Tivicay 5 Mg Dispersible Tablets

TIVICAY is indicated for the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral medicines in adults and children.

Posology: TIVICAY therapy should be initiated by a medical practitioner experienced in the management of HIV infection. TIVICAY can be taken with or without food. TIVICAY is available as film-coated tablets for patients aged at least 6 years and weighing at least 14 kg. TIVICAY is also available as dispersible tablets for patients aged at least 4 weeks and weighing at least 3 kg, or for patients in whom film-coated tablets are not appropriate. The bioavailability of film-coated tablets and dispersible tablets is not comparable therefore they must not be used as direct replacements (see section 5.2). For example, the recommended adult dose for film-coated tablets is 50 mg versus 30 mg for dispersible tablets. Patients changing between film-coated and dispersible tablets should follow the dosing recommendations that are specific for the formulation.

Dispersible Film-coated Tablets:

The dispersible tablets may be swallowed whole with drinking water or dispersed in drinking water. When dispersed, the amount of water will depend on the number of tablets prescribed. The tablet should not be chewed cut or crushed.

Method of administration:

TIVICAY 5mg Dispersible film-coated tablets:

Adults: Patients infected with HIV-1 without resistance to the integrase class: The recommended dose of TIVICAY 5 mg dispersible tablets is 30 mg once daily. Patients infected with HIV-1 with resistance to the integrase class (documented or clinically suspected): The recommended dose of dolutegravir dispersible tablets is 30 mg twice daily. The decision to use dolutegravir for such patients should be informed by the integrase resistance pattern.

Adolescents, children and infants aged at least 4 weeks and weighing at least 3 kg: Patients infected with HIV-1 without resistance to the integrase class: The recommended dose of TIVICAY dispersible tablets is determined according to weight and age and is presented in the table below.

Table 1a Dispersible tablet dose recommendations in adolescents, Children and infants aged at least 4 weeks and weighing at least 3 kg

Body Weight (kg) Dose

• 3 to less than 6: 5 mg once daily (taken as one 5 mg dispersible tablets)
• 6 to less than 10 < 6 months: 10 mg once daily (taken as two 5 mg dispersible tablets)
• u2265 6 months: 15 mg once daily (taken as three 5 mg dispersible tablets)
• 10 to less than 14: 20 mg once daily (taken as four 5 mg dispersible tablets)
• 14 to less than 20: 25 mg once daily (taken as five 5 mg dispersible tablets)
• 20 or greater: 30 mg once daily (taken as six 5 mg dispersible tablets)

Dispersible tablet dose recommendations in adolescents, children and infants aged at least 4 weeks and weighing at least 3 kg: There are insufficient safety and efficacy data available to recommend a dose for TIVICAY dispersible tablets in children below age 4 weeks or weighing less than 3 kg. Patients infected with HIV-1 with resistance to the integrase class: There are insufficient data to recommend a dose for TIVICAY dispersible tablets in integrase inhibitor resistant adolescents, children and infants.

Film-coated tablets:

Adults: Treatment-nau00efve: For patients initiating antiretroviral therapy for the first time (treatment-nau00efve) the recommended dose of TIVICAY 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 TIVICAY is 50 mg once daily.

Integrase inhibitor resistant: For patients with integrase inhibitor resistance, the recommended dose of TIVICAY is 50 mg twice daily.

Adolescents: In patients who have not previously been treated with an integrase inhibitor, (12 to less than 18 years of age and weighing greater than or equal to 40 kg) the recommended dose of TIVICAY film coated tablets is 50 mg once daily. There are insufficient data to recommend a dose for TIVICAY in integrase inhibitor resistant adolescents under 18 years of age.

Children aged at least 6 years and weighing at least 14 kg: In patients infected with HIV-1 without resistance to the integrase class, the recommended dose of TIVICAY film coated tablets in children (6 to less than 12 years of age) and weighing at least 14 kg is determined according to the weight of the child. Dose recommendations according to weight are presented in the table below:

Table 1b Film-coated tablet dose recommendations in children aged at least 6 years and weighing at least 14 kg

Body Weight (kg) Dose

• 14 to less than 20: 40 mg once daily (taken as four 10 mg film-coated tablets)
• 20 or greater: 50 mg once daily

To reduce the risk of choking, do not swallow more than one tablet at a time, and where possible, children weighing 14 to less than 20 kg should preferentially take the dispersible tablet formulation. There are insufficient safety and efficacy data available to recommend a dose for TIVICAY film-coated tablets in children aged less than 6 years of age or weighing less than 14 kg. TIVICAY film-coated tablets is not recommended for use in children under 6 years of age or weighing less than 14 kg.

There are insufficient data to recommend a dose for TIVICAY film-coated tablets in integrase inhibitor resistant children.

