunavir therapy. The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.
ANTIBIOTIC
Clarithromycin
500 mg twice daily
clarithromycin AUC β 57%
clarithromycin Cmin β 174%
clarithromycin Cmax β 26%
#darunavir AUC β 13%
#darunavir Cmin β 1%
#darunavir Cmax β 17%
14-OH-clarithromycin concentrations were not detectable when combined with darunavir/ritonavir.
(β clarithromycin from CYP3A inhibition and possible P-gp inhibition)
Caution should be exercised when clarithromycin is combined with boosted darunavir.
For patients with renal impairment the Summary of Product Characteristics for clarithromycin should be consulted for the recommended dose.
ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban Rivaroxaban
Not studied. Co-administration of boosted darunavir with these anticoagulants may increase concentrations of the anticoagulant.
(CYP3A and/or P-gp inhibition)
The use of boosted darunavir with a direct oral anticoagulant (DOAC) that is metabolised by CYP3A4 and transported by P-gp is not recommended as this may lead to an increased bleeding risk.
Dabigatran etexilate
Edoxaban
Β
Β
Β
Β
Β
Β
Β
Β
Β
Β
Ticagrelor
Β
Β
Clopidogrel
dabigatran etexilate (150 mg):
darunavir/ritonavir 800/100 mg single dose:
dabigatran AUC β 72%
dabigatran Cmax β 64%
darunavir/ritonavir 800/100 mg once daily:
dabigatran AUC β 18%
dabigatran Cmax β 22%
darunavir/cobicistat 800/150 mg single dose:
dabigatran AUC β 164%
dabigatran Cmax β 164%
darunavir/cobicistat 800/150 mg once daily:
dabigatran AUC β 88%
dabigatran Cmax β 99%
Based on theoretical considerations, co-administration of boosted darunavir with ticagrelor may increase concentrations of ticagrelor (CYP3A and/or P-glycoprotein inhibition).
Not studied. Co-administration of clopidogrel with boosted darunavir is expected to decrease clopidogrel active metabolite plasma concentration, which may reduce the antiplatelet activity of clopidogrel
Darunavir/ritonavir:
Clinical monitoring and/or dose reduction of the DOAC should be considered when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with Darunavir/rtv.
Darunavir/cobicistat:
Clinical monitoring and dose reduction is required when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with darunavir/cobi.
Concomitant administration of boosted darunavir with ticagrelor is contraindicated (see section 4.3).
Co-administration of clopidogrel with boosted darunavir is not recommended. Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended.
Warfarin
Not studied. Warfarin concentrations may be affected when co-administered with boosted darunavir.
It is recommended that the international normalised ratio (INR) be monitored when warfarin is combined with boosted darunavir.
ANTICONVULSANTS
Phenobarbital Phenytoin
Not studied. Phenobarbital and phenytoin are expected to decrease plasma concentrations of darunavir and its pharmacoenhancer.
(induction of CYP450 enzymes)
Darunavir co-administered with low dose ritonavir should not be used in combination with these medicines.
The use of these medicines with Darunavir/cobicistat is contraindicated (see section 4.3).
Carbamazepine 200 mg twice daily
carbamazepine AUC β 45%
carbamazepine Cmin β 54%
carbamazepine Cmax β 43%
darunavir AUC β
darunavir Cmin β 15%
darunavir Cmax β
No dose adjustment for darunavir/ritonavir is recommended. If there is a need to combine darunavir/ritonavir and carbamazepine, patients should be monitored for potential carbamazepine-related adverse events. Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response.
Based upon the findings, the carbamazepine dose may need to be reduced by 25% to 50% in the presence of darunavir/ritonavir.
The use of carbamazepine with darunavir co-administered with cobicistat is contraindicated (see section 4.3).
Clonazepam
Not studied. Co-administration of boosted darunavir with clonazepam may increase concentrations of clonazepam. (CYP3A inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir with clonazepam.
