Priprema 25mg. 200mg Tablet

Treatment of HIV-1 infection

PRIPREMA is indicated in combination with other antiretroviral medicines for the treatment of HIV-1 infection in adults and adolescents (aged 12 years and older with body weight of at least 35 kg) (see sections 4.2 and 5.1).

Therapy should be initiated by a medical practitioner experienced in the management of HIV infection.

Adults and adolescents aged 12 years and older, weighing at least 35 kg

PRIPREMA should be administered as shown in table below:

Dose of PRIPREMA Third medicine in HIV treatment regimen (see section 4.5) PRIPREMA 200/25 mg once daily Dolutegravir, efavirenz, maraviroc, nevirapine, rilpivirine, raltegravir.

If the patient misses a dose of PRIPREMA within 18 hours of the time it is usually taken, the patient should take PRIPREMA as soon as possible and resume the normal dosing schedule. If a patient misses a dose of PRIPREMA by more than 18 hours, the patient should not take the missed dose and simply resume the usual dosing schedule. If the patient vomits within 1 hour of taking PRIPREMA, another tablet should be taken.

Special populations

Elderly (patients u2265 65 years old) No dose adjustment of PRIPREMA is required in elderly patients.

Renal impairment Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in all individuals (see sections 4.3 and 4.4). No dose adjustment is required in adults or adolescents (aged at least 12 years and of at least 35 kg body weight) with estimated creatinine clearance (CrCl) u2265 30 mL/min. PRIPREMA should be discontinued in patients with estimated CrCl that declines below 30 mL/min during treatment (see sections 4.4 and 5.2). No dose adjustment of PRIPREMA is required in adults with end stage renal disease (estimated CrCl u02c2 15 mL/min) on chronic haemodialysis; however, PRIPREMA should generally be avoided but may be used in these patients (see sections 4.4 and 5.2). On days of haemodialysis, PRIPREMA should be administered after completion of haemodialysis treatment. PRIPREMA should be avoided in patients with estimated CrCl u2265 15 mL/min and u02c2 30 mL/min as the safety of PRIPREMA has not been established in this population. PRIPREMA should not be used in patients with CrCl u02c2 15 mL/min who are not receiving haemodialysis (see section 4.4). No data are available to make dose recommendations in children less than 18 years with end stage renal disease.

Hepatic impairment No dose adjustment of PRIPREMA is required in patients with mild to moderate hepatic impairment. PRIPREMA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); therefore, PRIPREMA is not recommended for use in patients with severe hepatic impairment as no dose recommendations can be made (see sections 4.4 and 5.2).

Paediatric population The safety and efficacy of PRIPREMA in children younger than 12 years or weighing u02c2 35 kg have not been established. No data are available.

Method of administration PRIPREMA should be taken orally, once daily with or without food (see section 5.2). The film-coated tablet should not be chewed, crushed or split.

• Hypersensitivity to the active substances or to any of the excipients of PRIPREMA listed in section 6.1.
• Pregnancy and lactation.

General Individuals should be fully informed about the use of precautionary measures including barrier contraception (condoms) that should be taken to prevent HIV-1 transmission in accordance with the national guidelines. Treatment compliance reduces risk but does not prevent the transmission of HIV-1 as PRIPREMA is not indicated for prophylaxis.

Patients co-infected with HIV and hepatitis B or C virus Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. The safety and efficacy of PRIPREMA in patients co-infected with HIV-1 and Hepatitis C (HCV) have not been established. Tenofovir alafenamide is active against hepatitis B virus (HBV). Discontinuation of PRIPREMA therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue PRIPREMA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Liver disease Use of PRIPREMA can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of PRIPREMA has not been established in patients with significant underlying liver disorders/diseases. In case of concomitant antiviral therapy for hepatitis B or C, please also consult the relevant package inserts for these medicines. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored. If there is evidence of worsening liver disease in such patients, temporary or permanent discontinuation of treatment must be considered.

