Prezista 400 Mg Tablets

PREZISTA, in combination with low dose ritonavir (PREZISTA/rtv) and with other antiretroviral medicines, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment experienced adult patients who are protease-inhibitor-nau00efve patients or after exclusion of darunavir resistance associated mutations (DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V). Genotypic or phenotypic testing should guide the use of PREZISTA/rtv. Ritonavir is used as a pharmacokinetic enhancer of darunavir. There is no information on the use of darunavir in combination with ritonavir in the paediatric population for the once daily dose.

PREZISTA must always be given with 100 mg ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicines. The package insert of ritonavir including the contraindications and warnings must therefore be consulted prior to initiation of therapy with PREZISTA/rtv.

Adults: Genotypic or phenotypic testing should guide the use of PREZISTA/rtv. PREZISTA/ritonavir 800/100 mg once daily dosing regimen is recommended in HIV protease-inhibitor-nau00efve patients and in treatment-experienced patients with demonstrated absence of DRV-RAMs. PREZISTA should be given with food. The type of food does not affect the exposure to darunavir. Ritonavir (100 mg) is used as a pharmacokinetic enhancer of darunavir (see INTERACTIONS and Pharmacokinetic Properties).

Children (less than 12 years of age) and adolescents (12 to 17 years of age): The safety and efficacy of the once daily dose of PREZISTA/rtv in paediatric patients has not been established.

Missed Dose(s): In case a dose of PREZISTA and/or ritonavir was missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of PREZISTA and ritonavir with food as soon as possible. If this was 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.

Hepatic impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no data regarding the use of PREZISTA/rtv when co-administered to patients with severe hepatic impairment; therefore, specific dosage recommendations cannot be made. PREZISTA/rtv should not be used in patients with severe hepatic impairment as safety and efficacy have not been demonstrated (see WARNINGS AND SPECIAL PRECAUTIONS).

Renal impairment: No dose adjustment is required in patients with renal impairment (see WARNINGS AND SPECIAL PRECAUTIONS and Pharmacokinetic Properties).

Hypersensitivity to darunavir or to any of the excipients of PREZISTA. The presence of a contraindication to ritonavir. Darunavir and ritonavir are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. PREZISTA/rtv should not be co-administered with medicines that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These medicines are included in the table below:

Medicines that are contraindicated with PREZISTA/rtv

• Anticonvulsants: Phenobarbitone, Phenytoin - Phenobarbitone and phenytoin are inducers of CYP450 enzymes. PREZISTA/rtv should not be used in combination with phenobarbitone, or phenytoin, as co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA (see INTERACTIONS).
• Antihistamines: Astemizole - CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac dysrhythmia.
• Antimycobacterial: Rifampicin, Rifabutin - Rifampicin is a potent inducer of CYP450 metabolism. PREZISTA/rtv should not be used in combination with rifampicin, as this may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA (see INTERACTIONS). The exposure to rifabutin and its active metabolite was increased 3-fold and the incidence of side effects was doubled when rifabutin was given at a dose of 150 mg every other day in combination with PREZISTA and ritonavir (see INTERACTIONS).
• Endothelin receptor antagonist: Bosentan - Concomitant use of bosentan and PREZISTA/rtv should be avoided (see INTERACTIONS).
• PDE-5 inhibitor: Sildenafil - when intended for the treatment of pulmonary arterial hypertension - A safe and effective dose of sildenafil for the treatment of pulmonary arterial hypertension has not been established. There is an increased potential for sildenafil-associated adverse events (including visual disturbances, hypotension, prolonged erection and syncope).
• Antigout: Colchicine in patients with hepatic or renal impairment - Co-administration of PREZISTA/rtv in patients with renal or hepatic impairment is contraindicated due to the potential risk of colchicine-induced toxic effects.
• Alpha 1-adreno-receptor antagonist: Alfuzosin - Potential for serious and/or life-threatening reactions such as hypotension.
• Ergot Derivatives: Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine - CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
• GI Motility Agents: Cisapride - CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac dysrhythmia.
• Hepatitis C virus (HCV) direct-acting antivirals: NS3-4A protease inhibitors - Boceprevir, Telaprevir - It is not recommended to co-administer PREZISTA/rtv with boceprevir or telaprevir (see INTERACTIONS).
• Herbal Products: St. Johnu2019s wort (Hypericum perforatum) - PREZISTA/rtv should not be used concomitantly with products containing St. Johnu2019s wort (Hypericum perforatum) because co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA (see INTERACTIONS).
• HMG-CoA reductase inhibitors: Lovastatin, Simvastatin - Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
• Neuroleptic: Pimozide - CONTRAINDICATED due to the potential for serious and/or life-threatening reactions such as cardiac dysrhythmia.
• Sedative/Hypnotics: Midazolam, Triazolam - CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
• Antifungals: Ketoconazole, Itraconazole, Voriconazole - CONTRAINDICATED because concomitant systemic use of ketoconazole, itraconazole or voriconazole and PREZISTA/rtv may increase plasma concentrations of darunavir. Simultaneously, plasma concentrations of ketoconazole or itraconazole may be increased by PREZISTA/rtv, while the plasma concentrations of voriconazole may be decreased in the presence of PREZISTA/rtv (see INTERACTIONS).

