Vitravir 400 mg, 50 mg Tablet

In combination with other antiretroviral medicines, VITRAVIR 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 VITRAVIR. There is no information on the use of darunavir in combination with ritonavir in the pediatric population (less than 18 years of age) for the once daily dose (see Section 4.2, 5.2 and 5.3).

Posology: VITRAVIR must always be given in combination with other antiretroviral medicines. Adults:

Genotypic or phenotypic testing, should guide the use of VITRAVIR. Two tablets once daily are recommended in HIV protease-inhibitor-nau00efve patients and in treatment-experienced patients with demonstrated absence of DRV-RAMs. (This is a dosage regimen of a daily dose of darunavir/ritonavir 800 mg/100 mg). The ritonavir included in the formulation is used as a pharmacokinetic enhancer of darunavir (see Sections 4.5 and 5.2). VITRAVIR should be given with food. The type of food does not affect the exposure to darunavir (see Section 5.2).

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 VITRAVIR in pediatric patients has not been established.

Missed Dose(s): In case a dose of VITRAVIR was missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of VITRAVIR 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 VITRAVIR when co-administered to patients with severe hepatic impairment; therefore, specific dosage recommendations cannot be made. VITRAVIR should not be used in patients with severe hepatic impairment as safety and efficacy have not been demonstrated (see Section 4.3 and 4.4).

Renal impairment: No dose adjustment is required in patients with renal impairment (see Section 4.4 and 5.2).

Hypersensitivity to darunavir or ritonavir or to any of the excipients of VITRAVIR. VITRAVIR is contraindicated in severe liver disease. Darunavir and ritonavir are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. VITRAVIR 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 VITRAVIR

• Anticonvulsants: Phenobarbitone, Phenytoin - Phenobarbitone and phenytoin are inducers of CYP450 enzymes. VITRAVIR 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 VITRAVIR (see Section 4.5).
• Antidysrhythmics: Amiodarone, Bepridil, Flecainide, Propafenone, Quinidine, Encainide, Digoxin - CONTRAINDICATED with VITRAVIR due to potential cardiac dysrhythmias.
• Antihistamines: Astemizole - CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac dysrhythmia.
• Antimycobacterial: Rifampicin - Rifampicin is a potent inducer of CYP450 metabolism. VITRAVIR 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 VITRAVIR (see Section 4.5).
• Rifabutin: 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 VITRAVIR (see Section 4.5).
• Antipsychotic: Blonanserin - May result in potential increase in frequency or intensity of known neurological or other toxicities associated with blonanserin.
• Endothelin receptor antagonist: Bosentan - Concomitant use of bosentan and VITRAVIR should be avoided (see Section 4.5).
• PDE-5 inhibitor: Sildenafil u2013 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 VITRAVIR in patients with renal or hepatic impairment is contraindicated due to the potential risk of colchicine-induced toxic effects.
• Alpha 1-adrenoreceptor 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 ischaemia 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 VITRAVIR with boceprevir or telaprevir (see Section 4.5).
• Herbal Products: St. John's wort (Hypericum perforatum) - VITRAVIR 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 VITRAVIR (see Section 4.5).
• 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 and voriconazole - CONTRAINDICATED because concomitant systemic use of ketoconazole, itraconazole or voriconazole and VITRAVIR may increase plasma concentrations of darunavir. Simultaneously, plasma concentrations of ketoconazole or itraconazole may be increased by VITRAVIR, while the plasma concentrations of voriconazole may be decreased in the presence of VITRAVIR (see Section 4.5).

Patients should be advised that current antiretroviral therapy, including VITRAVIR, 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 VITRAVIR in patients aged 65 and over, caution should be exercised in the administration of VITRAVIR in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see Section 5.2).

