Lamivudine/ Tenofovir Disoproxil Fumarate/ Dolutegravir

Registered South African indications:

• Treatment of HIV-1 infection

South African registered boxed 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. This combination product is not indicated for the treatment of chronic hepatitis B virus (HBV) infection. Safety and efficacy of this combination product have 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 infected with HBV who discontinue this combination product and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Pregnancy
• Lactation
• Women of child-bearing age not using highly effective contraception
• Uncontrolled renal failure
• Moderate and severe hepatic impairment
• Concomitant use with adefovir dipivoxil
• Co-administration with dofetilide and pilsicainide
• Co-administration with didanosine
• Patients younger than 18 years of age

South African recommendations

Renal impairment

• The dose of the individual components of this combination product cannot be altered, therefore not recommended as a combination. Adjust dose in patients with moderate to severe renal impairment
• Regular assessment of renal function recommended

Hepatic disease

• Use with caution in patients with pre-existing liver dysfunction or chronic active hepatitis
• Use can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). Safety and efficacy has not been established in patients with significant underlying liver disorders
• Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered

Elderly

• Pharmacokinetic studies have not been performed in the elderly (>65 years)

Depression and suicidal ideation

• Monitor patients with a history of depression or psychiatric illness for depression and suicidal behaviour

Metabolic abnormalities

• Risk of hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycaemia, and hyperlactatemia

Lipodystrophy

• Monitor for body fat redistribution/accumulation; manage lipid disorders clinically

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Monitor for IRIS in patients with low CD4 counts during the initial months of ART

Osteonecrosis

• Monitor for joint aches and pain, stiffness, or difficulty in movement, especially in patients with advanced HIV or long-term combination antiretroviral therapy (cART)

Opportunistic infections

• Patients may still develop opportunistic infections; remain under clinical observation

HIV transmission

• Continue using appropriate precautions to prevent HIV transmission

Lactic acidosis or severe hepatomegaly with steatosis

• Monitor for early symptoms; discontinue in symptomatic hyperlactatemia and metabolic/lactic acidosis
• Suspend in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity

Mitochondrial dysfunction

• Potential risk in HIV-negative infants exposed in utero and/or postnatally; monitor for signs or symptoms

Pancreatitis

• Consider pancreatitis in patients with abdominal pain, nausea, vomiting, or elevated biochemical markers
• Discontinue use until diagnosis of pancreatitis is excluded

Co-administration and risk of renal toxicity

• Avoid concomitant use with nephrotoxic medicines; monitor renal function if unavoidable

K65R mutation

• Avoid in patients with HIV-1 harbouring the K65R mutation

Bone mineral density

• Monitor for decreases in bone mineral density; consider supplementation with calcium and vitamin D

Patients with HIV and Hepatitis B or C co-infection

• Increased risk for severe hepatic adverse reactions
• Lamivudine/ tenofovir disoproxil fumarate/dolutegravir is not indicated for the treatment of chronic HBV infection. Safety and efficacy has not been established for the treatment of patients co-infected with HBV and HIV

Exacerbations of hepatitis

• Monitor hepatic function closely, especially after discontinuation of hepatitis B therapy

Immune Reactivation Syndrome

• Monitor for inflammatory reactions to opportunistic pathogens

Paediatric use

• Safety and effectiveness not established in patients under 18 years

Geriatric use

• Insufficient data to determine differences in response in patients aged 65 and over

Lactose content

• Not suitable for patients with hereditary conditions of galactose intolerance

Sodium content

• Contains less than 1 mmol sodium (23mg) per tablet

Effects on ability to drive and use machines

• Lamivudine/ tenofovir disoproxil fumarate/ dolutegravir may affect the ability to drive and use machines. Patients should ensure that they do not engage in driving or using machines until they know how this combination product affects them

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Treatment of HIV-1 infection

Lamivudine/ Tenofovir disoproxil fumarate/ Dolutegravir
300/300/50 (mg)

• Oral (fct): 1 tab, once daily, without regard to food

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Therapy should be initiated by a doctor experienced in the management of HIV infection