Weight and metabolic parameters An increase in weight and in levels of blood lipids (hyperlipidaemia) and glucose may occur during antiretroviral therapy. Such changes may in part be linked to diseases control and lifestyle. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Mitochondrial dysfunction following exposure in utero Nucleoside and nucleotide analogues such as PRIPREMA have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or post-natally to nucleoside analogues. Manifestations of mitochondrial dysfunction include haematological disorders (anaemia, neutropenia), peripheral neuropathy and metabolic disorders (hyperlactataemia, lactic acidosis, hyperlipasaemia). Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). It is not known whether the neurological disorders are transient or permanent. Possible mitochondrial dysfunction should be considered in any newborn/infant/child exposed in utero to nucleoside or nucleotide analogues, including HIV negative infants/children who present with severe clinical findings of unknown etiology, particularly neurologic findings. Their babies/infants and children should have clinical, and laboratory follow up and be fully investigated for possible mitochondrial dysfunction.

Lactic acidosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of PRIPREMA, and tenofovir disoproxil fumarate, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with PRIPREMA should be suspended in any individual who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Clinical features of lactic acidosis are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/L) and the serum bicarbonate and respond as follows:

• Lactate 2 to 5 mmol/L with minimum symptoms: switch to medicines that are less likely to cause lactic acidosis.
• Lactate 5 to 10 mmol/L with symptoms and/or with reduced standard bicarbonate: Stop NRTIs and change treatment option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes, (e.g., sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism.
• Lactate > 10 mmol/L: STOP all therapy (80 % mortality). The above lactate values may not be applicable to paediatric patients.

Caution should be exercised when administering PRIPREMA to patients with known risk factors for liver disease.

Immune reactivation syndrome (IRS) / Immune reconstitution inflammatory syndrome (IRIS) Immune Reactivation Syndrome (IRS) 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 antiretroviral 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. IRS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4+ counts. Relevant examples include cytomegalovirus retinitis, generalised and/or focal mycobacterial and other infections such as tuberculosis, cryptococcal meningitis and Pneumocystis jirovecii pneumonia. Appropriate treatment of the opportunistic infections and diseases 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 IRS.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Patients with HIV-1 harbouring mutations PRIPREMA should not be started in antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation (see section 5.1)

Triple nucleoside therapy There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when tenofovir disoproxil was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen. Therefore, the same problems may be seen if PRIPREMA is administered with a third nucleoside analogue.

Opportunistic infections Patients receiving PRIPREMA 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.

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.

Nephrotoxicity A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofovir alafenamide cannot be excluded (see section 5.3).

Patients with end stage renal disease on chronic haemodialysis PRIPREMA should generally be avoided but may be used in adults with end stage renal disease (estimated CrCl u02c2 15 mL/min) on chronic haemodialysis with close monitoring for the risks (see section 4.2).

Co-administration of other medicines The co-administration of PRIPREMA is not recommended with certain anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbitone and phenytoin), antimycobacterials (e.g., rifampicin, rifabutin, rifapentine), boceprevir, St. Johnu2019s wort and HIV protease inhibitors (PIs) other than atazanavir, lopinavir and darunavir (see section 4.5). PRIPREMA should not be administered concomitantly with medicines containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine or adefovir dipivoxil.

Use in paediatrics The safety and efficacy of PRIPREMA in children younger than 12 years of age, or weighing u02c2 35 kg, have not been established. No data are available.

Use in elderly Studies in the elderly have not been conducted. However, dose selection for the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medicine therapy.

Interaction studies have only been performed in adults.

Emtricitabine In vitro and clinical pharmacokinetic interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicines is low. Co-administration of emtricitabine with medicines that are eliminated by active tubular secretion may increase concentrations of emtricitabine, and/or the co-administered medicine. Medicines that decrease renal function may increase concentrations of emtricitabine.

Tenofovir alafenamide Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Medicines that strongly affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption. Medicines that induce P-gp activity (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of PRIPREMA and development of resistance. Co-administration of PRIPREMA with other medicines that inhibit P-gp and BCRP activity (e.g., cobicistat, ritonavir, ciclosporin) is expected to increase the absorption of tenofovir alafenamide and xanthine oxidase inhibitors (e.g., febuxostat) is not expected to increase systemic exposure to tenofovir in vivo. Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6 in vitro. It is not an inhibitor or inducer of CYP3A in vivo. Tenofovir alafenamide is a substrate of OATP1B1 and OATP1B3 in vitro. The distribution of tenofovir alafenamide in the body may be affected by the activity of OATP1B1 and OATP1B3.