Patients should be advised that current antiretroviral therapy, including PREZISTA, does not prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Elderly: As limited information is available on the use of PREZISTA/rtv in patients aged 65 and over, caution should be exercised in the administration of PREZISTA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see Pharmacokinetic Properties).

General: PREZISTA must be co-administered with ritonavir and food to exert its therapeutic effect (see DOSAGE AND DIRECTIONS FOR USE). Failure to correctly administer PREZISTA with ritonavir and food will result in reduced plasma concentrations of darunavir that will be insufficient to achieve the desired antiviral effect. PREZISTA should be used in combination with 100 mg of ritonavir as a pharmacokinetic enhancer (see Pharmacokinetic Properties). Increasing the dose of ritonavir did not significantly affect darunavir concentrations and is not recommended.

Severe skin reactions: During the clinical development program, severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported. Stevens-Johnson Syndrome has been reported; and during post-marketing experience toxic epidermal necrolysis has also been reported. PREZISTA 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 with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia. Rash (all grades, regardless of causality) occurred in 10,3 % of patients treated with PREZISTA. The discontinuation rate due to rash in patients using PREZISTA/rtv was 0,5 %. Rash occurred more commonly in treatment-experienced subjects receiving regimens containing PREZISTA/rtv + raltegravir compared to subjects receiving PREZISTA/rtv without raltegravir or raltegravir without PREZISTA/rtv. However, rash that was considered medicine related occurred at similar rates for all three groups.

Sulpha allergy: Darunavir contains a sulphonamide moiety. PREZISTA should be used with caution in patients with a known sulphonamide allergy.

Patients with coexisting conditions: Hepatic impairment: PREZISTA should not be used in patients with severe hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment (see DOSAGE AND DIRECTIONS FOR USE and Pharmacokinetic Properties).

Hepatotoxicity: Medicine-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events. Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv 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 PREZISTA/rtv treatment. Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, liver tenderness, hepatomegaly) in patients on PREZISTA/rtv should prompt consideration of interruption or discontinuation of treatment.

Renal impairment: Since the renal clearance of darunavir is limited, a decrease in the elimination of PREZISTA is not expected 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 (see DOSAGE AND DIRECTIONS FOR USE and Pharmacokinetic Properties).

Haemophilia 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 such as PREZISTA. Haemophilia patients should therefore be made aware of the possibility of increased bleeding.

Hyperglycaemia: New onset diabetes mellitus, hyperglycaemia, or exacerbation of pre-existing diabetes mellitus has been reported in patients receiving PREZISTA.

Lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy has been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and elevated serum lipid and glucose levels in HIV patients. Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment.