Contraindicated in patients younger than 18 years of age

Pregnancy

South African recommendations

• Contraindicated
• 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 such as tenofovir and lamivudine
• 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

Women of childbearing potential / Contraception in males and females

• Lamivudine/ tenofovir disoproxil fumarate/ dolutegravir should not be prescribed to women who plan to become pregnant
• Women of childbearing age should use this combination product only if they are reliably using highly effective contraception
• A medically supervised negative pregnancy test is required before initiating treatment with this combination product
• Repeat pregnancy tests should be conducted at frequent intervals during treatment, especially if pregnancy is suspected
• Women should be counselled about the potential risk of neural tube defects associated with dolutegravir. Effective contraceptive measures should be considered to mitigate this risk
• The benefits and risks of starting or continuing treatment with lamivudine/tenofovir disoproxil fumarate/dolutegravir versus other antiretroviral regimens should be thoroughly discussed with women planning pregnancy

Breastfeeding

South African recommendations

• Contraindicated
• Mothers breast-feeding their infants should not use this combination product
• 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. Lamivudine is excreted in human milk at similar concentrations to those found in serum and tenofovir is excreted in breast milk. Lamivudine passes into breast milk

Fertility

South African recommendations

• 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

South African recommendations

• CrCl<50ml/min or patients who require haemodialysis: Caution; not recommended
  The dose of the individual components of this combination product cannot be altered
  Significantly increased exposure occurred when tenofovir, as in lamivudine/ tenofovir disoproxil fumarate/ dolutegravir, was administered to patients with moderate to severe renal impairment
• Uncontrolled renal failure: Contraindicated

South African recommendations

• Mild: Caution; no dose adjustment recommended
  There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. Change in tenofovir dosing is not required in patients with hepatic impairment
  No dosage adjustment of dolutegravir is necessary for patients with mild hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied
• Moderate and severe hepatic impairment: Contraindicated

South African recommendations

• Caution; no information available
  Pharmacokinetic studies have not been performed in the elderly (> 65 years)

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Lamivudine/ Tenofovir Disoproxil Fumarate/ Dolutegravir

Psychiatric Disorders

Less frequent

• Depression

Lamivudine

Blood and Lymphatic System Disorders

Less frequent

• Neutropenia
• Anaemia
• Thrombocytopenia
• Pure red cell aplasia

Metabolism and Nutrition Disorders

Frequent

• Hyperlactataemia

Less frequent

• Lactic acidosis
• Lipodystrophy (redistribution/accumulation of body fat)

Nervous System Disorders

Frequent

• Headache
• Insomnia

Less frequent

• Paraesthesia
• Peripheral neuropathy (causal relationship to treatment uncertain)
• Late onset neurological disorders in children exposed in utero

Gastrointestinal Disorders

Frequent

• Nausea
• Vomiting
• Upper abdominal pain
• Diarrhoea

Less frequent

• Pancreatitis (causal relationship to treatment uncertain)
• Rise in serum amylase

Hepatobiliary Disorders

Less frequent

• Transient rises in liver enzymes (AST, ALT)

Skin and Subcutaneous Tissue Disorders

Frequent

• Rash
• Alopecia

Musculoskeletal and Connective Tissue Disorders

Frequent

• Arthralgia
• Muscle disorders

Less frequent

• Rhabdomyolysis
• Decrease in bone mineral density
• Osteopenia
• Fractures

General Disorders and Administration Site Conditions

Frequent

• Fatigue
• Malaise
• Fever

Tenofovir Disoproxil Fumarate

Immune System Disorders

Less frequent

• Allergic reaction

Metabolism and Nutrition Disorders

Frequency unknown

• Hypophosphataemia
• Lactic acidosis

Respiratory, Thoracic, and Mediastinal Disorders

Frequency unknown

• Dyspnoea

Gastrointestinal Disorders

Frequency unknown

• Abdominal pain
• Increased amylase
• Pancreatitis

Hepatobiliary Disorders

Frequency unknown

• Increased liver enzymes
• Hepatitis

Renal and Urinary Disorders

Frequency unknown

• Renal insufficiency
• Renal failure
• Acute renal failure
• Fanconi syndrome
• Proximal tubulopathy
• Proteinuria
• Increased creatinine
• Acute tubular necrosis
• Nephrogenic diabetes insipidus