General: VITRAVIR must be co-administered with food to exert its therapeutic effect (see Section 4.2 and 5.2). Failure to correctly administer VITRAVIR with food will result in reduced plasma concentrations of darunavir that will be insufficient to achieve the desired antiviral effect. The two-tablet dose of VITRAVIR contains 100 mg of ritonavir as a pharmacokinetic enhancer (see Section 5.2). Adding more ritonavir will 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. VITRAVIR 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 VITRAVIR. The discontinuation rate due to rash in patients using VITRAVIR was 0.5%. Rash occurred more commonly in treatment-experienced subjects receiving regimens containing VITRAVIR + raltegravir compared to subjects receiving VITRAVIR without raltegravir or raltegravir without VITRAVIR. However, rash that was considered medicine related occurred at similar rates for all three groups.

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

Patients with coexisting conditions:

Hepatic impairment: VITRAVIR should not be used in patients with severe hepatic impairment (see Section 4.3). No dose adjustment is required in patients with mild or moderate hepatic impairment (see Sections 5.2 and 5.3).

Hepatotoxicity: Medicine-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with VITRAVIR. 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 VITRAVIR 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 VITRAVIR 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 VITRAVIR 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 VITRAVIR 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 Sections 4.2 and 5.2).

Haemophilia patients: There have been reports of increased bleeding, including spontaneous skin haematomas and hemarthrosis in patients with haemophilia type A and B treated with PIs such as VITRAVIR. 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 VITRAVIR.

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.

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).

Opportunistic infections: Patients receiving VITRAVIR 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.

Ritonavir and darunavir in VITRAVIR are both inhibitors of CYP3A. Co-administration of VITRAVIR 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 Sections 4.3 and 4.5). 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 VITRAVIR. This can lead to prolongation or increase of their therapeutic effect and adverse events (see Section 4.5).

Methadone: No adjustment of methadone dosage is required when initiating co-administration of VITRAVIR. However, clinical monitoring is recommended as maintenance therapy may need to be adjusted (see Section 4.5).

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 Section 4.5).

Allergic reactions: Allergic reactions including urticaria, skin eruptions, bronchospasm and angio-edema have been reported. Cases of anaphylaxis and Stevens-Johnson syndrome have also been reported (see boxed warning in beginning of Professional Information).

Hepatic reactions: Hepatic transaminase elevations exceeding five times the upper limit of normal, clinical hepatitis and jaundice have occurred in patients receiving VITRAVIR alone or in combinations with other antiretroviral medicines. There may be an increased risk of transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering VITRAVIR to patients with pre-existing mild to moderate liver disease, liver enzyme abnormalities or hepatitis. Increased AST/ALT monitoring should be considered in these patients during the first three months of VITRAVIR treatment.

Pancreatitis: Pancreatitis has been observed in patients receiving VITRAVIR therapy, including those who developed hypertriglyceridemia. Fatalities have been observed. Patients with advanced HIV disease may be at increased risk of elevated blood levels of triglycerides and of pancreatitis. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and VITRAVIR therapy should be discontinued if a diagnosis of pancreatitis is made.

Diabetes mellitus/hyperglycaemia: New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycaemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy such as VITRAVIR. Some patients required either initiation or dose adjustment of insulin or oral hypoglycaemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. Patients who discontinued protease inhibitor therapy, the hyperglycaemia persisted in some cases.

Corticosteroids: Concomitant use of VITRAVIR and fluticasone propionate can significantly increase fluticasone propionate plasma concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushingu2019s syndrome and adrenal suppression have been reported when VITRAVIR has been co-administered with inhaled or intranasally administered fluticasone propionate. Similar findings with concomitant administration of VITRAVIR and other inhaled corticosteroids that are metabolised similarly to fluticasone, such as budesonide, cannot be excluded. Particular caution should be used when administering VITRAVIR and any of these inhaled or intranasally administered glucocorticoids (see Section 4.5).

PDE 5 inhibitors: Caution should be used when prescribing sildenafil, tadalafil or vardenafil for the treatment of erectile dysfunction or pulmonary hypertension in patients receiving VITRAVIR. Co-administration of VITRAVIR with these medicines is expected to increase their concentrations and may result in increased associated adverse events, such as hypotension and prolonged erection. Concomitant use of sildenafil with VITRAVIR is contraindicated in pulmonary arterial hypertension patients (see Section 4.3 and 4.5).