ANTIDEPRESSANTS
Paroxetine
20 mg once daily
Β Β Β
Sertraline
50 mg once daily
Β
Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone
paroxetine AUC β 39%
paroxetine Cmin β 37%
paroxetine Cmax β 36%
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
sertraline AUC β 49%
sertraline Cmin β 49%
sertraline Cmax β 44%
#darunavir AUC β
#darunavir Cmin β 6%
#darunavir Cmax β
In contrast to these data with darunavir/ritonavir, darunavir/cobicistat may increase these antidepressant plasma concentrations (CYP2D6 and/or CYP3A inhibition).
Concomitant use of boosted darunavir and these antidepressants may increase concentrations of the antidepressant.
(CYP2D6 and/or CYP3A inhibition)
If antidepressants are co-administered with boosted darunavir, the recommended approach is a dose titration of the antidepressant based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of these antidepressants who start treatment with boosted darunavir should be monitored for antidepressant response.
Β Β Β
Clinical monitoring is recommended when co-administering boosted darunavir with these antidepressants and a dose adjustment of the antidepressant may be needed.
ANTI-DIABETICS
Metformin
Not studied. Based on theoretical considerations darunavir co-administered with cobicistat is expected to increase metformin plasma concentrations.
(MATE1 inhibition)
Careful patient monitoring and dose adjustment of metformin is recommended in patients who are taking darunavir co-administered with cobicistat. (not applicable for darunavir co-administered with ritonavir)
ANTIEMETICS
Domperidone
Not studied.
Co-administration of domperidone with boosted darunavir is contraindicated.
ANTIFUNGALS
Voriconazole
Not studied. Ritonavir may decrease plasma concentrations of voriconazole.
(induction of CYP450 enzymes)
Concentrations of voriconazole may increase or decrease when co-administered with darunavir co-administered with cobicistat. (inhibition of CYP450 enzymes)
Voriconazole should not be combined with boosted darunavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Fluconazole Isavuconazole Itraconazole Posaconazole
Β
Clotrimazole
Not studied. Boosted darunavir may increase antifungal plasma concentrations and posaconazole, isavuconazole, itraconazole or fluconazole may increase darunavir concentrations.
(CYP3A and/or P-gp inhibition)
Not studied. Concomitant systemic use of clotrimazole and boosted Darunavir may increase plasma concentrations of darunavir and/or clotrimazole.
Darunavir AUC24h β 33% (based on population pharmacokinetic model)
Caution is warranted and clinical monitoring is recommended.
When co-administration is required the daily dose of itraconazole should not exceed 200 mg.
ANTIGOUT MEDICINES
Colchicine
Not studied. Concomitant use of colchicine and boosted darunavir may increase the exposure to colchicine.
(CYP3A and/ or P-gp inhibition)
A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with boosted darunavir is required. For patients with renal or hepatic impairment colchicine with boosted darunavir is contraindicated (see sections 4.3 and 4.4).
ANTIMALARIALS
Artemether/Lumefantrine 80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours
artemether AUC β 16%
artemether Cmin β
artemether Cmax β 18%
dihydroartemisinin AUC β 18%
dihydroartemisinin Cmin β
dihydroartemisinin Cmax β 18%
lumefantrine AUC β 175%
lumefantrine Cmin β 126%
lumefantrine Cmax β 65%
darunavir AUC β
darunavir Cmin β 13%
darunavir Cmax β
The combination of boosted darunavir and artemether/lumefantrine can be used without dose adjustments; however, due to the increase in lumefantrine exposure, the combination should be used with caution.
ANTIMYCOBACTERIALS
Rifampicin Rifapentine
Not studied. Rifapentine and rifampicin are strong CYP3A inducers and have been shown to cause profound decreases in concentrations of other protease inhibitors, which can result in virological failure and resistance development (CYP450 enzyme induction). During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with low dose ritonavir, a high frequency of liver reactions was seen with rifampicin.
The combination of rifapentine and boosted darunavir is not recommended.
The combination of rifampicin and boosted darunavir is contraindicated (see section 4.3).
