Tenofovir Disoproxil Fumarate/ Efavirenz/ Lamivudine

Registered South African indications:

• HIV-1 infection

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. Tenofovir as contained in tenofovir disoproxil fumarate/ efavirenz/ lamivudine is not indicated for the treatment of chronic hepatitis B virus (HBV) infection. Safety and efficacy of tenofovir 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 tenofovir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue tenofovir and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

 

Registered South African contraindications

300/600/300 (mg) tablets

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Severe hepatic impairment (Child-Pugh Class C)
• Moderate or severe renal impairment (creatinine clearance (CrCl) < 50 ml/min). Moderate to severe uncontrolled renal failure
• Pregnancy
• Lactation
• Co-administration with tenofovir-containing products, or other lamivudine-containing products, or other efavirenz-containing products
• Co-administration with adefovir dipivoxil
• Co-administration with astemizole, bepridil, cisapride, midazolam, pimozide, triazolam, or ergot derivatives (e.g. ergotamine, dihydroergotamine, ergonovine, and methylergonovine), or zalcitabine
• Use with herbal preparations containing St John’s Wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz
• Concurrent administration with voriconazole because efavirenz significantly decreases voriconazole plasma concentrations
• Children less than 18 years due to lack of data on safety and efficacy

300/400/300 (mg) tablets

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• A history of previous liver injury/failure with efavirenz-containing antiretroviral treatment
• Severe hepatic impairment (Child-Pugh Class C)
• Moderate to severe renal impairment (CrCl<50ml/min). Uncontrolled renal failure
• Pregnancy
• Lactation
• Concurrent administration with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, ergot alkaloids, St John’s wort (Hypericum perforatum), zalcitabine, or with elbasvir/grazoprevir

South African recommendations

Tenofovir disoproxil fumarate/ Efavirenz/ Lamivudine

Caution in the following patient groups:

• Mild renal impairment
• Mild to moderate hepatic impairment
• Elderly

Similar medication

• Tenofovir disoproxil fumarate/ efavirenz/ lamivudine should not be co-administered with other medications containing tenofovir disoproxil fumarate, lamivudine, or efavirenz

Lipodystrophy and metabolic abnormalities

• Antiretroviral therapy may cause body fat redistribution and metabolic issues such as central obesity and elevated lipid/glucose levels
• Clinical evaluations for signs of fat redistribution and cardiovascular risk assessments are recommended for patients with lipodystrophy symptoms

Immune Reconstitution Inflammatory Syndrome (IRIS)

• IRIS can occur upon initiation of antiretroviral therapy (ART), characterised by worsening of existing infections or unmasking of latent ones. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, and cryptococcal meningitis
• It typically arises within three months of ART initiation, especially in those with low CD4 counts
• Management includes appropriate treatment of opportunistic diseases and continuation of ART
• Severe IRIS cases might benefit from glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS

Autoimmune disorders as IRIS reactions

• Autoimmune conditions such as Graves' disease can emerge as IRIS reactions, with variable onset times after starting ART

Osteonecrosis

• Osteonecrosis in patients is believed to be caused by a combination of factors, including corticosteroid use, alcohol consumption, severe immunosuppression, and a higher body mass index
• Cases of osteonecrosis have been notably reported in patients with advanced HIV disease or those who have been exposed to combination antiretroviral therapy (cART) for a long time 
• Patients experiencing symptoms such as joint aches and pain, joint stiffness, or difficulty moving should be advised to seek medical advice promptly

Opportunistic infections

• Patients on tenofovir disoproxil fumarate/ efavirenz/ lamivudine may still develop opportunistic infections or other HIV-related complications and should be closely monitored by healthcare professionals. Regular checks of viral load and CD4 counts are essential

Risk of HIV transmission

• Tenofovir disoproxil fumarate/ efavirenz/ lamivudine does not prevent HIV transmission through sexual contact or blood. Patients should continue using appropriate preventive measures

Lactic acidosis / hyperlactataemia

• Tenofovir disoproxil fumarate/ efavirenz/ lamivudine use can lead to potentially fatal lactic acidosis due to mitochondrial dysfunction, presenting with symptoms such as nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss
• Actions based on lactate levels:
  • 2-5mmol/L with mild symptoms: Switch to medicines less likely to cause lactic acidosis
  • 5-10mmol/L with symptoms or low bicarbonate: Stop NRTIs and change treatment. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes, (e.g., sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism
  • >10mmol/L: Cease all treatment due to high mortality risk
• Patients with liver disease risk factors should use cautiously, and it should be stopped if lactic acidosis or hepatotoxicity signs develop

