DARUNAVIR MYLAN

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.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer. 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.

ART-naïve 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 Mylan 800 mg tablets can be used to construct the once daily 800 mg regimen.

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 800 mg tablets can be used to construct the once daily 800 mg regimen. ● 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 Mylan 75 mg, 150 mg, 300 mg or 600 mg tablets. * DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V ART-naïve 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 Mylan 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.

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 Mylan 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. ● In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen described in the Summary of Product Characteristics for Darunavir Mylan 75 mg, 150 mg, 300 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 Mylan 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 Mylan with cobicistat or ritonavir until the next regularly scheduled time.

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. 2). 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 […]

3% of subjects experienced at least one adverse reaction. 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-naïve 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-naïve subjects.

This was driven by mild intensity nausea. 5 weeks. 5% of subjects experienced at least one adverse reaction. 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 (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 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, leucopenia 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 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 […]

Regular assessment of virological response is advised. In the setting of lack or loss of virological response, resistance testing should be performed. 2). The Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with darunavir.

2 did not significantly affect darunavir concentrations. It is not recommended to alter the dose of cobicistat or ritonavir. Darunavir binds predominantly to α1-acid glycoprotein. This protein binding is concentration-dependent indicative for saturation of binding.

5). 2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIs have not been studied in this population. 1). 3). Pregnancy Darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk.

2). 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. 6). Darunavir given with low dose ritonavir may be considered as an alternative.

2). 4% of patients. 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. 8). Darunavir contains a sulphonamide moiety.

Darunavir should be used with caution in patients with a known sulphonamide allergy. g. acute hepatitis, cytolytic hepatitis) has been reported with darunavir. 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 […]

1. Patients with severe (Child-Pugh Class C) hepatic impairment. 5). 5). - The strong CYP3A inducers rifampicin and herbal preparations containing St John's wort (Hypericum perforatum). 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. g. 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).

g. 5).