Herbal products: Patients on VITRAVIR should not use products containing St Johnu2019s Wort (Hypericum perforatum) because co-administration may be expected to reduce plasma concentrations of ritonavir. This may result in loss of therapeutic effect and development of resistance (see Section 4.3).

HMG-CoA Reductase Inhibitors: The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for metabolism, thus concomitant use of VITRAVIR with simvastatin or lovastatin is contraindicated due to increased risk of myopathy including rhabdomyolysis. Caution must be exercised and reduced doses should be considered if VITRAVIR is used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A4. While rosuvastatin elimination is not dependent on CYP3A, an elevation of rosuvastatin exposures has been reported with VITRAVIR co-administration. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (See Table 2).

Resistance/cross-resistance: Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of VITRAVIR therapy following loss of viral suppression may increase the likelihood of cross-resistance to the other protease inhibitors. The potential for HIV cross-resistance between protease inhibitors has not been fully explored. Therefore, it is unknown what effect VITRAVIR therapy will have on the activity of concordantly or subsequently administered protease inhibitors.

Laboratory tests: VITRAVIR has been associated with alterations in triglyceride, ALT, AST, GGT, CPK and uric acid. Appropriate laboratory testing should be performed prior to initiating VITRAVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.

Pregnancy: VITRAVIR is contraindicated in pregnancy and lactation as safety has not been established. Studies in animals do not indicate direct harmful effects of darunavir with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Section 5.3). A large amount (6100 live births) of pregnant women were exposed to ritonavir during pregnancy; of these, 2800 live births were exposed during the first trimester. These data largely refer to exposures where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower doses as a pharmacokinetic enhancer for other PIs. These data indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems. Animal data have shown reproductive toxicity (see Section 5.3).

Lactation: It is not known whether darunavir or ritonavir 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 VITRAVIR.

Dizziness and somnolence has been reported in some patients and this should be borne in mind when considering a patientu2019s ability to drive or operate machinery (see Section 4.8).

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

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

System Organ Class & Frequency category

Adverse Drug Reaction

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

* Excluding laboratory abnormalities reported as ADRs # Optimised Background Regimen

Laboratory abnormalities, considered ADRs, in antiretroviral treatment experienced HIV-1 infected adult patients of at least Grade 2 in the ODIN trial, are shown in the table below:

Laboratory Abnormalities of at least Grade 2 - ODIN trial (darunavir/rtv 800 mg daily + OBR#, n=[286])

Worst Treatment Emergent Toxicity Grades*

DRV/rtv 800/100 mg once daily (N=286)

• General Biochemistry
• Amylase Grade 2 3.1 % Grade 3 2.4 % Grade 4 0.3 %
• Lipase Grade 2 1 % Grade 3 0.3 %
• Lipids and Glucose
• Glucose Grade 2 6.3 % Grade 3 0.7 %
• Low Density Lipoprotein Calculated Grade 2 7 % Grade 3 2.8 %
• Total Cholesterol Grade 2 7.7 % Grade 3 2.4 %
• Triglycerides Grade 2 3.5 % Grade 3 1.4 % Grade 4 0.3 %
• Liver Function
• Alanine Amino Transferase Grade 2 1.7 %
• Alkaline Phosphatase Grade 2 0.7 %
• Aspartate Amino Transferase Grade 2 1.4 % Grade 3 0.7 %

In overdose of VITRAVIR, side effects can be precipitated and/or be of increased severity (see Section 4.8). Ritonavir: One patient in clinical trials took ritonavir 1 500 mg/day for two days and reported paraesthesias which resolved after dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose. Management of overdose of VITRAVIR: There is no specific antidote for overdose with darunavir or ritonavir. Treatment of overdose with VITRAVIR 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 substances is to be achieved by emesis. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since darunavir and ritonavir both are highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.