Prezista 600 Mg Tablets

PREZISTA, in combination with 100 mg ritonavir (PREZISTA/rtv) and with other antiretroviral agents, is indicated for the treatment of HIV infection in antiretroviral treatment experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor. This indication is based on week-24 analyses from 2 controlled clinical trials in treatment-experienced, HIV-1-infected patients, where PREZISTA/rtv showed a significantly greater reduction of plasma HIV RNA levels and greater increase in CD4+ cell counts when compared to a protease inhibitor (PI) regimen of choice, each given in combination with other antiretrovirals. (Additional data is available from open label studies (see Pharmacodynamic Properties)). There is no information on the use of PREZISTA/rtv in HIV-infected paediatric patients and in antiretroviral treatment-nau00efve adult patients. Treatment history and, when available, genotypic or phenotypic testing should guide the use of PREZISTA/rtv.

• 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) isoforms. PREZISTA/rtv should not be co-administered with medicinal products 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 medicinal products are included in the table below:

Medicines that are contraindicated with PREZISTA/rtv

Medicine Class: Medicine Name Clinical Comment

• Anticonvulsants: Carbamazepine, Phenobarbital, Phenytoin - Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. PREZISTA/rtv should not be used in combination with phenobarbital, phenytoin or carbamazepine as co-administration may cause significant decreases in darunavir plasma concentrations. This may result in loss of the therapeutic effect of PREZISTA (see INTERACTIONS).
• 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. 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 the therapeutic effect of PREZISTA (see INTERACTIONS).
• PDE5 inhibitors: Sildenafil - for 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).
• 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 characterised by peripheral vasospasm and ischaemia of the extremities and other tissues.
• Herbal Products: St. John's 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 the therapeutic effect of 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 and 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 does not cure HIV and has not been proven to prevent the transmission of HIV and that they may continue to develop opportunistic infections and other complications associated with HIV disease. Appropriate precautions should continue to be employed.

Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a medical practitioner while using PREZISTA.

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. The type of food does not affect exposure to PREZISTA. Patients should be instructed to swallow whole tablets with a drink such as water or milk. PREZISTA must always be used with 100 mg of ritonavir in combination with other antiretroviral medicines. Patients should not alter the dose of either PREZISTA or ritonavir, discontinue ritonavir, or discontinue therapy with PREZISTA without consulting their medical practitioner. If a patient misses a dose of PREZISTA or ritonavir by more than 6 hours, the patient should be told to wait and then take the next dose of PREZISTA and ritonavir at the regularly scheduled time. If the patient misses a dose of PREZISTA or ritonavir by less than 6 hours, the patient should be told to take PREZISTA and ritonavir immediately, and then take the next dose of PREZISTA and ritonavir at the regularly scheduled time. If a dose of PREZISTA or ritonavir is skipped, the patient should not double the next dose.

Inform the patient that he or she should not take more or less than the prescribed dose of PREZISTA or ritonavir at any one time.

Please refer to ritonavir prescribing information for additional information on precautionary measures.

Skin rash: During the clinical development programme, severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported. Stevens-Johnson Syndrome has also been rarely reported and during post-marketing experience toxic epidermal necrolysis has been reported very rarely. Discontinue PREZISTA 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. Rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in patients using PREZISTA/rtv was 0,5 %.

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

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).

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 PREZISTA. Some patients required either initiation or dose adjustments of insulin or oral hypoglycaemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PREZISTA, hyperglycaemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PREZISTA and these events have not been established. Many patients had confounding medical conditions, some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycaemia.

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 u201cINTERACTIONSu201d). The phosphodiesterase type 5 (PDE5) inhibitors sildenafil, vardenafil and tadalafil are highly dependent on CYP3A for their metabolism. If concomitant use of PREZISTA/rtv with sildenafil, vardenafil or tadalafil is indicated, reduced doses of the PDE5 inhibitors are recommended (see INTERACTIONS). There are insufficient data at this time to recommend a dose in antiretroviral treatment-nau00efve patients and in children.

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).

Patients with coexisting conditions: Hepatic impairment: There are no data regarding the use of PREZISTA/rtv when co-administered to patients with severe hepatic impairment; therefore, PREZISTA should not be used. 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 or 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, dark urine, 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 total body clearance 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).

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 causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Fat redistribution and metabolic disorders: Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV-infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age and with medicine-related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see SIDE EFFECTS).

Immune reactivation syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jeroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

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.

Fertility: There was no effect on mating or fertility with PREZISTA treatment in rats.

