Aspen Dolutegravir 50mg FC tablets

ASPEN DOLUTEGRAVIR 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
ASPEN DOLUTEGRAVIR therapy should be initiated by a medical practitioner experienced in the management of HIV infection.
Adults:
Treatment-nau00efve: For patients initiating antiretroviral therapy for the first time (treatment-nau00efve) the recommended dose of ASPEN DOLUTEGRAVIR 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 ASPEN DOLUTEGRAVIR is 50 mg once daily.
Integrase inhibitor resistant: For patients with integrase inhibitor resistance, the recommended dose of ASPEN DOLUTEGRAVIR is 50 mg twice daily.
Medicine interactions: Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir should be given to patients taking ASPEN DOLUTEGRAVIR. There is evidence that the concentration of isoniazid is increased by dolutegravir, as contained in ASPEN DOLUTEGRAVIR.
Special populations
Children
ASPEN DOLUTEGRAVIR should not be used in children.
Elderly population
There are limited data available on the use of ASPEN DOLUTEGRAVIR 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).
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). Treatment with ASPEN DOLUTEGRAVIR resulted in an early small increase of mean serum creatinine levels by 10 % to 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). ASPEN DOLUTEGRAVIR is contraindicated in patients with moderate or severe hepatic impairment (see section 4.3).
Method of administration
ASPEN DOLUTEGRAVIR is taken orally with or without food.

ASPEN DOLUTEGRAVIR is contraindicated in:
u2022 Patients with hypersensitivity to dolutegravir or to any excipients in ASPEN DOLUTEGRAVIR (see section 6.1).
u2022 Combination with dofetilide and pilsicainide (see section 4.5).
u2022 Moderate and severe hepatic impairment.
u2022 Metformin is contraindicated in patients taking ASPEN DOLUTEGRAVIR (see section 4.5).
u2022 Lactation (see section 4.6)
u2022 Women who plan to become pregnant, during peri/preconception period and in the first trimester of pregnancy (see section 4.6).
u2022 Women of child-bearing age not using highly effective contraception (see section 4.6).

Hypersensitivity
Hypersensitivity reactions have been reported with integrase inhibitors, including ASPEN DOLUTEGRAVIR and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue ASPEN DOLUTEGRAVIR and other suspect medicines immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, 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 ASPEN DOLUTEGRAVIR 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 (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-Barru00e9 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 ASPEN DOLUTEGRAVIR 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 coinfected 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.

Caution should be given to co-administering medicines (prescription and non-prescription) that may change the exposure of ASPEN DOLUTEGRAVIR or medicines that may have their exposure changed by ASPEN DOLUTEGRAVIR (see sections 4.3 and 4.5). The co-administration of ASPEN DOLUTEGRAVIR 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 ASPEN DOLUTEGRAVIR is 50 mg twice daily when co-administered with efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin (see section 4.5). ASPEN DOLUTEGRAVIR should not be co-administered with polyvalent cation-containing antacids. ASPEN 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 ASPEN DOLUTEGRAVIR. Metformin is contraindicated in patients taking ASPEN DOLUTEGRAVIR (see section 4.3).
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 ASPEN DOLUTEGRAVIR therapy, particularly in those whose anti-hepatitis B therapy was withdrawn.
Opportunistic infections
Patients receiving ASPEN DOLUTEGRAVIR 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. ASPEN DOLUTEGRAVIR should not be used in children.
Transmission of infection
Patients should be advised that current antiretroviral therapy, including ASPEN DOLUTEGRAVIR, 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.
Integrase class resistance of particular concern
The decision to use ASPEN DOLUTEGRAVIR in the presence of integrase class resistance should take into account that the activity of dolutegravir, as contained in ASPEN DOLUTEGRAVIR, is considerably compromised for viral strains harbouring Q148+u22652 secondary mutations from G140A/C/S, E138A/K/T, L74I (see section 5.1). To what extent ASPEN DOLUTEGRAVIR provides added efficacy in the presence of such integrase class resistance is uncertain (see section 5.2).

