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.

Posology Darunavir Mylan 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.

ART-experienced adult patients The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food. Darunavir Mylan 75 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 difficulty in swallowing the 300 mg or 600 mg tablets.

Before prescribing darunavir tablets, young children should be assessed for the ability to swallow intact tablets. For young children unable to swallow tablets, more suitable formulations containing darunavir should be checked for their availability.

ART-naïve adult patients For dosage recommendations in ART-naïve patients see the Summary of Product Characteristics for Darunavir Mylan 400 mg and 800 mg tablets. ART-naïve 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-naïve paediatric patients (3 to 17 years) with darunavir tablets and ritonavira Body weight (kg) Dose (once daily with food) ≥ 15 kg to < 30 kg 600 mg darunavir/100 mg ritonavir once daily ≥ 30 kg to < 40 kg 675 mg darunavir/100 mg ritonavir once daily ≥ 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 ≥ 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) ≥ 15 kg–< 30 kg 600 mg darunavir/100 mg ritonavir once daily 375 mg darunavir/50 mg ritonavir twice daily ≥ 30 kg–< 40 kg 675 mg darunavir/100 mg ritonavir once daily 450 mg darunavir/60 mg ritonavir twice daily ≥ 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-naïve 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 Mylan 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 Mylan with 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). 1). 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. […]

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. 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 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 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 diarrhoea vomiting, nausea, abdominal pain, increased blood amylase, dyspepsia, abdominal distension, flatulence Uncommon Rare 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 § 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.

4. During the clinical development […]

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 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 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). 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 Mylan 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/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.

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.

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 […]

1. Patients with severe (Child-Pugh Class C) hepatic impairment. 5). 5). 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.

g. 5).