Mitochondrial dysfunction

• Nucleoside and nucleotide analogues can cause mitochondrial damage, leading to conditions such as haematological disorders and peripheral neuropathy. Monitoring for mitochondrial dysfunction is advised, especially in HIV negative infants exposed to these drugs in utero or post-natally

Pancreatitis

• Pancreatitis, indicated by abdominal pain, nausea, or elevated biochemical markers, has been observed in some patients receiving tenofovir disoproxil fumarate/ efavirenz/ lamivudine and should lead to the medication's discontinuation until pancreatitis is ruled out

Hepatomegaly and hepatic steatosis

• Tenofovir disoproxil fumarate/ efavirenz/ lamivudine usage can lead to hepatomegaly due to non-alcoholic fatty liver disease (NAFLD) or hepatic steatosis
• Its safety and efficacy in individuals with significant underlying liver disorders or diseases have not been determined
• Patients undergoing concomitant antiviral therapy for hepatitis B or C should also consult the specific package inserts for those medications

Monitoring and management of liver dysfunction

• Patients with pre-existing liver dysfunction or chronic active hepatitis exhibit an increased frequency of liver function abnormalities during antiretroviral therapy and require close monitoring
• Evidence of worsening liver disease necessitates considering a temporary or permanent halt of tenofovir disoproxil fumarate/ efavirenz/ lamivudine treatment

HIV and hepatitis B or C co-infection

• Co-infected patients face a heightened risk of severe and potentially fatal hepatic adverse reactions under antiretroviral therapy
• Medical practitioners should consult current HIV treatment guidelines for managing HIV infection in patients co-infected with hepatitis B virus (HBV)
• Upon discontinuation, co-infected patients need close clinical and laboratory follow-up
• For those with advanced liver disease or cirrhosis, discontinuing treatment is not advised due to the risk of post-treatment hepatitis exacerbation potentially leading to hepatic decompensation
• Stopping tenofovir disoproxil fumarate/ efavirenz/ lamivudine in co-infected individuals might result in severe, acute hepatitis exacerbations

Lactose content

• This combination product contains a 133.070mg of lactose per tablet. Patients with rare hereditary conditions of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take

Efavirenz

Efavirenz-associated liver failure

• Efavirenz has been linked to a pattern of sub massive necrosis and high morbidity/mortality risk in HIV positive patients, and may present many months after therapy has been initiated or even stopped, with risk factors including younger age, CD4+ counts ≥350 cells/μ, and female gender
• Regular monitoring for jaundice and bleeding tendencies is advised for patients on tenofovir disoproxil fumarate/ efavirenz/ lamivudine or efavirenz-containing ART. Discontinuation of efavirenz or tenofovir disoproxil fumarate/ efavirenz/ lamivudine should be considered upon early detection of liver failure
• The safety and efficacy of tenofovir disoproxil fumarate/ efavirenz/ lamivudine in patients with both HIV and hepatitis B virus infection have not been established

Rash with efavirenz

• Mild to moderate rash is common and usually resolves with continued therapy. Severe rash leading to discontinuation occurs in less than 1% of efavirenz-treated patients. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash
• Children have a higher incidence of rash with efavirenz, and prophylaxis with antihistamines may be considered before starting therapy

Nervous system symptoms

• Reports of nervous system symptoms, psychosis-like reactions, and severe depression have been associated with efavirenz use, especially in patients with a history of mental illness or substance abuse
• Immediate consultation with a doctor is advised if such symptoms occur, as discontinuation of efavirenz may be necessary

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

South African registered indications and dosages

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

HIV infection
- For patients who have been treated and stabilised on a combination of the three antiretrovirals as separate formulations at similar dosages as contained in this combination product

Tenofovir disoproxil fumarate/ Efavirenz/ Lamivudine
300/600/300 (mg)
300/400/300 (mg)

• Oral (fct): 1 tab, once daily, on an empty stomach; Bedtime dosing is recommended

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In exceptional circumstances in patients having difficulty in swallowing, tenofovir disoproxil fumarate/ efavirenz/ lamivudine can be administered following disintegration of the tablet in at least 100ml of water, orange juice or grape juice

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It is recommended that efavirenz be taken on an empty stomach. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse events. In order to improve the tolerability of nervous system undesirable effects, bedtime dosing is recommended