Adverse drug reactions (ADRu2019s) identified in the safety assessment: The safety assessment is based on all safety data from the Phase IIb clinical trials reported with the recommended dose of PREZISTA/rtv 600/100 mg twice daily in patients who immediately started treatment with the recommended dose (de novo patients). In clinical trials, the most frequent (u2265 10 %) ADRs were diarrhoea, headache, abdominal pain, nausea and fatigue. The most frequent grade 3 or 4 ADRs were increased hepatic and pancreatic enzymes, hypertriglyceridaemia, diarrhoea, hypercholesterolaemia, headache, abdominal pain and vomiting. All other grade 3 or 4 ADRs were reported in less than 1 % of the patients. 2,1 percent of the patients discontinued treatment due to ADRs.

Adverse drug reactions to PREZISTA/rtv 600/100 mg twice daily, all grades, in antiretroviral treatment-experienced HIV-1-infected adult patients in the pooled Phase IIb clinical trials are mentioned in the table below*: * excluding laboratory abnormalities reported as ADRs

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.

Pooled analysis Phase IIb clinical trials (PREZISTA/rtv 600/100 mg twice daily + OBR # , n=467)

System Organ Class & Frequency Category Adverse Drug Reaction

• Immune system disorders: uncommon: Immune reconstitution syndrome
• Metabolism and nutrition disorders: common: Diabetes mellitus, anorexia
• Psychiatric disorders: uncommon: Abnormal dreams
• Nervous system disorders: very common: Headache
• Gastrointestinal disorders: very common: common: uncommon: Diarrhoea, nausea, abdominal pain Vomiting, dyspepsia, abdominal distension, flatulence Acute pancreatitis
• Hepatobiliary disorders: uncommon: Hepatitis acute
• Skin and subcutaneous tissue disorders: common: Lipodystrophy (lipohypertrophy, lipodystrophy, and lipoatrophy), rash, pruritus
• Musculoskeletal and connective tissue disorders: common: Myalgia
• Reproductive system and breast disorders: common: Gynaecomastia
• General disorders and administration site conditions: very common: common: Fatigue Asthenia

# Optimised Background Regimen. Laboratory abnormalities, considered ADRs, in antiretroviral treatment-experienced HIV-1-infected adult patients in the pooled Phase IIb clinical trials are shown in the table below:

Pooled analysis Phase IIb clinical trials

Laboratory Parameter Preferred Term Limit PREZISTA/rtv 600/100 mg twice daily + OBR # N=467

• ALT Grade 2 Grade 3 Grade 4 > 2,5 to u2264 5,0 x ULN > 5,0 to u2264 10,0 x ULN > 10,0 x ULN 6,1 % 2,4 % 0,9 %
• AST Grade 2 > 2,5 to u2264 5,0 x ULN 6,9 % Grade 3 > 5,0 to u2264 10,0 x ULN 3,0 % Grade 4 > 10,0 x ULN 0,6 %
• ALP Grade 2 Grade 3 Grade 4 > 2,5 to u2264 5,0 x ULN > 5,0 to u2264 10,0 x ULN > 10,0 x ULN 3,9 % 0,9 % 0 %
• Triglycerides Grade 2 Grade 3 Grade 4 5,65 to 8,47 mmol/l 8,48 to 13,56 mmol/l > 13,56 mmol/l 9,3 % 8,2 % 3,9 %
• Total cholesterol* Grade 2 Grade 3 6,22 to 7,77 mmol/l > 7,77 mmol/l 17,7 % 7,1 %
• LDL cholesterol* Grade 2 Grade 3 4,14 to 4,92 mmol/l u2265 4,92 mmol/l 13,2 % 9,1 %
• Elevated glucose levels Grade 2 Grade 3 Grade 4 6,99 to 13,87 mmol/l 13,93 to 27,75 mmol/l > 27,75 mmol/l 15,4 % 1,7 % 0,2 %
• Pancreatic lipase Grade 2 Grade 3 Grade 4 > 1,5 to u2264 3,0 x ULN > 3,0 to u2264 5,0 x ULN > 5,0 x ULN 5,2 % 2,6 % 0,9 %
• Pancreatic amylase Grade 2 Grade 3 > 1,5 to u2264 2,0 x ULN > 2,0 to u2264 5,0 x ULN 7,4 % 7,8 % Grade 4 > 5,0 x ULN 1,1 %

# Optimised Background Regimen. * Grade 4 data not applicable in division of AIDS grading scale.

Symptoms: Human experience of acute overdose with PREZISTA/rtv is limited.

Treatment: 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.