Rifabutin
150 mg once every other day
rifabutin AUC** β 55%
rifabutin Cmin** β ND
rifabutin Cmax ** β
darunavir AUC β 53%
darunavir Cmin β 68%
darunavir Cmax β 39%
**sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite)
The interaction trial showed a comparable daily systemic exposure for rifabutin between treatment at 300 mg once daily alone and 150 mg once every other day in combination with darunavir/ritonavir (600/100 mg twice daily) with an about 10-fold increase in the daily exposure to the active metabolite 25-O-desacetylrifabutin.
Furthermore, AUC of the sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite) was increased 1.6-fold, while Cmax remained comparable.
Data on comparison with a 150 mg once daily reference dose is lacking.
(Rifabutin is an inducer and substrate of CYP3A.) An increase of systemic exposure to darunavir was observed when Darunavir co-administered with 100 mg ritonavir was co-administered with rifabutin (150 mg once every other day).
A dosage reduction of rifabutin by 75% of the usual dose of 300 mg/day (i.e. rifabutin 150 mg once every other day) and increased monitoring for rifabutin related adverse events is warranted in patients receiving the combination with darunavir co-administered with ritonavir. In case of safety issues, a further increase of the dosing interval for rifabutin and/or monitoring of rifabutin levels should be considered.
Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV infected patients.
Based upon the safety profile of darunavir/ritonavir, the increase in darunavir exposure in the presence of rifabutin does not warrant a dose adjustment for darunavir/ritonavir.
Based on pharmacokinetic modeling, this dosage reduction of 75% is also applicable if patients receive rifabutin at doses other than 300 mg/day.
Co-administration of darunavir co-administered with cobicistat and rifabutin is not recommended.
ANTINEOPLASTICS
Dasatinib Nilotinib Vinblastine Vincristine
Β Β Β
Everolimus
Irinotecan
Not studied. Boosted Darunavir is expected to increase these antineoplastic plasma concentrations.
(CYP3A inhibition)
Concentrations of these medicinal products may be increased when co-administered with boosted darunavir resulting in the potential for increased adverse events usually associated with these agents.
Caution should be exercised when combining one of these antineoplastic agents with boosted darunavir.
Concomitant use of everolimus or irinotecan and boosted darunavir is not recommended.
ANTIPSYCHOTICS/NEUROLEPTICS
Quetiapine
Not studied. Boosted darunavir is expected to increase these antipsychotic plasma concentrations.
(CYP3A inhibition)
Concomitant administration of boosted darunavir and quetiapine is contraindicated as it may increase quetiapine-related toxicity. Increased concentrations of quetiapine may lead to coma (see section 4.3).
Perphenazine
Risperidone
Thioridazine
Lurasidone
Pimozide
Sertindole
Not studied. Boosted darunavir is expected to increase these antipsychotic plasma concentrations.
(CYP3A, CYP2D6 and/or P-gp inhibition)
A dose decrease may be needed for these drugs when co-administered with boosted darunavir.
Β
Concomitant administration of boosted darunavir and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).
Ξ²-BLOCKERS
Carvedilol
Metoprolol
Timolol
Not studied. Boosted darunavir is expected to increase these Ξ²-blocker plasma concentrations.
(CYP2D6 inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir with Ξ²-blockers. A lower dose of the Ξ²-blocker should be considered.
CALCIUM CHANNEL BLOCKERS
Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil
Not studied. Boosted darunavir can be expected to increase the plasma concentrations of calcium channel blockers.
(CYP3A and/or CYP2D6 inhibition)
Clinical monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with boosted darunavir.
CORTICOSTEROIDS
Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone)
Fluticasone: in a clinical study where ritonavir 100 mg capsules twice daily were co-administered with 50 ΞΌg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82-89%). Greater effects may be expected when fluticasone is inhaled.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone. The effects of high fluticasone systemic exposure on ritonavir plasma levels are unknown.
