Darunavir Krka D.D.

Medicinal Product no longer authorised 3 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. 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.

This product is only available as film coated tablets and is thus not suitable for patients who are unable to swallow intact tablets, for example young children. For use in these patients, more suitable formulations containing darunavir should be checked for their availability.

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. d. 400 mg and 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. d. 400 mg and 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.

d. 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).

d. 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.

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)Medicinal Product no longer authorised 24 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 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 disordersMedicinal Product no longer authorised 25 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, […]

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. 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 1-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.

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).