Women of childbearing potential
Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir, as in ASPEN DOLUTEGRAVIR, (see below), including consideration of using effective contraceptive measures. Perform pregnancy testing before initiation of ASPEN DOLUTEGRAVIR in women of childbearing potential to exclude inadvertent (unintentional) use of ASPEN DOLUTEGRAVIR during the first trimester of pregnancy. If a woman plans pregnancy, the benefits and the risks of starting or continuing treatment with dolutegravir, as in ASPEN DOLUTEGRAVIR, versus using another antiretroviral regimen should be discussed with her.
Pregnancy
ASPEN DOLUTEGRAVIR is contraindicated in mothers who plan to become pregnant, during peri/preconception period and in the first trimester of pregnancy (see section 4.3). Use of dolutegravir, as in ASPEN 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, as in ASPEN DOLUTEGRAVIR, the benefits and risks of continuing dolutegravir, as in ASPEN 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 in ASPEN DOLUTEGRAVIR, may be used during the second and third trimester of pregnancy when the expected benefit outweighs the potential risk to the foetus. Dolutegravir, as in ASPEN DOLUTEGRAVIR is 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
Mothers taking ASPEN DOLUTEGRAVIR should not breastfeed their babies. HIV infected women should not breastfeed their baby in order to avoid transmission of HIV to the baby or follow appropriate guidelines. Dolutegravir, as in ASPEN 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 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, as in ASPEN DOLUTEGRAVIR on human male or female fertility. Animal studies indicate no effects of dolutegravir on male or female fertility.

Patients should be informed that dizziness has been reported during treatment with ASPEN DOLUTEGRAVIR. The clinical status of the patient and the adverse event profile of ASPEN DOLUTEGRAVIR should be borne in mind when considering the patient's ability to drive or operate machinery. ASPEN DOLUTEGRAVIR may affect the ability to drive and use machines. Patients should not drive, use machinery or perform any tasks that require concentration until they are certain that ASPEN DOLUTEGRAVIR does not adversely affect their ability to do so safely (see section 4.8).

a) Summary of the safety profile
The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4). The most commonly seen treatment emergent adverse reactions were nausea, diarrhoea and headache.
b) Tabulated list of adverse reactions
System organ class Frequent Less frequent
Immune system disorders Hypersensitivity, Immune Reconstitution Syndrome (see section 4.4)
Psychiatric disorders Insomnia Depression, anxiety Suicidal ideation, suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness)
Nervous system disorders Headache, dizziness, abnormal dreams
Gastrointestinal disorders Nausea, diarrhoea, vomiting, flatulence, upper abdominal pain Abdominal pain, abdominal discomfort
Hepatobiliary disorders Hepatitis Acute hepatic failure
Skin and subcutaneous tissue disorders Rash, pruritus
Musculoskeletal and connective tissue disorders Arthralgia, myalgia
General disorders and administrative site conditions Fatigue
Investigations Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) elevations, Creatine phosphokinase (CPK) elevations
The safety profile was similar across the treatment nau00efve, treatment experienced (and integrase nau00efve) and integrase resistant patient populations.
c) Description of selected adverse reactions
Changes in laboratory chemistries Increases in serum creatinine occurred within the first week of treatment with ASPEN DOLUTEGRAVIR 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). Small increases in total bilirubin (without clinical jaundice) were observed on ASPEN DOLUTEGRAVIR and raltegravir (but not efavirenz) arms. These changes are not considered clinically relevant as they likely reflect competition between ASPEN DOLUTEGRAVIR and unconjugated bilirubin for a common clearance pathway (UGT1A1) (see section 5.2). Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with ASPEN DOLUTEGRAVIR therapy. 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 dolutegravir therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (see section 4.4). Immune reactivation syndrome In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (cART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).
Paediatric population
Based on limited available data in children and adolescents (6 to less than 18 years of age and weighing at least 15 kg), there were no additional types of adverse reactions beyond those observed in the adult population.
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: https://www.sahpra.org.za/health-products-vigilance/ Aspen Pharmacare: E-mail: [email protected] Tel: 0800 118 088

Symptoms
In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8).
Treatment
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 ASPEN DOLUTEGRAVIR. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As ASPEN DOLUTEGRAVIR is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.