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Tenofovir disoproxil fumarate/ efavirenz/ lamivudine is contraindicated during pregnancy
• Barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives)
• Women of childbearing potential should undergo pregnancy testing before initiation of tenofovir disoproxil fumarate/ efavirenz/ lamivudine due to the efavirenz component

Tenofovir disoproxil fumarate

• No clinical data on exposed pregnancies are available for tenofovir disoproxil fumarate
• Animal studies do not indicate direct or indirect harmful effects of tenofovir disoproxil fumarate with respect to pregnancy, foetal development, parturition, or postnatal development
• However, given that the potential risks to developing human foetuses are unknown, the use of tenofovir disoproxil fumarate is not recommended in women of childbearing potential

Efavirenz

• Pregnancy should be avoided in women treated with efavirenz
• Barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz. Efavirenz should not be used during pregnancy
• There are no adequate and well-controlled studies of efavirenz in pregnant women. In post marketing experience through an antiretroviral pregnancy registry, more than 200 pregnancies with first-trimester exposure to efavirenz as part of a combination antiretroviral regimen have been reported with no specific malformation pattern
• Retrospectively in this registry, a small number of cases of neural tube defects, including meningomyelocele, have been reported but causality has not been established. Studies in animals have shown reproductive toxicity including marked teratogenic effects

Lamivudine

• The safety of lamivudine in human pregnancy has not been established
• Reproductive studies in animals have not shown evidence of teratogenicity and showed no effect on male or female fertility
• Lamivudine induces early embryonic death when administered to pregnant rabbits at exposure levels comparable to those achieved in man. In humans, consistent with passive transmission of lamivudine across the placenta, lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum at delivery

Breastfeeding

South African recommendations

• Contraindicated
• Tenofovir disoproxil fumarate/ efavirenz/ lamivudine is contraindicated during breastfeeding

Tenofovir disoproxil fumarate

• In animal studies it has been shown that tenofovir is excreted into milk. It is not known whether tenofovir is excreted in human milk
• Therefore, it is recommended that mothers being treated with tenofovir disoproxil fumarate do not breastfeed their infants. As a general rule, it is recommended that HIV-infected women do not breast-feed their infants in order to avoid transmission of HIV to the infant

Lamivudine

• Following oral administration lamivudine was excreted in breast milk at similar concentrations to those found in serum
• Since lamivudine and the virus pass into breast milk, it is recommended that mothers taking lamivudine tablets do not breastfeed their infants. It is recommended that HIV-infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV

Efavirenz

• Studies in rats have demonstrated that efavirenz is excreted in milk reaching concentrations much higher than those in maternal plasma. It is not known whether efavirenz is excreted in human milk
• Since animal data suggest that the substance may be passed into breast milk, it is recommended that mothers taking efavirenz do not breastfeed their infants
• It is recommended that HIV infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV

Fertility

South African recommendations

• No information available

South African recommendations

• Mild (CrCl ≥50ml/min): Caution; no dose adjustment recommended
• Moderate to severe (CrCl <50ml/min): Contraindicated

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated

South African recommendations

• Caution; no information available
  No data are available on which to make a dose recommendation for patients over the age of 65 years

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

Tenofovir disoproxil fumarate
Central Nervous System Disorders

• Dizziness
• Headache

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Abdominal distension
• Flatulence
• Pancreatitis

Hepatobiliary Disorders

• Increased transaminases
• Hepatic steatosis
• Hepatitis

Genitourinary Disorders

• Increased creatinine
• Proximal renal tubulopathy
• Acute renal failure
• Renal failure
• Acute tubular necrosis
• Nephritis
• Nephrogenic diabetes insipidus

Endocrine and Metabolic Disorders

• Hypophosphataemia
• Hypokalaemia
• Lactic acidosis

Musculoskeletal Disorders

• Rhabdomyolysis
• Muscular weakness
• Osteomalacia 
• Myopathy

Skin and Subcutaneous Tissue Disorders

• Rash
• Angioedema

Efavirenz
Central Nervous System Disorders

• Anxiety
• Depression
• Insomnia
• Affect lability
• Aggression
• Confusional state
• Euphoric mood
• Hallucination
• Mania
• Paranoia
• Psychosis
• Suicide attempt
• Suicide ideation
• Delusion 
• Neurosis
• Balance disturbances
• Disturbance in attention
• Dizziness 
• Headache 
• Somnolence 
• Agitation
• Amnesia
• Ataxia
• Convulsions
• Abnormal thinking 
• Tremor
• Fatigue