Other interactions Tenofovir alafenamide is not an inhibitor of human uridine diphosphate glucuronosyltransferase (UGT) 1A1 in vitro. It is not known whether tenofovir alafenamide is an inhibitor of other UGT enzymes. Emtricitabine did not inhibit the glucuronidation reaction of a non-specific UGT substrate in vitro.

Interactions between the individual components of PRIPREMA and other medicines

Medicine by therapeutic area Effect on medicine levels Recommendation concerning co-administration with PRIPREMA ANTI-INFECTIVES Antifungals Ketoconazole Itraconazole Interaction not studied with either of the components of PRIPREMA. Co-administration of ketoconazole or itraconazole, which are potent P-gp inhibitors, is expected to increase plasma concentrations of tenofovir alafenamide. The recommended dose of PRIPREMA is 200 mg/10 mg once daily.

Fluconazole Isavuconazole Interaction not studied with either of the components of PRIPREMA. Co-administration of fluconazole or isavuconazole may increase plasma concentrations of tenofovir alafenamide. Dose PRIPREMA according to the concomitant antiretroviral (see section 4.2).

Antimycobacterials Rifabutin Rifampicin Rifapentine Interaction not studied with either of the components of PRIPREMA. Co-administration of rifampicin, rifabutin and rifapentine, all of which are P-gp inducers, may decrease tenofovir alafenamide plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Co-administration of PRIPREMA and rifabutin, rifampicin or rifapentine is not recommended.

Anti-hepatitis C virus medicines Ledipasvir (90 mg once daily) Ledipasvir: AUC: Increases 79 % No dose adjustment of ledipasvir or sofosbuvir is required. Dose PRIPREMA according to the concomitant antiretroviral (see section 4.2).

Sofosbuvir (400 mg once daily) Emtricitabine (200 mg once daily) Alafenamide (10 mg once daily) C max: Increases 65 % C min: Increases 93 % Sofosbuvir: AUC: Increases 47 % C max: Increases 29 % Sofosbuvir metabolite GS-331007: AUC: Increases 48 % C max: No change C min: Increases 66 % Emtricitabine: AUC: No change C max: No change C min: No change Tenofovir alafenamide: AUC: No change C max: No change required. Dose PRIPREMA according to the concomitant antiretroviral (see section 4.2).

Ledipasvir (90 mg once daily) Ledipasvir: AUC: No change No dose adjustment of ledipasvir or sofosbuvir is required. Dose PRIPREMA according to the concomitant antiretroviral (see section 4.2).

Sofosbuvir (400 mg once daily) Emtricitabine (200 mg once daily) Alafenamide (25 mg once daily) C max: No change C min: No change Sofosbuvir: AUC: No change C max: No change Sofosbuvir metabolite GS-331007: AUC: No change C max: No change required. Dose PRIPREMA according to the concomitant antiretroviral (see section 4.2).

Sofosbuvir (400 mg once daily) Sofosbuvir: AUC: Increases 37 % No dose adjustment of sofosbuvir, velpatasvir or voxilaprevir is required. Dose PRIPREMA according to the concomitant antiretroviral (see section 4.2).

Velpatasvir (100 mg once daily) Emtricitabine (200 mg once daily) Alafenamide (10 mg once daily) C max: No change Sofosbuvir metabolite GS-331007: AUC: Increases 48 % C max: No change C min: Increases 58 % Velpatasvir: AUC: Increases 50 % C max: Increases 30 % C min: Increases 60 % Emtricitabine: AUC: No change C max: No change C min: No change Tenofovir alafenamide: AUC: No change C max: Decreases 20 % voxilaprevir is required. Dose PRIPREMA according to the concomitant antiretroviral (see section 4.2).

