Efavirenz/ Tenofovir Disoproxil Fumarate/ Emtricitabine

Registered South African indications:

• HIV-1 infection

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Severe hepatic impairment (Child-Pugh Class C)
• Porphyria 
• Family history of sudden death or congenital prolongation of the QTc interval
• History of symptomatic cardiac arrhythmias, bradycardia (clinically relevant) or congestive heart failure by reduced left ventricle ejection fraction
• Severe electrolyte imbalances (e.g. hypokalaemia or hypomagnesemia)
• Coadministration with proarrhythmic agents (e.g. antiarrhythmics (classes IA and III), neuroleptics, antidepressants, macrolides, fluoroquinolones, imidazole and triazole antifungals, flecainide, antimalarials, methadone)
• Coadministration with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids
• Coadministration with elbasvir/grazoprevir
• Coadministration with voriconazole
• Coadministration with herbal preparations containing St. John's wort (Hypericum perforatum)

Cautions

• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Patients at risk of renal or hepatic impairment
• Patients at risk of Torsade de Pointes
• Switch from protease inhibitor-based antiretroviral regimen
• Immune Reconstitution Inflammatory Syndrome (IRIS)
• Opportunistic infections
• Autoimmune disorders
• Sexual HIV transmission
• Administration with food
• Co-infection with hepatitis B or C
• Chronic hepatitis B infection
• Prior history of psychiatric disorders
• History of seizures
• Osteoporosis
• Bone abnormalities
• Lipid disorders
• History of life-threatening cutaneous reaction while taking an non-nucleoside reverse transcriptase inhibitors
• HIV-1 harbouring the K65R, M184V/I or K103N mutation
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive or operate machinery

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

HIV infection

Efavirenz/ Tenofovir disoproxil fumarate/ Emtricitabine
600mg/ 300mg /200mg

• Oral (tab): 1 tab, dly

Not recommended for patients <40kg

Swallow whole with water on an empty stomach

Bedtime dosing is recommended to improve tolerability with respect to adverse effects

See Additional Prescribing Points

Paed. forms avail. in SA and covered in this monograph: tab

HIV infection

Efavirenz/ Tenofovir disoproxil fumarate/ Emtricitabine
600mg/ 300mg /200mg

Children younger than 15 years or less than 40kg

• Not established for use

Children older than 15 years or greater than 40kg

• See adult dosage

Consult HIV/infectious disease specialists prior to any decisions related to ARV regimen termination/switch

Pregnancy

• Caution
• Efavirenz: There have been seven retrospective reports of findings consistent with neural tube defects, including meningomyelocele, all in mothers exposed to efavirenz-containing regimens (excluding any efavirenz-containing fixed-dose combination tablets) in the first trimester. Two additional cases (1 prospective and 1 retrospective) including events consistent with neural tube defects have been reported with the fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil. A causal relationship of these events to the use of efavirenz has not been established, and the denominator is unknown. As neural tube defects occur within the first 4 weeks of foetal development (at which time neural tubes are sealed), this potential risk would concern women exposed to efavirenz during the first trimester of pregnancy
• As of July 2013, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 904 pregnancies with first-trimester exposure to efavirenz-containing regimens, resulting in 766 live births. One child was reported to have a neural tube defect, and the frequency and pattern of other birth defects were similar to those seen in children exposed to non-efavirenz-containing regimens, as well as those in HIV negative controls. The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births
• Malformations have been observed in foetuses from efavirenz-treated monkeys
• Emtricitabine and tenofovir disoproxil: A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicates no malformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil. Animal studies on emtricitabine and tenofovir disoproxil do not indicate reproductive toxicity
• The combination product should not be used during pregnancy unless the clinical condition of the woman requires treatment with efavirenz/emtricitabine/tenofovir disoproxil

Breastfeeding

• Caution
• Efavirenz, emtricitabine and tenofovir have been shown to be excreted in human milk. There is insufficient information on the effects of efavirenz, emtricitabine and tenofovir in newborns/infants. A risk to the infants cannot be excluded
• South African HIV guidelines recommend exclusive breastfeeding for the first 6 months, after which the nutritional needs of the child will require the introduction of complementary foods, while breastfeeding continues. Mothers failing 2nd or 3rd line regimens should not breastfeed, provided the mother fulfils the AFASS (affordable, feasible, acceptable, sustainable and safe) criteria