Missed doses: If the patient misses a dose of TIVICAY, the patient should take TIVICAY as soon as possible, providing the next dose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

Elderly: There are limited data available on the use of TIVICAY 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 TIVICAY 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). TIVICAY is contraindicated in patients with severe hepatic impairment (Child-Pugh grade C) (see section 4.3).

TIVICAY is contraindicated in combination with dofetilide and pilsicainide. TIVICAY is contraindicated in patients with known hypersensitivity to dolutegravir or to any of the excipients. TIVICAY is contraindicated in severe hepatic impairment (Child-Pugh grade C). TIVICAY is contraindicated in the first trimester of pregnancy (see Section 4.6).

Hypersensitivity reactions: Hypersensitivity reactions have been reported with integrase inhibitors, including TIVICAY and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue TIVICAY 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 TIVICAY 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: 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 are tuberculosis, cytomegalovirus retinitis, generalised and/or focal atypical mycobacterial infections and Pneumocystis jiroveci pneumonia (PJP). 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 TIVICAY 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, high 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 dolutegravir in the blood is doubled in patients with moderate hepatic impairment. TIVICAY is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh grade C) (see section 4.3). The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir have not been studied.

Caution should be given to co-administering medicines (prescription and non-prescription) that may change the exposure of TIVICAY or medicines that may have their exposure changed by TIVICAY (see sections 4.3 and section 4.5). The recommended adult dose of TIVICAY should be given twice daily when co-administered with etravirine (without boosted protease inhibitors), efavirenz, nevirapine, tipranavir/ritonavir, rifampicin, carbamazepine, phenytoin, phenobarbital and St. Johnu2019s wort (see section 4.5). In paediatric patients, the weight-based once daily dose should be administered twice daily. TIVICAY should not be co-administered with polyvalent cation-containing antacids. TIVICAY is recommended to be administered 2 hours before or 6 hours after these medicines (see section 4.5). TIVICAY is recommended to be administered 2 hours before or 6 hours after taking calcium or iron supplements, or alternatively, administered after food. TIVICAY increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping co-administration of TIVICAY with metformin, to maintain glycaemic control.

Co-infection with Hepatitis B or C: In Phase III studies, patients with hepatitis B and/or C co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C co-infection for all treatment groups. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C co-infection at the start of TIVICAY therapy, particularly in those whose anti-hepatitis B therapy was withdrawn.

Opportunistic infections: Patients receiving TIVICAY 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: Patients should be advised that current antiretroviral therapy, including TIVICAY, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.

Women of childbearing potential: Women of childbearing potential should be counseled 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 TIVICAY in women of childbearing potential to exclude inadvertent (unintentional) use of TIVICAY 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 at the time of conception 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 in small amounts. 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 TIVICAY should be borne in mind when considering the patient's ability to drive or operate machinery.

Clinical trial data: Adverse drug reactions (ADRs) identified in an analysis of pooled data from clinical studies are listed below by system organ class and by frequency. Frequencies are defined as: very common (u22651/10), common (u22651/100 and <1/10), uncommon (u22651/1 000 and <1/100 ), rare (u22651/10 000 and <1/1 000) and very rare (<1/10 000), including isolated reports.

Table 3: Adverse reactions

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

Psychiatric disorders: Common Insomnia Common Abnormal dreams Common Depression Common Anxiety Uncommon Suicide ideation or suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness)

Nervous system disorders: Very common Headache Common Dizziness

Gastrointestinal disorders: Very common Nausea Very common Diarrhoea Common Vomiting Common Flatulence Common Upper abdominal pain Uncommon Abdominal pain Uncommon Abdominal discomfort

Hepatobiliary disorders: Uncommon Hepatitis

Skin and subcutaneous tissue disorders: Common Rash Common Pruritus

General disorders and administration site conditions: Common Fatigue

The safety profile was similar across the treatment nau00efve, treatment experienced (and integrase nau00efve) and integrase resistant patient populations. Changes in laboratory chemistries: Increases in serum creatinine occurred within the first week of treatment with TIVICAY and remained stable through 48 weeks. In treatment nau00efve patients a mean change from baseline of 9,96 u03bc mol/u2113 (range: -53 u03bc mol/u2113 to 54,8 u03bc mol/u2113) 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 TIVICAY and raltegravir (but not efavirenz) arms in the programme. These changes are not considered clinically relevant as they likely reflect competition between TIVICAY 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 TIVICAY therapy.

Paediatric population: Based on limited available data in children and adolescents (6 to less than 18 years of age), there were no additional types of adverse reactions beyond those observed in the adult population.

Post-marketing data: Hepatobiliary disorders: acute hepatic failure (acute hepatic failure has been reported in a dolutegravir-containing regimen. The contribution of dolutegravir in these cases is unclear) Musculoskeletal and connective tissue disorders: arthralgia, myalgia Investigations: weight increased.

Reporting of 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.

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 TIVICAY. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As TIVICAY is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.