Volutrip Tablets

The VOLUTRIP is a triple combination therapy which is indicated for the treatment of human immunodeficiency virus (HIV) infection in adults aged 18 years and older.

Posology
Therapy should be initiated by a medical practitioner experienced in the management of HIV infection.

Adults:
The dose of VOLUTRIP is one tablet taken orally, once daily, without regard to food.

Special populations
Renal impairment: Significantly increased exposure occurred when tenofovir, as in VOLUTRIP , was administered to patients with moderate to severe renal impairment (see section 4.3). The pharmacokinetics of tenofovir, as in VOLUTRIP , have not been evaluated in non-haemodialysis patients with creatinine clearance u02c2 80 ml/min); therefore, no dosing recommendations is available for these patients.

VOLUTRIP is not suitable for use in patients with renal impairment with creatinine clearance less than 50 ml/min.

For treatment-nau00efve and treatment experienced patients the recommended dose of VOLUTRIP is one tablet once daily.

VOLUTRIP tablets are contra-indicated in patients with known hypersensitivity to lamivudine, tenofovir or dolutegravir or to any of the components of the tablets.

Impairment of renal function.

Pregnancy and lactation (see section 4.6).

Women of child-bearing age not using highly effective contraception.

Concomitant use with adefovir dipivoxil.

Co-administration with dofetilide and pilsicainide.

Co-administration with didanosine.

Co-administration with metformin.

Patients younger than 18 years of age.

Moderate and severe hepatic impairment.

WARNING
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS AND SPECIAL PRECAUTIONS).

VOLUTRIP IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION. THE SAFETY AND EFFICACY OF VOLUTRIP HAS NOT BEEN ESTABLISHED IN PATIENTS CO-INFECTED WITH HBV AND HIV. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED WITH HBV AND HIV AND HAVE DISCONTINUED THE COMBINATION TABLET. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE VOLUTRIP AND ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS AND SPECIAL PRECAUTIONS).

Safety and efficacy of the individual active ingredients in various antiretroviral combination regimens with similar dosages as contained in VOLUTRIP have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the fixed-drug combination as in VOLUTRIP for the treatment of HIV has not been established in clinical studies.

Metabolic abnormalities
Combination antiretroviral therapy, including VOLUTRIP has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.

Lipodystrophy
Combination antiretroviral therapy, including VOLUTRIP , has also been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat enlargement (buffalo hump), peripheral wasting, facial wasting and breast enlargement in HIV patients. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicine related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Fasting serum lipids and blood glucose levels should be monitored. Lipid disorders should be managed as clinically appropriate. Patients with evidence of lipodystrophy should also have a thorough cardiovascular risk assessment.

Immune Reconstitution Inflammatory 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 reactions present 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, atypical mycobacterial infections, cytomegalovirus retinitis, Pneumocystis jirovecii, 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. Autoimmune disorders (such as Gravesu2019 disease, Guillain-Barre Syndrome, Polymyositis) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

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), including components of VOLUTRIP . 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 VOLUTRIP may continue to develop opportunistic infections and other complications of HIV infection and therefore patients should remain under close clinical observation by doctors experienced in the treatment of patients with HIV associated diseases.

The risk of HIV transmission to others:
Patients should be advised that treatment with VOLUTRIP , 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.

Lactic acidosis/severe hepatomegaly with steatosis:
Lactic acidosis, usually associated with hepatic steatosis, including fatal cases, has been reported with the use of nucleoside analogues, such as in VOLUTRIP . Early symptoms (symptomatic hyperlactataemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure or renal failure.