Other corticosteroids: interaction not studied. Plasma concentrations of these medicinal products may be increased when co-administered with boosted darunavir, resulting in reduced serum cortisol concentrations.
Concomitant use of boosted darunavir and corticosteroids (all routes of administration) that are metabolised by CYP3A may increase the risk of development of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.
Co-administration with CYP3A- metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects.
Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone should be considered, particularly for long term use.
Dexamethasone (systemic)
Not studied. Dexamethasone may decrease plasma concentrations of darunavir.
(CYP3A induction)
Systemic dexamethasone should be used with caution when combined with boosted darunavir.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan
Not studied. Concomitant use of bosentan and boosted darunavir may increase plasma concentrations of bosentan.
Bosentan is expected to decrease plasma concentrations of darunavir and/or its pharmacoenhancer.
(CYP3A induction)
When administered concomitantly with darunavir and low dose ritonavir, the patient's tolerability of bosentan should be monitored.
Co-administration of darunavir co-administered with cobicistat and bosentan is not recommended.
HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A protease inhibitors
Elbasvir/grazoprevir
Boosted darunavir may increase the exposure to grazoprevir.
(CYP3A and OATP1B inhibition)
Concomitant use of boosted darunavir and elbasvir/grazoprevir is contraindicated (see section 4.3).
Glecaprevir/pibrentasvir
Based on theoretical considerations boosted darunavir may increase the exposure to glecaprevir and pibrentasvir. (P-gp, BCRP and/or OATP1B1/3 inhibition)
It is not recommended to co-administer boosted darunavir with glecaprevir/pibrentasvir.
HERBAL PRODUCTS
St John's Wort
(Hypericum perforatum)
Not studied. St John's Wort is expected to decrease the plasma concentrations of darunavir or its pharmacoenhancers. (CYP450 induction)
Boosted darunavir must not be used concomitantly with products containing St John's Wort (Hypericum perforatum) (see section 4.3). If a patient is already taking St John's Wort, stop St John's Wort and if possible check viral levels. Darunavir exposure (and also ritonavir exposure) may increase on stopping St John's Wort. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's Wort.
HMG CO-A REDUCTASE INHIBITORS
Lovastatin
Simvastatin
Not studied. Lovastatin and simvastatin are expected to have markedly increased plasma concentrations when co-administered with boosted darunavir.
(CYP3A inhibition)
Increased plasma concentrations of lovastatin or simvastatin may cause myopathy, including rhabdomyolysis. Concomitant use of boosted darunavir with lovastatin and simvastatin is therefore contraindicated (see section 4.3).
Atorvastatin
10 mg once daily
atorvastatin AUC β 3-4 fold
atorvastatin Cmin β β5.5-10 fold
atorvastatin Cmax β β2 fold
#darunavir/ritonavir
atorvastatin AUC β 290% Ξ©
atorvastatin Cmax β 319% Ξ©
atorvastatin Cmin ND Ξ©
Ξ© with darunavir/cobicistat 800/150 mg
When administration of atorvastatin and boosted darunavir is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily. A gradual dose increase of atorvastatin may be tailored to the clinical response.
Pravastatin
40 mg single dose
pravastatin AUC β 81%ΒΆ
pravastatin Cmin ND
pravastatin Cmax β 63%
ΒΆΒΆan up to five-fold increase was seen in a limited subset of subjects
When administration of pravastatin and boosted darunavir is required, it is recommended to start with the lowest possible dose of pravastatin and titrate up to the desired clinical effect while monitoring for safety.
Rosuvastatin
10 mg once daily
rosuvastatin AUC β 48%β
rosuvastatin Cmax β 144%β
βbased on published data with darunavir/ritonavir
rosuvastatin AUC β 93%Β§
rosuvastatin Cmax β 277%Β§
rosuvastatin Cmin ND§
Β§ with darunavir/cobicistat 800/150 mg
When administration of rosuvastatin and boosted darunavir is required, it is recommended to start with the lowest possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for safety.
