Vulante FC tablets

VULANTE is indicated in adults aged 18 years and older for :

• The treatment of human immunodeficiency virus (HIV - 1) infection.

Posology

VULANTE therapy should be initiated by a medical practitioner experienced in the management of HIV infection.

Adults

The dose of VULANTE is one tablet taken orally, once daily, without regard to food. For treatment-nau00efve and treatment experienced patients, the recommended dose of VULANTE is one tablet daily. Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir should be given to patients taking VULANTE. There is evidence that the concentration of isoniazid is increased by dolutegravir, as in VULANTE.

Special populations

Elderly population

There are limited data available on the use of dolutegravir in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients. Special care is advised in this age group due to age-associated changes such as the decrease in renal function and alteration of haematological parameters.

Renal impairment

VULANTE is contraindicated in patients with renal impairment with creatinine clearance less than 80 mL/min) (see section 4.3, 4.4 and 5.2). Significantly increased exposure occurred when tenofovir, as in VULANTE, was administered to patients with renal impairment (see section 4.3). The pharmacokinetics of tenofovir, as in VULANTE, has not been evaluated in non-haemodialysis patients with creatinine clearance < 80 mL/min; therefore, no dosing recommendations are available for these patients. Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir should be given to patients taking VULANTE (see section 4.5).

Hepatic impairment

VULANTE is contraindicated in patients with moderate or severe hepatic impairment (see section 4.3).

Paediatric population

VULANTE is not recommended for use in patients younger than 18 years of age (see section 4.3).

Method of administration

For oral administration (see section 4.2)

VULANTE is contraindicated in:

• Patients with hypersensitivity to dolutegravir, lamivudine or tenofovir or to any of the excipients in VULANTE (see section 6.1).
• Concomitant use with adefovir dipivoxil.
• Co-administration with dofetilide and pilsicainide.
• Co-administration with didanosine.
• Co-administration with metformin (see section 4.5).
• Moderate and severe hepatic impairment.
• Impairment of renal function (see sections 4.2, 4.4 and 5.2).
• Patients younger than 18 years of age.
• Women of child-bearing age not using highly effective contraception (see section 4.6).
• Women planning to become pregnant, are pregnant or breastfeeding their babies (see section 4.6).

WARNINGS

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 SECTION 4.4). VULANTE IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION. THE SAFETY AND EFFICACY OF VULANTE HAVE NOT BEEN ESTABLISHED IN PATIENTS CO-INFECTED WITH HBV AND HIV. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS CO-INFECTED WITH HBV AND HIV WHO 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 VULANTE AND ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE, RESUMPTION OR INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE SECTION 4.4).

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

The complete professional information of the other medicines used in combination should be consulted before initiation of therapy.

Hypersensitivity reactions to dolutegravir

Hypersensitivity reactions have been reported with integrase inhibitors, such as dolutegravir included in VULANTE and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue VULANTE 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) (see section 4.8). Clinical status including liver aminotransferases and bilirubin should be monitored and appropriate therapy initiated. Delay in stopping treatment with VULANTE or other suspect medicines after the onset of hypersensitivity may result in a life-threatening allergic reaction.

Metabolic abnormalities

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

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No medicine interaction studies have been conducted using VULANTE. As VULANTE contains dolutegravir, tenofovir disoproxil fumarate and lamivudine, any interactions that have been identified with these individual medicines may occur with VULANTE. Important medicine interaction information for VULANTE is summarised in Tables 2 and 3. The medicine interactions described are based on studies conducted with dolutegravir, tenofovir disoproxil fumarate or lamivudine as individual medicines, or are potential medicine interactions. While the tables include potentially significant interactions, they are not all inclusive.

Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450-mediated interactions involving tenofovir with other medicines is low. An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40 % increase in lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment. Administration of co-trimoxazole with the lamivudine/zidovudine combination in patients with renal impairment should be carefully assessed.

Renally eliminated medicines

Tenofovir, as in VULANTE, is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Co-administration of VULANTE with medicines that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir or the co-administered medicines due to competition for this elimination pathway. Medicines that decrease renal function may also increase serum concentrations of tenofovir, as in VULANTE.

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Women of childbearing potential

Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir (see below), as in VULANTE, including consideration of using effective contraceptive measures.

Perform pregnancy testing before initiation of VULANTE in women of childbearing potential to exclude inadvertent (unintentional) use of VULANTE 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 VULANTE, versus using another antiretroviral regimen should be discussed with her.

Pregnancy

Use of dolutegravir, as in VULANTE, 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 VULANTE, the benefits and risks of continuing dolutegravir, as in VULANTE, 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 VULANTE, 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 VULANTE, 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.

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VULANTE has a minor influence on the ability to drive and use machines. VULANTE 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 VULANTE affects them. Since adverse reactions such as dizziness have been reported in patients receiving VULANTE, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that VULANTE does not adversely affect their ability to do so (see section 4.8).

a) Tabulated list of adverse reactions

VULANTE adverse reactions:

System organ class Frequent Less frequent Frequency unknown

Blood and the lymphatic system disorders Neutropenia, anaemia, thrombocytopenia Pure red cell aplasia,

Immune system disorders Hypersensitivity, immune reconstitution inflammatory syndrome, angioedema Allergy, allergic reactions.

Metabolism and nutrition disorders Hypophosphataemia Lactic acidosis, lipodystrophy (including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorso-cervical fat accumulation (buffalo hump)), metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia, hypokalaemia

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Symptoms

In overdose, side effects can be precipitated and/or of increased severity.

Treatment

Tenofovir

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