Daprohin 400/50 Mg 400 mg, 40 mg Tablet

DAPROHIN, in combination 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 DAPROHIN. There is no information on the use of DAPROHIN in the paediatric population for the once daily dose.

DAPROHIN must always be given in combination with other antiretroviral medicines.

Posology

Adults: Genotypic or phenotypic testing should guide the use of DAPROHIN. DAPROHIN 800/100 mg (two tablets) once daily dosing regimen is recommended in HIV protease-inhibitor-nau00efve patients and in treatment-experienced patients with demonstrated absence of DRV-RAMs. The ritonavir included in the formulation is used as a pharmacokinetic enhancer of darunavir (see Sections 4.5 and 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 DAPROHIN in paediatric patients have not been established.

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

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

Method of administration

Orally. DAPROHIN should be taken with food. The type of food does not affect the exposure to DAPROHIN.

Hypersensitivity to darunavir or ritonavir or to any of the excipients of DAPROHIN (listed in section 6.1). Darunavir and ritonavir are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. DAPROHIN should not be co-administered with medicines that are 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 DAPROHIN

• Anticonvulsants: Phenobarbitone, Phenytoin - Phenobarbitone and phenytoin are inducers of CYP450 enzymes. DAPROHIN 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 DAPROHIN (see section 4.5).
• 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. DAPROHIN 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 DAPROHIN (see section 4.5).
• Endothelin receptor antagonist: Bosentan - Concomitant use of bosentan and DAPROHIN 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 DAPROHIN 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 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 DAPROHIN with boceprevir or telaprevir (see section 4.5).
• Herbal Products: St. Johnu2019s wort (Hypericum perforatum) - DAPROHIN should not be used concomitantly with products containing St. Johnu2019s wort (Hypericum perforatum) because coadministration may cause significant decreases in darunavir plasma concentrations. This may result in loss of therapeutic effect to DAPROHIN (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, Voriconazole - CONTRAINDICATED because concomitant systemic use of ketoconazole, itraconazole or voriconazole and DAPROHIN may increase plasma concentrations of darunavir.
• Antidysrhythmics: Amiodarone, Bepridil, Flecainide, Propafenone, Quinidine, Encainide, Digoxin - CONTRAINDICATED with DAPROHIN due to potential cardiac dysrhythmias.

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

General

DAPROHIN must be co-administered with food to exert its therapeutic effect (see section 4.2). Failure to correctly administer DAPROHIN with food will result in reduced plasma concentrations of darunavir that will be insufficient to achieve the desired antiviral effect.

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. DAPROHIN 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 DAPROHIN. The discontinuation rate due to rash in patients using DAPROHIN was 0,5 %.

Rash occurred more commonly in treatment-experienced patients receiving regimens containing DAPROHIN + raltegravir compared to patients receiving DAPROHIN without raltegravir or raltegravir without DAPROHIN. However, rash that was considered medicine related occurred at similar rates for all three groups.

Sulpha allergy

Darunavir contains a sulphonamide moiety. DAPROHIN should be used with caution in patients with a known sulphonamide allergy.

Patients with coexisting conditions

Hepatic impairment

DAPROHIN should not be used in patients with severe hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment (see section 4.2 and 5.2).

Hepatotoxicity

Medicine-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with DAPROHIN. 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 DAPROHIN 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 pretreatment elevations of transaminases, especially during the first several months of DAPROHIN 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 DAPROHIN 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 DAPROHIN 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 section 4.2 and 5.2).

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 protease inhibitors such as DAPROHIN. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship has been postulated, although a mechanism of action has not been established. Haemophilia patients should therefore be made aware of the possibility of increased bleeding.

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 DAPROHIN. Some patients required either initiation or dose adjustment of insulin or oral hypoglycaemic medicines for treatment of these events. In some cases, diabetic ketoacidosis has occurred. Patients who discontinued protease inhibitor therapy, the hyperglycaemia persisted in some cases.

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 DAPROHIN 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.

Darunavir and ritonavir are both inhibitors of CYP3A. Co-administration of DAPROHIN 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 section 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 DAPROHIN. This can lead to prolongation or increase of their therapeutic effect and adverse events (see section 4.5).

HMG-CoA Reductase Inhibitors

The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for metabolism, thus concomitant use of DAPROHIN with simvastatin or lovastatin is contraindicated due to an increased risk of myopathy including rhabdomyolysis. Caution must be exercised and reduced doses should be considered if DAPROHIN 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 exposure has been reported with DAPROHIN co-administration. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see TABLE 2).

Methadone

No adjustment of methadone dosage is required when initiating co-administration of DAPROHIN. 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).

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 DAPROHIN. Co-administration of DAPROHIN 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 DAPROHIN is contraindicated in pulmonary arterial hypertension patients (see section 4.3 and 4.5).

Ritonavir

Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and 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 ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made.

Corticosteroids

Concomitant use of RITONAVIR 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 RITONAVIR has been co-administered with inhaled or intranasally administered fluticasone propionate. Similar findings with concomitant administration of RITONAVIR and other inhaled corticosteroids that are metabolised similarly to fluticasone, such as budesonide, cannot be excluded. Particular caution should be used when administering RITONAVIR and any of these inhaled or intranasally administered glucocorticoids (see section 4.5).

Herbal Products

Patients on RITONAVIR 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 and 4.4).

Resistance/Cross-Resistance

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

Laboratory Tests

RITONAVIR has been associated with alterations in triglycerides, ALT, AST, GGT, CPK and uric acid. Appropriate laboratory testing should be performed prior to initiating RITONAVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy. For comprehensive information concerning laboratory test alterations associated with nucleoside analogues, medical practitioner should refer to the complete product information for each of these medicines.

PR Interval Prolongation

Ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some patients. Reports of second or third degree atrioventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving medicines known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving RITONAVIR. RITONAVIR should be used with caution in such patients.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement and u201ccushingoid appearanceu201d have been observed in patients receiving protease inhibitors.

Lipid Disorders

Treatment with RITONAVIR therapy in combination with saquinavir has resulted in substantial increases in the concentration of total triglycerides and cholesterol. Triglyceride and cholesterol testing should be performed prior to initiating ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. See TABLE 2 for additional information on potential medicine interactions with RITONAVIR and HMG-CoA Reductase Inhibitors (hypolipidemics).

Pregnancy

DAPROHIN is contraindicated in pregnancy and lactation as safety and efficacy have not been demonstrated. Animal studies do not indicate direct harmful effects of darunavir with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Studies with ritonavir 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.

Breastfeeding

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 DAPROHIN.

Carcinogenesis and Mutagenesis

Long-term carcinogenicity studies of RITONAVIR in animal systems have not been completed. RITONAVIR was not found to be mutagenic or clastogenic.

No studies on the effects of DAPROHIN on the ability to drive or use machines have been performed. However, somnolence and dizziness have been reported in some patients during treatment with regimens containing darunavir and ritonavir, and should be borne in mind when considering a patientu2019s ability to drive or operate machinery.

Summary of the safety profile

RITONAVIR The most frequent reported clinical adverse events, other than asthenia, among patients receiving ritonavir were gastrointestinal and neurological disturbances including nausea, diarrhoea, vomiting, anorexia, abdominal pain, taste perversion and circumoral and peripheral paraesthesias.

Tabulated summary of adverse reactions

Darunavir

RITONAVIR

Human experience of acute overdose with DAPROHIN is limited.

Management of Overdosage: There is no specific antidote for overdose with DAPROHIN. Treatment of overdose with DAPROHIN should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. It is proposed that management of overdose could also entail and administration of activated charcoal. Since DAPROHIN is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the medicine.