OTHER LIPID MODIFYING AGENTS
Lomitapide
Based on theoretical considerations boosted darunavir is expected to increase the exposure of lomitapide when co-administered.
(CYP3A inhibition)
Co-administration is contraindicated (see section 4.3).
H2-RECEPTOR ANTAGONISTS
Ranitidine
150 mg twice daily
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Boosted darunavir can be co-administered with H2-receptor antagonists without dose adjustments.
IMMUNOSUPPRESSANTS
Ciclosporin
Sirolimus
Tacrolimus
Everolimus
Not studied. Exposure to these immunosuppressants will be increased when co-administered with boosted darunavir.
(CYP3A inhibition)
Therapeutic drug monitoring of the immunosuppressive agent must be done when co-administration occurs.
Concomitant use of everolimus and boosted darunavir is not recommended.
INHALED BETA AGONISTS
Salmeterol
Not studied. Concomitant use of salmeterol and boosted darunavir may increase plasma concentrations of salmeterol.
Concomitant use of salmeterol and boosted darunavir is not recommended. The combination may result in increased risk of cardiovascular adverse event with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE
Methadone individual dose ranging from 55 mg to 150 mg once daily
R(-) methadone AUC β 16%
R(-) methadone Cmin β 15%
R(-) methadone Cmax β 24%
Darunavir/cobicistat may, in contrast, increase methadone plasma concentrations (see cobicistat SmPC).
No adjustment of methadone dosage is required when initiating co-administration with boosted darunavir. However, adjustment of the methadone dose may be necessary when concomitantly administered for a longer period of time. Therefore, clinical monitoring is recommended, as maintenance therapy may need to be adjusted in some patients.
Buprenorphine/naloxone 8/2 mgβ16/4 mg once daily
buprenorphine AUC β 11%
buprenorphine Cmin β
buprenorphine Cmax β 8%
norbuprenorphine AUC β 46%
norbuprenorphine Cmin β 71%
norbuprenorphine Cmax β 36%
naloxone AUC β
naloxone Cmin ND
naloxone Cmax β
The clinical relevance of the increase in norbuprenorphine pharmacokinetic parameters has not been established. Dose adjustment for buprenorphine may not be necessary when co-administered with boosted darunavir but a careful clinical monitoring for signs of opiate toxicity is recommended.
Fentanyl
Oxycodone
Tramadol
Based on theoretical considerations boosted darunavir may increase plasma concentrations of these analgesics.
(CYP2D6 and/or CYP3A inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir with these analgesics.
OESTROGEN-BASED CONTRACEPTIVES
Drospirenone
Ethinylestradiol (3 mg/0.02 mg once daily)
Β Β Β
Ethinylestradiol
Norethindrone
35 ΞΌg/1 mg once daily
drospirenone AUC β 58%β¬
drospirenone Cmin NDβ¬
drospirenone Cmax β 15%β¬
ethinylestradiol AUC β 30%β¬
ethinylestradiol Cmin NDβ¬
ethinylestradiol Cmax β14%β¬
β¬ with darunavir/cobicistat
ethinylestradiol AUC β 44%Ξ²
ethinylestradiol Cmin β 62%Ξ²
ethinylestradiol Cmax β 32%Ξ²
norethindrone AUC β 14%Ξ²
norethindrone Cmin β 30%Ξ²
norethindrone Cmax βΞ²
Ξ² with darunavir/ritonavir
When darunavir is coadministered with a drospirenone-containing product, clinical monitoring is recommended due to the potential for hyperkalaemia.
Alternative or additional contraceptive measures are recommended when oestrogen-based contraceptives are co-administered with boosted darunavir. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.
OPIOID ANTAGONIST
Naloxegol
Not studied.
Co-administration of boosted darunavir and naloxegol is contraindicated.
PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of erectile dysfunction
Avanafil
Sildenafil
Tadalafil
Vardenafil
In an interaction study#, a comparable systemic exposure to sildenafil was observed for a single intake of 100 mg sildenafil alone and a single intake of 25 mg sildenafil co-administered with darunavir and low dose ritonavir.