Lactic acidosis generally occurs after a few or several months of treatment. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels. Suspicious biochemical features include mild raised transaminases, raised lactate dehydrogenase (LDH) and/or creatine kinase. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/L) and respond as follows:
- Lactate 2-5 mmol/L: monitor regularly and be alert for clinical signs.
- Lactate 5-10 mmol/L without symptoms, monitor closely.
- Lactate 5-10 mmol/L with symptoms: STOP all therapy. Exclude - other causes (e.g. sepsis, uraemia, diabetic ketoacidosis, hyperthyroidism, lymphoma).
- Lactate > 10 mmol/L: STOP all therapy (80 % mortality in case studies).

The above lactate values may not be applicable to paediatric patients. Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased anion gap and raised lactate level. Therapy should be stopped in any acidotic patient with a raised lactate level. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases have been reported with the use of VOLUTRIP alone or in combination, in the treatment of HIV infection. Most cases were women. Caution should be exercised when administering VOLUTRIP to patients with known risk factors for liver disease.

Treatment with VOLUTRIP should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatoxicity. Caution should be exercised when administering nucleoside analogues as contained in VOLUTRIP to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicines and alcohol). Patients co-infected with Hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely. However, cases have also been reported in patients with no known risk factors.

Patients at increased risk should be followed closely.

There are no study results demonstrating the effect of VOLUTRIP on clinical progression of HIV-1.

Caution should be given to co-administering medications (prescription and non-prescription) that may change the exposure of dolutegravir or medications that may have their exposure changed by dolutegravir ( see sections 4.3 and 4.5u201d).

The co-administration of 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 dolutegravir is 50 mg twice daily when co-administered with efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin (see section 4.5). Dolutegravir 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 dolutegravir. Metformin is contra-indicated in patients taking dolutegravir (see section 4.3).

Women of childbearing potential / Contraception in males and females
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 VOLUTRIP in women of childbearing potential to exclude inadvertent (unintentional) use of VOLUTRIP 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
VOLUTRIP is contraindicated in pregnancy and lactation (see section 4.3). 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.

Tenofovir, dolutegravir and lamivudine were shown to cross the placenta in reproductive toxicity studies in animals. Late onset neurological disorders, including seizures, have been observed in children who have been exposed to nucleoside analogues in utero such as tenofovir and lamivudine, (see Mitochondrial Dysfunction under section 4.4).

VOLUTRIP should not be prescribed in women who plan to become pregnant. Women of childbearing age should not use VOLUTRIP unless they are reliably using highly effective contraception. Treatment with VOLUTRIP should not be initiated without a medically supervised negative pregnancy test. This test should be repeated at frequent intervals during treatment with VOLUTRIP ; and especially in the event that pregnancy is suspected.

Breastfeeding
HIV infected women should not breast-feed their infants in order to avoid transmission of HIV or follow appropriate guidelines. Tenofovir is excreted in breast milk. 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.

Lamivudine is excreted in human milk at similar concentrations to those found in serum.

VOLUTRIP may affect the ability to drive and use machines as it may cause dizziness and drowsiness. Patients should ensure that they do not engage in driving or using machines until they know how VOLUTRIP affects them.

a) Summary of the safety profile
Studies revealed the most severe adverse reactions linked to dolutegravir treatment are hypersensitivity reactions that include rash and severe liver effects. The most common adverse reactions of dolutegravir are nausea (13 %), diarrhoea (18 %) and headache (13%).

Renal impairment, renal failure and proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported rarely in patients receiving tenofovir disoproxil. Monitoring of renal function is recommended for patients receiving VOLUTRIP (see section 4.4).

b) Tabulated list of adverse reactions
u2022 Frequency not known- cannot be estimated from the available data.

Signs and symptoms:
If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), and standard supportive treatment applied as necessary.

Tenofovir disoproxil fumarate:
If overdose occurs the patient must be monitored for evidence of toxicity and palliative supportive treatment be applied as necessary. Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 ml/min. The elimination of tenofovir by peritoneal dialysis has not been studied.

Lamivudine:
Limited data are available on the consequences of ingestion of acute overdose in humans. If overdosage occurs the patient should be monitored, and palliative supportive treatment applied as required.

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