Cardiovascular Disorders

• Flushing 

Gastrointestinal Disorders

• Abdominal pain
• Diarrhoea
• Nausea and vomiting
• Pancreatitis

Hepatobiliary Disorders

• Aspartate aminotransferase (AST) increase
• Alanine aminotransferase (ALT) increased
• Gamma-glutamyltransferase (GGT) increased
• Acute hepatitis 
• Hepatic failure

Endocrine and Metabolic Disorders

• Gynaecomastia
• Hypertriglyceridaemia
• Hypercholesterolaemia

Skin and Subcutaneous Tissue Disorders

• Rash 
• Pruritus
• Erythema multiforme
• Stevens-Johnson syndrome
• Photoallergic dermatitis

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity

Sensory Disorders

• Blurred vision 
• Tinnitus
• Vertigo

Lamivudine
Central Nervous System Disorders

• Headache
• Insomnia
• Peripheral neuropathy

Respiratory Disorders

• Cough
• Nasal symptoms

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain 
• Diarrhoea
• Pancreatitis
• Elevations in serum amylase

Hepatobiliary Disorders

• Transient elevations in liver enzymes
• Hepatitis

Endocrine and Metabolic Disorders

• Lactic acidosis

Musculoskeletal Disorders

• Arthralgia
• Muscle disorders
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders

• Rash
• Alopecia
• Angioedema

Immune, Blood and Lymphatic System Disorders

• Neutropenia
• Anaemia 
• Thrombocytopenia
• Pure red cell aplasia

Others

• Fatigue
• Malaise
• Fever

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

Tenofovir Disoproxil Fumarate/ Efavirenz/ Lamivudine

• Adefovir dipivoxil
• Astemizole
• Cisapride
• Midazolam
• Triazolam
• Pimozide
• Bepridil
• Ergot derivatives (e.g. ergotamine, dihydroergotamine, ergonovine, and methylergonovine)
• Zalcitabine
• Elbasvir/grazoprevir
• Terfenadine
• Voriconazole

Other interactions

• St John’s wort (Hypericum perforatum)

Tenofovir disoproxil fumarate

• Adefovir 
• Didanosine
• Medicinal products that reduce renal function
• OAT1 substrates
• OAT3 substrates
• MRP4 substrates
• Nephrotoxic medicinal products
• Tacrolimus
• Hepatitis C virus antiviral agents
• Atazanavir
• Lopinavir/Ritonavir

Efavirenz

• Erfenadine
• Astemizole
• Cisapride
• Midazolam
• Triazolam
• Pimozide
• Bepridil
• Ergot alkaloids
• CYP3A4 substrates
• CYP2B6 substrates
• UGT1A1substrates
• CYP450 substrates
• St. John's wort
• Atazanavir/ritonavir
• Ritonavir
• Simeprevir  
• Itraconazole
• Posaconazole
• Artemether/lumefantrine
• Atovaquone/proguanil
• Warfarin
• Acenocoumarol
• Phenytoin
• Phenobarbital

Lamivudine

• Trimethoprim/sulfamethoxazole
• Cladribine
• Cytidine analogues
• Zalcitabine

• Hepatic function
• Coagulation studies
• Full blood count
• Renal function - before initiation, 1 month, 2 month,3 month, 6 monthly thereafter

Specific cases may require

• Lactate levels
• Bone density

Tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate, a prodrug, is converted to tenofovir. Tenofovir is a nucleotide reverse transcriptase inhibitor (nRTIs).  It is an analogue of the naturally occurring deoxynucleotides required to synthesize the viral DNA. Tenofovir inhibits HIV-1 reverse transcriptase and the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate and, after incorporation into DNA, by DNA chain termination.

Efavirenz
Efavirenz is a non-nucleoside reverse transcriptase inhibitor. It is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT) and does not significantly inhibit HIV-2 RT or cellular DNA polymerases.

Lamivudine
Lamivudine is a nucleoside analogue which has activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). It is metabolised intracellularly to the active moiety, lamivudine 5'-triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. The triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication and is also active against zidovudine-resistant clinical isolates of HIV.

COMBINATION PREPARATIONS

Tenofovir disoproxil fumarate/ Efavirenz/  Lamivudine

Tablet 300mg/600mg/300mg

• Arion (Novagen)
• Eflaten (Mylan)
• Elteno (Macleods)
• Tenarenz (Pharmacare)
• Virlaten (Sandoz)