Teralavid 50 mg Fim-coated tablets

TERALAVID is indicated for the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral medicines in adults aged 18 years and older.

Posology: TERALAVID therapy should be initiated by a medical practitioner experienced in the management of HIV infection. TERALAVID can be taken with or without food.

Adults: Treatment-nau00efve: For patients initiating antiretroviral therapy for the first time (treatment-nau00efve), the recommended dose of TERALAVID is 50 mg once daily. Treatment-experienced, and integrase inhibitor nau00efve: For patients who are treatment experienced and have not previously been treated with an integrase inhibitor, the recommended dose of TERALAVID is 50 mg once daily. Integrase inhibitor resistant: For patients with integrase inhibitor resistance, the recommended dose of TERALAVID is 50 mg twice daily. Elderly: There are limited data available on the use of TERALAVID in patients aged 65 years and over. However, there is no evidence that elderly patients require a different dose than younger adult patients (see section 5.2, Special Patient Populations). Renal impairment: No dosage adjustment is required in patients with mild, moderate or severe (CrCl < 30 ml/min, not on dialysis) renal impairment. No data are available in subjects receiving dialysis, although differences in pharmacokinetics are not expected in this population (see section 5.2, Special Patient Populations). Treatment with dolutegravir has been found to result in an early small increase of mean serum creatinine levels by 10 - 14 %, which was found to remain stable over time and is not considered clinically relevant (see section 4.8). Hepatic impairment: No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh grade A or B).

TERALAVID is contraindicated in patients with known hypersensitivity to dolutegravir or to any of the excipients. TERALAVID is contraindicated in combination with dofetilide and pilsicainide. TERALAVID is contraindicated in moderate and severe hepatic impairment. Metformin is contraindicated in patients taking TERALAVID. TERALAVID is contraindicated in the first trimester of pregnancy.

Hypersensitivity reactions: Hypersensitivity reactions have been reported with integrase inhibitors, including dolutegravir, the active component of TERALAVID, and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue TERALAVID and other suspect medicines 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. A delay in stopping treatment with TERALAVID or other suspect medicines after the onset of hypersensitivity may result in a life-threatening reaction.

Lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy (cART) 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: 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). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Hepatic impairment: The unbound fraction of TERALAVID in the blood is doubled in patients with moderate hepatic impairment. TERALAVID is contraindicated in patients with moderate or severe hepatic impairment (see section 4.3).

Interactions: Caution should be given to co-administering medicines (prescription and non-prescription) that may change the exposure of TERALAVID or medicines that may have their exposure changed by TERALAVID (see sections 4.3 and 4.5).

Caution should be given to co-administering medicines (prescription and non-prescription) that may change the exposure of TERALAVID or medicines that may have their exposure changed by TERALAVID (see sections 4.3 and 4.5). The co-administration of TERALAVID with etravirine (ETR) is not recommended, unless the patient is also receiving concomitant atazanavir and ritonavir (ATV + RTV), lopinavir and ritonavir (LPV + RTV) or darunavir and ritonavir (DRV + RTV) (see section 4.5). The recommended dose of TERALAVID is 50 mg twice daily when co-administered with efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin (see section 4.5). TERALAVID should not be co-administered with polyvalent cation-containing antacids. TERALAVID is recommended to be administered 2 hours before or 6 hours after these medicines (see section 4.5). Metformin concentrations may be increased by TERALAVID. Metformin is contraindicated in patients taking TERALAVID (see section 4.3).

Women of childbearing potential: Women of childbearing potential should be counselled about the potential risk of neural tube defects with TERALAVID (see below), including consideration of using effective contraceptive measures. Perform pregnancy testing before initiation of TERALAVID in women of childbearing potential to exclude inadvertent (unintentional) use of TERALAVID during the first trimester of pregnancy. If a woman plans pregnancy, the benefits and the risks of starting or continuing treatment with TERALAVID versus using another antiretroviral regimen should be discussed with her.

Pregnancy: Use of dolutegravir 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). If a pregnancy is confirmed in the first trimester while on TERALAVID, 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. TERALAVID 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, but the implications of such exposure are not yet known.

Breastfeeding: HIV infected women should not breastfeed their infants in order to avoid transmission of HIV. Dolutegravir is excreted in human breast milk, and there is significant exposure to the neonate/infant due to slow elimination; the half-life of dolutegravir in the newborn was 33 hr compared to 14 hr in the adults. There is insufficient information on the effects of dolutegravir in neonates/infants.

Fertility: There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no effects of dolutegravir on male or female fertility.

TERALAVID can cause undesirable effects (including headache, dizziness, fatigue), which may affect the ability to drive and operate machines. Patients should be advised not to engage in driving or operating machines until they know how TERALAVID might affect them.

Immune system disorders: Less frequent: Hypersensitivity (see section 4.4), Immune Reconstitution Syndrome (see section 4.4).

Psychiatric disorders: Frequent: Insomnia. Frequency unknown: Anxiety.

Nervous system disorders: Frequent: Headache, dizziness, abnormal dreams.

Gastrointestinal disorders: Frequent: Nausea, diarrhoea, vomiting, flatulence, upper abdominal pain. Less frequent: Abdominal pain, abdominal discomfort.

Hepato-biliary disorders: Frequent: Hepatitis. Frequency unknown: Acute liver failure, hepatotoxicity.

Skin and subcutaneous tissue disorders: Frequent: Rash, pruritus.

Musculoskeletal and connective tissue disorders: Frequency unknown: Arthralgia, myalgia.

General disorders and administration site conditions: Frequent: Fatigue.

Investigations: Frequency unknown: Weight increased.

Changes in laboratory chemistries: Increases in serum creatinine occurred within the first week of treatment with dolutegravir (the active component of TERALAVID) and remained stable through 48 weeks. In treatment nau00efve patients a mean change from baseline of 9.96 u03bcmol/l (range: -53 u03bcmol/l to 54.8 u03bcmol/l) was observed after 48 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment experienced patients. These changes are not considered to be clinically relevant since 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 on dolutegravir and raltegravir (but not efavirenz) arms in the programme. 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 with dolutegravir therapy.

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 u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of TERALAVID. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As TERALAVID is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.