The combination of avanafil and boosted darunavir is contraindicated (see section 4.3). Concomitant use of other PDE-5 inhibitors for the treatment of erectile dysfunction with boosted darunavir should be done with caution. If concomitant use of boosted darunavir with sildenafil, vardenafil or tadalafil is indicated, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours or tadalafil at a single dose not exceeding 10 mg in 72 hours is recommended.
For the treatment of pulmonary arterial hypertension
Sildenafil
Tadalafil
Not studied. Concomitant use of sildenafil or tadalafil for the treatment of pulmonary arterial hypertension and boosted darunavir may increase plasma concentrations of sildenafil or tadalafil.
(CYP3A inhibition)
A safe and effective dose of sildenafil for the treatment of pulmonary arterial hypertension co-administered with boosted darunavir has not been established. There is an increased potential for sildenafil-associated adverse events (including visual disturbances, hypotension, prolonged erection and syncope). Therefore, co-administration of boosted darunavir and sildenafil when used for the treatment of pulmonary arterial hypertension is contraindicated (see section 4.3).
Co-administration of tadalafil for the treatment of pulmonary arterial hypertension with boosted darunavir is not recommended.
PROTON PUMP INHIBITORS
Omeprazole
20 mg once daily
#darunavir AUC β
#darunavir Cmin β
#darunavir Cmax β
Boosted darunavir can be co-administered with proton pump inhibitors without dose adjustments.
SEDATIVES/HYPNOTICS
Buspirone
Clorazepate
Diazepam
Estazolam
Flurazepam
Midazolam (parenteral)
Zolpidem
Midazolam (oral)
Triazolam
Not studied. Sedative/hypnotics are extensively metabolised by CYP3A. Co-administration with boosted darunavir may cause a large increase in the concentration of these medicines.
If parenteral midazolam is co-administered with boosted darunavir it may cause a large increase in the concentration of this benzodiazepine.
Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.
Clinical monitoring is recommended when co-administering boosted darunavir with these sedatives/hypnotics and a lower dose of the sedatives/hypnotics should be considered.
If parenteral midazolam is co-administered with boosted darunavir, it should be done in an intensive care unit (ICU) or similar setting, which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Boosted darunavir with triazolam or oral midazolam is contraindicated (see section 4.3).
TREATMENT FOR PREMATURE EJACULATION
Dapoxetine
Not studied.
Co-administration of boosted darunavir with dapoxetine is contraindicated.
UROLOGICAL DRUGS
Fesoterodine Solifenacin
Not studied.
Use with caution. Monitor for fesoterodine or solifenacin adverse reactions, dose reduction of fesoterodine or solifenacin may be necessary.
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology).
β The efficacy and safety of the use of darunavir with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavir and tipranavir) has not been established in HIV patients. According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.
β‘ Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.
4.6 |
Darunavir 800 mg film-coated tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.
There are no adequate and well controlled studies on pregnancy outcome with darunavir in pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
Darunavir co-administered with low dose ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk.
Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure (see section 5.2), which may be associated with an increased risk of treatment failure and an increased risk of HIV transmission to the child. Therapy with darunavir/cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with darunavir/cobicistat should be switched to an alternative regimen (see sections 4.2 and 4.4).
Breast-feeding
It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted in toxicity of the offspring.
Because of the potential for adverse reactions in breast-fed infants, women should be instructed not to breast-feed if they are receiving darunavir.
In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed.
Fertility
No human data on the effect of darunavir on fertility are available. There was no effect on mating or fertility with darunavir treatment in rats (see section 5.3).
4.7 |
Darunavir 800 mg film-coated tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Darunavir in combination with cobicistat or ritonavir has no or negligible influence on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing darunavir co-administered with cobicistat or low dose ritonavir and should be borne in mind when considering a patient's ability to drive or operate machinery (see section 4.8).
4.8 |
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