Jasupa 50 mg, 25 mg FC tablets

JASUPA is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults who are virologically suppressed (HIV-1 RNA < 50 copies/ml), for at least 6 months on a stable protease inhibitor (PI), integrase strand transfer inhibitor (INSTI) or non-nucleoside reverse transcriptase inhibitor (NRTI) plus nucleoside reverse transcriptase inhibitor (NRTI) based regimens, without known or suspected resistance to either antiretroviral component. Co-administration with any other NNRTI medicines is not recommended (see section 4.5).

Therapy should be initiated by a medical practitioner experienced in the management of HIV infection. If the patient misses a dose of JASUPA, the patient should take it with a meal as soon as they remember, if it is more than 12 hours until the next dose. If the next dose is due within 12 hours, the patient should skip the missed dose and resume the usual dosing schedule. Separate preparations of dolutegravir and rilpivirine should be used, where dose adjustment or discontinuation of one of the individual components is indicated (see section 4.5).

Adults: The recommended dose of JASUPA in adults is one tablet once daily, taken orally with a meal.

Adolescents and Children: JASUPA is not recommended in paediatric patients below 18 years of age due to insufficient safety and efficacy data.

Elderly: No dose adjustment of JASUPA is required in elderly patients. There are limited data available on the use of JASUPA in patients aged 65 years and over (see section 5.2 Special Patient Populations).

Renal impairment: No dosage adjustment of JASUPA is required in patients with renal impairment (see section 5.2 Special Patient Populations).

Hepatic impairment: No dosage adjustment of JASUPA is required in patients with mild hepatic impairment (Child-Pugh score A). JASUPA is contraindicated in severe hepatic impairment (Child-Pugh score B and C) (see section 4.3 and section 5.2 Special Patient Populations).

JASUPA is contraindicated in patients with known hypersensitivity to dolutegravir or rilpivirine or to any of the excipients of JASUPA listed in section 6.1. JASUPA is contraindicated in patients with severe hepatic impairment. JASUPA is contraindicated in combination with the following (see section 4.5):

• products with narrow therapeutic windows, that are substrates of organic cation transporter 2 (OCT2), including but not limited to antidysrhythmic medicines dofetilide or pilsicainide, or the potassium channel blocker fampridine (also known as dalfampridine).
• anticonvulsants carbamazepine, oxcarbazepine, phenobarbitone, phenytoin
• antimycobacterials rifampicin, rifapentine
• proton pump inhibitors (such as omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole)
• glucocorticoid systemic dexamethasone (except as a single dose treatment)
• St Johnu2019s wort (Hypericum perforatum)
• Pre and peri-conception period, during the first trimester of pregnancy and lactation (see section 4.6).

Safety and efficacy of the individual active ingredients in various ART combination regimes with similar dosages as contained in JASUPA have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the actives combined in a fixed drug combination (FDC) as in JASUPA have not been established.

Hypersensitivity reactions: Hypersensitivity reactions have been reported with integrase inhibitors, including dolutegravir as in JASUPA and were characterised by rash, constitutional findings, and sometimes, organ dysfunction, including liver injury. JASUPA and other suspected medicines should be discontinued immediately, if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping treatment with JASUPA or other suspect medicines after the onset of hypersensitivity may result in a life-threatening reaction.

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 Syndrome (IRIS): In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples of IRIS include tuberculosis, cytomegalovirus retinitis, generalised and/or focal atypical mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Auto-immune disorders (such as Gravesu2019 disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable and can occur many months after initiation of treatment and sometimes can be an atypical presentation.

Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of JASUPA therapy. Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B co-infected patients (see section 4.8).

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.

Patients with HIV and hepatitis B or C virus co-infection: 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. Medical practitioners should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant professional information for these medicines. Patients co-infected with HIV and HBV who discontinue JASUPA should be closely monitored with both clinical and laboratory follow-up 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.

Caution should be given to prescribing JASUPA with medicines that may reduce the exposure of dolutegravir or rilpivirine (see section 4.5). Opportunistic infections: Patients receiving JASUPA or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by medical practitioners experienced in the treatment of these associated HIV diseases. Transmission of infection: While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Safety in pregnancy and lactation has not been established. Women of childbearing potential: Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir, as contained in JASUPA,), including consideration of using effective contraceptive measures. Perform pregnancy testing before initiation of JASUPA in women of childbearing potential to exclude inadvertent (unintentional) use of JASUPA during the first trimester of pregnancy. If a woman plans pregnancy, the benefits and the risks of starting or continuing treatment with dolutegravir versus using another antiretroviral regimen should be discussed with her.

Pregnancy: JASUPA is contraindicated in pre/periconception period and in the first trimester of pregnancy (see section 4.3). Women of childbearing age should not use JASUPA, unless they are on highly effective contraception. Treatment with JASUPA should not be started without a medically/laboratory supervised negative pregnancy (urine and/or blood) test, repeated at frequent intervals as needed.

There is some evidence of neural tube defects with the use of dolutegravir, as contained in JASUPA, if started at the time of conception or in early pregnancy. Use of dolutegravir, as contained in JASUPA, during pregnancy, was associated with a small increase in the prevalence of neural tube defects (0.19%) compared to non-dolutegravir regimens (0.11%). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period).