Sofosbuvir/Velpatasvir/Sofosbuvir: AUC: No change No dose adjustment of sofosbuvir, velpatasvir or voxilaprevir is required. Dose PRIPREMA according to the concomitant antiretroviral (see section 4.2).

Voxilaprevir (400 mg/100 mg/100 mg + 100 mg once daily) Emtricitabine (200 mg once daily)/Tenofovir alafenamide (10 mg once daily) C max: Increases 27 % Sofosbuvir metabolite GS-331007: AUC: Increases 43 % C max: No change Velpatasvir: AUC: Increases 50 % C min: Increases 46 % C max: No change Voxilaprevir: AUC: Increases 171 % C min: Increases 350 % C max: Increases 92 % Emtricitabine: AUC: No change C min: No change C max: No change Tenofovir alafenamide: voxilaprevir is required. Dose PRIPREMA according to the concomitant antiretroviral (see section 4.2).

AUC: No change C max: Decreases 21 % Sofosbuvir/Velpatasvir/Voxilaprevir (400 mg/100 mg/100 mg + 100 mg once daily) Emtricitabine (200 mg once daily)/Tenofovir alafenamide (25 mg once daily) Sofosbuvir: AUC: No change C max: No change Sofosbuvir metabolite GS-331007: AUC: No change C max: No change Velpatasvir: AUC: No change C min: No change C max: No change Voxilaprevir: AUC: No change C min: No change C max: No change Emtricitabine: AUC: No change No dose adjustment of sofosbuvir, velpatasvir or voxilaprevir is required. Dose PRIPREMA according to the concomitant antiretroviral (see section 4.2).

Pregnancy There are limited data in pregnant women. PRIPREMA should not be used during pregnancy (see section 4.3).

Lactation PRIPREMA should not be used by women breastfeeding their babies as possible harm to their babies cannot be excluded (see section 4.3). Emtricitabine is excreted in human milk and animal studies show that tenofovir is excreted in milk. In order to avoid transmission of HIV to the infant it is recommended that HIV infected women do not breastfeed their infants under any circumstances.

Fertility There are no data on fertility from the use of PRIPREMA in humans. In animal studies there were no effects of emtricitabine and tenofovir alafenamide on mating or fertility parameters.

PRIPREMA has a moderate influence on the ability to drive and use machines. PRIPREMA may affect the ability to drive and use machines. Patients should not drive and use machines until they know how treatment with PRIPREMA affects them. Patients should be informed that dizziness and fatigue have been reported during treatment with PRIPREMA.

Summary of the safety profile Assessment of adverse reactions based on safety data from studies performed in HIV infected patients who received medicines containing emtricitabine and tenofovir alafenamide, as in PRIPREMA, and from post-marketing experience showed that the most frequently reported adverse reactions were diarrhoea, nausea and headache.

Tabulated summary of adverse reactions

Blood and lymphatic system disorders Less frequent Anaemia. Psychiatric disorders Frequent Abnormal dreams. Nervous system disorders Frequent Headache, dizziness. Gastrointestinal disorders Frequent Nausea, diarrhoea, vomiting, abdominal pain, flatulence. Less frequent Dyspepsia. Skin and subcutaneous tissue disorders Frequent Rash. Musculoskeletal and connective tissue disorders Less frequent Arthralgia. General disorders and administration site conditions Frequent Fatigue.

Post marketing reported side effects Blood and lymphatic system disorders Anaemia. Psychiatric disorders Angiodema.

Description of selected adverse reactions Metabolic parameters u2013 Weight and levels of blood lipids and glucose may increase during PRIPREMA therapy. Paediatric population According to studies performed, the safety profile of emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat to adolescents was similar to that in adults.

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8). Treatment of overdose with PRIPREMA consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Emtricitabine Emtricitabine can be removed by haemodialysis, which removes approximately 30 % of the emtricitabine dose over a 3-hour dialysis period starting within 1,5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and dialysate flow rate of 600 mL/min). it is not known whether emtricitabine can be removed by peritoneal dialysis. Tenofovir alafenamide fumarate Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54 %.