Vidoteg Tedotig 144.4 mg FC tablet

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

[PRODUCT NAME] therapy should be initiated by a medical practitioner experienced in the management of HIV infection. [PRODUCT NAME] can be taken with or without food. Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir should be given to patients taking [PRODUCT NAME]. There is evidence that the concentration of isoniazid is increased by dolutegravir, as contained in [PRODUCT NAME].

Adults: Treatment-naive: For patients initiating antiretroviral therapy for the first time (treatment-naive) the recommended dose of [PRODUCT NAME] 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 [PRODUCT NAME] is 50 mg once daily. Integrase inhibitor resistant: For patients with integrase inhibitor resistance, the recommended dose of [PRODUCT NAME] is 50 mg twice daily. Elderly: There are limited data available on the use of [PRODUCT NAME] 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 (CrCI< 30 ml/min, not on dialysis) renal impairment. No data are reported in subjects receiving dialysis, although differences in pharmacokinetics are not expected in this population (see section 5.2 - Special Patient Populations). Treatment with [PRODUCT NAME] resulted in an early small increase of mean serum creatinine levels by 10-14 % which remained 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). [PRODUCT NAME] is contra-indicated in patients with moderate or severe hepatic impairment (see section 4.3).

• [PRODUCT NAME] is contraindicated in patients with known hypersensitivity to dolutegravir or to any of the excipients.
• [PRODUCT NAME] is contraindicated in moderate and severe hepatic impairment.
• [PRODUCT NAME] is contraindicated in combination with dofetilide and pilsicainide.
• Metformin is contraindicated in patients taking [PRODUCT NAME].

Hypersensitivity reactions: Hypersensitivity reactions have been reported with integrase inhibitors, including [PRODUCT NAME] and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue [PRODUCT NAME] 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. Delay in stopping treatment with [PRODUCT NAME] 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 Inflammatory Syndrome: 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 reported within the first few weeks or months of initiation of ART. Relevant examples are 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. 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.

Auto-immune disorders (such as Graves' 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 reported in some hepatitis B and/or C co-infected patients at the start of [PRODUCT NAME] 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.

Opportunistic infections: Patients receiving [PRODUCT NAME] 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.

The risk of HIV transmission to others: Patients should be advised that current antiretroviral therapy, including [PRODUCT NAME], does not prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Hepatic impairment: The unbound fraction of dolutegravir in the blood is doubled in patients with moderate hepatic impairment. [PRODUCT NAME] is contra-indicated 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 [PRODUCT NAME] or medicines that may have their exposure changed by [PRODUCT NAME] (see section 4.3 and 4.5). The co-administration of [PRODUCT NAME] with etravirine (ETR) is not recommended unless the patient is also receiving concomitant atazanavir + ritonavir (ATV + RTV), lopinavir + ritonavir (LPV + RTV) or darunavir + ritonavir (DRV + RTV) (see section 4.5). The recommended dose of [PRODUCT NAME] is 50 mg twice daily when co-administered with efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin (see section 4.5). [PRODUCT NAME] should not be co-administered with polyvalent cation-containing antacids. Dolutegravir is recommended to be administered 2 hours before or 6 hours after these medicines (see section 4.5). Metformin concentrations may be increased by [PRODUCT NAME]. Metformin is contraindicated in patients taking [PRODUCT NAME] (see section 4.3).

Women of childbearing potential: Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir (see below), including consideration of using effective contraceptive measures. Perform pregnancy testing before initiation of [PRODUCT NAME] in women of childbearing potential to exclude inadvertent (unintentional) use of [PRODUCT NAME] 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: 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 dolutegravir, 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 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 breast-feed their infants in order to avoid transmission of HIV or follow appropriate guidelines. Dolutegravir is excreted in human breast milk, and there is significant exposure to the neonate/infants due to slow elimination; the half-life of dolutegravir in the new born 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.

The clinical status of the patient and the adverse event profile of [PRODUCT NAME] should be borne in mind when considering the patient's ability to drive or operate machinery. [PRODUCT NAME] 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 [PRODUCT NAME] affects them.

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

Psychiatric disorders: Frequent Insomnia Frequent Depression Frequent Headache

Nervous system disorders: Frequent Dizziness Frequent Abnormal dreams

Gastrointestinal disorders: Frequent Nausea Frequent Diarrhoea Frequent Vomiting Frequent Flatulence Frequent Upper abdominal pain Less frequent Abdominal pain Less frequent Abdominal discomfort

Hepatobiliary disorders: Less frequent Hepatitis

Skin and subcutaneous tissues: Frequent Rash Frequent Pruritus

General disorders and administration site conditions: Frequent Fatigue

Investigations: Frequent Increased AST, ALT, CPK, bilirubin

The safety profile was reported to be similar across the treatment nau00efve, treatment experienced (and integrase nau00efve) and integrase resistant patient populations. Description of changes in laboratory chemistry: Increases in serum creatinine: Increases in serum creatinine occurred within the first week of treatment with [PRODUCT NAME] 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 reported 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). Increases in total bilirubin: Small increases in total bilirubin (without clinical jaundice) were reported with [PRODUCT NAME] and raltegravir (but not efavirenz). These changes are not considered clinically relevant as they likely reflect competition between [PRODUCT NAME] and unconjugated bilirubin for a common clearance pathway (UGT1A1) [see section 5.2- Metabolism]. Increase in creatine phosphokinase (CPK): Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with [PRODUCT NAME] therapy. Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care 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 [PRODUCT NAME]. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As [PRODUCT NAME] is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.