JASUPA should not be prescribed to women who plan to become pregnant. If a pregnancy is confirmed in the first trimester while on dolutegravir, as contained in JASUPA, the benefits and risks of continuing dolutegravir versus switching to another antiretroviral regimen should be discussed with the patient, taking the gestational age and the critical time period of neural tube defect development into account.

Dolutegravir, as contained in JASUPA, may be used during the second and third trimester of pregnancy when the expected benefit outweighs the potential risk to the foetus. Dolutegravir was shown to cross the placenta in humans, leading to significant exposure to the foetus (see next paragraph below), but the implications of such exposure are not yet known.

Dolutegravir readily crosses the placenta in humans. In HIV-infected pregnant women, the median (range) foetal umbilical cord concentrations of dolutegravir were 1.28 (1.21 to 1.28) fold greater compared with maternal peripheral plasma concentrations. There is insufficient information on the effects of dolutegravir on neonates.

Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 pregnant women during the second and third trimesters, and postpartum. The pharmacokinetic data demonstrate that total exposure (AUC) to rilpivirine as a part of an antiretroviral regimen was approximately 30 % lower during pregnancy compared with postpartum (6-12 weeks).

Studies in rats and rabbits with rilpivirine have shown no evidence of relevant embryonic or foetal toxicity, effect on reproductive function, or teratogenicity.

JASUPA may affect the ability to drive and use machines. Patients should ensure that they do not engage in driving or operating machines until they know how JASUPA affects them.

JASUPA contains dolutegravir plus rilpivirine, therefore the adverse drug reactions (ADRs) associated with these individual components may be expected (Table 2). Side effects are listed below by MedDRA system organ class and by frequency. Frequencies are defined as: very common (u2265 1/10), common (u2265 1/100 and < 1/10), uncommon (u2265 1/1 000 and < 1/100), rare (u2265 1/10 000 and < 1/1 000) and very rare (< 1/10 000), including isolated reports.

The ADRs observed for dolutegravir plus rilpivirine in analysis of data from clinical trials were consistent with the ADR profiles and severities for the individual components when administered with other antiretroviral agents. No additional ADRs or increased frequency or severity of ADRs were observed with the combination of dolutegravir plus rilpivirine. Treatment-emergent ADRs observed in at least 2 % of subjects in either treatment arm of the pooled analysis of these studies were diarrhoea and headache.

Table 2 Side Effects with the Individual Components of JASUPA

System Frequency* Dolutegravir (DTG) Rilpivirine (RPV) Immune system disorders Uncommon Hypersensitivity (see section 4.4 Special warnings and precautions for use), Immune Reconstitution Syndrome Metabolism and nutrition disorders Common Decreased appetite Psychiatric disorders Common Insomnia, abnormal dreams, depression, anxiety Depression, insomnia, abnormal dreams, sleep disorders Uncommon Suicidal ideation or suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness) Depressed mood Nervous system disorders Very common Headache Common Dizziness Headache, dizziness Uncommon Somnolence Gastrointestinal disorders Very common Nausea, diarrhea Common Abdominal pain Vomiting Flatulence Upper abdominal pain Abdominal discomfort Abdominal pain Nausea Vomiting Uncommon Abdominal discomfort Hepatobiliary disorders Uncommon Hepatitis

Changes in laboratory chemistries: Increases in serum creatinine occurred within the first four weeks of treatment with dolutegravir plus rilpivirine and remained stable through 48 weeks. A mean change from baseline of 8,22 u03bcmol/u2113 (range: -26,5 u03bcmol/u2113 to 51,2 u03bcmol/u2113) was observed after 48 weeks of treatment. These changes are related to inhibition of active transport and are not considered to be clinically relevant as they do not reflect a change in glomerular filtration rate (see section 5.1 Effects on Renal Function).

Small increases in total bilirubin (without clinical jaundice) were observed with dolutegravir plus rilpivirine. These changes are not considered clinically relevant as they likely reflect competition between dolutegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1) (see section 5.2 Metabolism).

Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported. No clinically relevant differences in lipid profiles were noted throughout the 48 weeks in either treatment group.

Co-infection with Hepatitis B or C: A higher incidence of liver chemistry elevations (Grade 1) were observed in patients treated with dolutegravir and rilpivirine co-infected with hepatitis C compared to those who were not co-infected. Dolutegravir plus rilpivirine has not been studied in patients with hepatitis B co-infection.

Post-marketing data: In addition to the side effects included from clinical trial data, below are side effects identified during post-approval use of dolutegravir in combination with other antiretroviral agents. These events have been chosen for inclusion due to a potential causal connection to dolutegravir. Musculoskeletal and connective disorders: arthralgia, myalgia Investigations: weight increased. The following event has been reported in a dolutegravir-containing regimen. The contribution of dolutegravir in this case is unclear. Hepatobiliary disorders: acute hepatic failure.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u20186.04 Adverse Drug Reactions Reporting Formu2019, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Experience with overdose of JASUPA, or the individual components, dolutegravir and rilpivirine is limited. Management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for overdose with JASUPA. If overdose occurs, the patient should be treated supportively with appropriate monitoring, vital signs and observation of the clinical status of the patient, as necessary. As dolutegravir and rilpivirine are highly bound to plasma proteins, it is unlikely they will be significantly removed by dialysis.