Dolutegravir

Immune System Disorders

Less frequent

• Hypersensitivity
• Immune reconstitution syndrome

Psychiatric Disorders

Frequent

• Insomnia

Nervous System Disorders

Frequent

• Headache
• Dizziness
• Abnormal dreams

Gastrointestinal Disorders

Frequent

• Nausea
• Vomiting
• Upper abdominal pain
• Diarrhoea
• Flatulence

Less frequent

• Abdominal pain
• Abdominal discomfort

Hepatobiliary Disorders

Less frequent

• Hepatitis

Skin and Subcutaneous Tissue Disorders

Frequent

• Rash
• Pruritus

General Disorders and Administration Site Conditions

Frequent

• Fatigue

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Lamivudine/ Tenofovir Disoproxil Fumarate/ Dolutegravir

• Dofetilide
• Pilsicainide
• Medicines eliminated by active tubular secretion
• Medicines that decrease renal function
• Etravirine
• Adefovir dipivoxil
• Didanosine

Lamivudine

• Zalcitabine
• Trimethoprim

Tenofovir Disoproxil Fumarate

• Medicines eliminated by active tubular secretion
• Medicines that decrease renal function
• Didanosine
• Atazanavir
• Indinavir
• Lopinavir/ ritonavir
• Abacavir

Dolutegravir

• Dofetilide
• Pilsicainide
• Etravirine
• Efavirenz
• Nevirapine
• Atazanavir
• Atazanavir/ ritonavir
• Tipranavir/ ritonavir
• Fosamprenavir/ ritonavir
• Oxcarbazepine
• Phenytoin
• Phenobarbital
• Carbamazepine
• Antacids containing polyvalent cations (e.g., Mg, Al or Ca)
• Calcium supplements
• Iron supplements
• Metformin
• Rifampicin
• Isoniazid

Other interactions

• St. John’s wort

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

• Renal function

Specific cases may require

• Lactate levels
• Fasting serum lipids
• Fasting blood glucose levels
• Bone mineral density
• Hepatic function
• Cardiovascular risk assessment

Lamivudine
Lamivudine, a nucleoside reverse transcriptase inhibitor (NRTI), is a selective inhibitor of HIV-1 and HIV-2 replication in vitro. Lamivudine is metabolised intracellularly to the 5’-triphosphate. Lamivudine 5’-triphosphate is a weak inhibitor of the RNA and DNA dependent activities of HIV reverse transcriptase, its mode of action is a chain terminator of HIV reverse transcription.

Tenofovir Disoproxil Fumarate
Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate and is converted in vivo to tenofovir. It is a nucleoside reverse transcriptase inhibitor. Tenofovir is phosphorylated by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase, by competing with the natural substrate deoxyadenosine 5’-triphosphate and, after incorporation in DNA, by chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, ß and mitochondrial DNA polymerase Ɣ.

Dolutegravir
Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.

COMBINATION PREPARATION

Lamivudine/ Tenofovir disoproxil fumarate/ Dolutegravir

Film-coated tablet 300mg/300mg/50mg

• Acriptega (Mylan)
• Doltelam (Austell Laboratories)
• Dovimil (Hetero)
• Kovatrax (Macleods) 
• Lavem (Emcure)
• Lanograv (Ranbaxy)
• Luvigen (Hetero)
• Milutin (Hetero)
• Nuvaco (Adcock Ingram)
• Odystra (Mylan)
• Ranega (Mylan)
• Reydin (Cipla Medpro)
• Telado (Cipla Medpro) originator
• Telatri (Ranbaxy)
• Temiv (Emcure)
• Tladeez (Kiara Health)
• Viraten (Macleods Pharmaceuticals)
• Volutrip (Aurobindo)
• Vulante (Pharmacare Limited)