Immune Reconstitution Inflammatory Syndrome: Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted or continued and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS. Autoimmune disorders (such as Graves' disease) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

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.

Opportunistic infections: Patients receiving PREZISTA should be advised that they may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by healthcare professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done.

PREZISTA and ritonavir are both inhibitors of CYP3A. Co-administration of PREZISTA/rtv with medicines primarily metabolised by CYP3A may result in increased plasma concentrations of such medicines, which could increase or prolong their therapeutic effect and adverse events (see CONTRAINDICATIONS and INTERACTIONS). For medicines that are highly dependent on the metabolism by CYP3A and that have a narrow therapeutic index, such as amiodarone, bepridil, (systemic) lidocaine and quinidine, plasma concentrations of such medicines could increase when combined with PREZISTA/rtv. This can lead to prolongation or increase of their therapeutic effect and adverse events (see INTERACTIONS).

HMG-CoA Reductase Inhibitors: Concomitant use of PREZISTA/rtv with simvastatin, pravastatin or lovastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis, as a consequence of increased plasma concentrations of simvastatin, pravastatin or lovastatin.

Methadone: No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/rtv. However, clinical monitoring is recommended as maintenance therapy may need to be adjusted (see INTERACTIONS).

Oestrogen-based contraceptives: Plasma concentrations of ethinylestradiol are decreased by induction of its metabolism by ritonavir and alternative methods of non-hormonal contraception are recommended (see INTERACTIONS).

PDE-5-Inhibitors: If concomitant use of PREZISTA/rtv with sildenafil, vardenafil, or tadalafil is indicated, reduced doses of the PDE-5 inhibitors are recommended (see CONTRAINDICATIONS and INTERACTIONS).

Pregnancy: Safety and efficacy have not been demonstrated. In animal studies the exposure was lower than in human exposure and no conclusions were possible.

Lactation: It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk. Because of the potential for serious adverse events in nursing infants, mothers should be instructed not to breastfeed if they are receiving PREZISTA.

No trials on the effects of PREZISTA in combination with ritonavir on the ability to drive or use machines have been performed. However, dizziness has been reported in some patients during treatment with regimens containing PREZISTA/rtv and should be borne in mind when considering a patientu2019s ability to drive or operate machinery.

Adverse Drug Reactions to PREZISTA/rtv identified in the ODIN trial Adverse Drug Reactions to PREZISTA/rtv 800/100 mg once daily (q.d.) of at least moderate intensity (grade 2 to 4) in antiretroviral treatment-experienced HIV-1 infected adult patients in the ODIN trial are mentioned in the table below.

Within each System Organ Class, the ADRs are ranked under CIOMS headings of frequency, using the following convention: Very common (u2265 1/10); common (u2265 1/100, < 1/10); uncommon (u2265 1/1 000, < 1/100); rare (u2265 1/10 000, < 1/1 000); very rare (u2264 1/10 000), including isolated reports.

*Adverse Drug Reactions of at Least Grade 2 - ODIN trial* (PREZISTA/rtv 800/100 mg daily + OBR # , n=[294])

System Organ Class & Frequency category Adverse Drug Reaction

• Metabolism and nutrition disorders Common: Hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia Uncommon: Diabetes mellitus, anorexia, dyslipidaemia, lipodystrophy, low density lipoprotein increased
• Nervous system disorders Common: Headache
• Gastrointestinal disorders Common: Diarrhoea, vomiting, nausea, abdominal pain Uncommon: Abdominal distension, dyspepsia, flatulence, pancreatic enzymes increased
• Skin and subcutaneous tissue disorders Common: Rash Uncommon: Pruritus
• Musculoskeletal and connective tissue disorders Uncommon: Myalgia
• General disorders and administration site conditions Uncommon: Asthenia, fatigue

Human experience of acute overdose with PREZISTA/rtv is limited. There is no specific antidote for overdose with PREZISTA. Treatment of overdose with PREZISTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.