Fertility

• No human data on the effect of efavirenz/ emtricitabine/ tenofovir are available
• Animal studies do not indicate harmful effects of efavirenz, emtricitabine or tenofovir disoproxil on fertility
• Pregnancy should be avoided in women receiving efavirenz/ emtricitabine/ tenofovir disoproxil. Women of childbearing potential should undergo pregnancy testing before initiation of treatment
• Barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives) while on therapy with efavirenz/ emtricitabine/ tenofovir disoproxil
• Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of efavirenz/ emtricitabine/ tenofovir disoproxil is recommended

Renal Impairment

• CrCl ≥50ml/min: No dose adjustment recommended
• CrCl <50ml/min: Caution; dose adjustment recommended 
  Dose interval adjustment of emtricitabine and tenofovir disoproxil cannot be achieved with the combination tablet

Hepatic Impairment

• Caution; no dose adjustment recommended
  Consult HIV/infectious disease specialists prior to any decisions related to ARV regimen termination/switch

Elderly

• Caution; no dose adjustment recommended
• >65 years: Caution; no information available 

Porphyria Information

• Probably porphyrinogenic (PRP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Depression
• Anxiety
• Abnormal dreams
• Insomnia
• Suicide attempt
• Suicide ideation
• Psychosis
• Mania
• Paranoia
• Hallucination
• Euphoric mood
• Affect lability
• Confusional state
• Aggression
• Catatonia
• Delusion
• Neurosis
• Headache
• Cerebellar coordination and balance disturbances
• Somnolence
• Disturbance in attention
• Dizziness
• Convulsions
• Amnesia
• Ataxia
• Tremor
• Asthenia
• Fatigue

Cardiovascular Disorders

• Flushing

Gastrointestinal Disorders

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

Hepatobiliary Disorders

• Elevated aspartate aminotransferase  
• Elevated alanine aminotransferase  
• Elevated gamma-glutamyltransferase
• Elevated serum transaminases
• Hyperbilirubinaemia
• Acute hepatitis
• Hepatic failure
• Hepatic steatosis

Genitourinary Disorders

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

Endocrine and Metabolic Disorders

• Gynaecomastia
• Hypophosphataemia
• Hypertriglyceridaemia
• Hyperglycaemia
• Hypercholesterolaemia
• Hypokalaemia
• Lactic acidosis
• Elevated amylase including elevated pancreatic amylase
• Elevated serum lipase

Musculoskeletal Disorders

• Elevated creatine kinase
• Rhabdomyolysis
• Osteomalacia
• Bone pain
• Myopathy
• Osteonecrosis

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Vesiculobullous rash
• Pustular rash
• Maculopapular rash
• Urticaria
• Skin discolouration
• Stevens-Johnson syndrome
• Erythema multiforme
• Angioedema
• Photoallergic dermatitis
• Flushing

Immune, Blood and Lymphatic System Disorders

• Neutropenia
• Anaemia
• Allergic reaction
• Hypersensitivity

Sensory Disorders

• Vision blurred
• Tinnitus
• Vertigo

• CYP3A4 inhibitors
• CYP3A4 substrates
• CYP2B6 inhibitors
• CYP2B6 substrates
• UGT1A1 substrates
• Agents that reduce renal function or compete for active tubular secretion
• Cidofovir
• Agents that prolong QTc interval (proarrythmics)
• Antiarrhythmics (classes IA and III)
• Neuroleptics
• Antidepressants
• Macrolides
• Fluoroquinolones
• Imidazole and triazole antifungals
• Flecainide
• Antimalarials
• Methadone
• Fumarate
• Cytidine analogues
• Lamividine  
• Adefovir dipivoxil  
• Tenofovir alafenamide
• Didanosine  
• Ginkgo biloba extracts
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Nephrotoxic agents
• Aminoglycosides
• Amphoterin B
• Foscarnet
• Ganciclovir
• Pentamidine
• Vancomycin
• Interleukin-2  
• Erfenadine
• Astemizole
• Terfenadine
• Cisapride
• Midazolam
• Triazolam
• Pimozide
• Bepridil
• Ergot alkaloids
• Voriconazole
• Atazanavir
• Ritonavir
• Elbasvir/grazoprevir
• Sofosbuvir/velpatasvir
• Sofosbuvir/velpatasvir/voxilaprevir
• Rifampicin
• St. John's wort (Hypericum perforatum)
• Grapefruit juice

• Hepatic function
• Renal function
• Full blood count
• Viral load
• CD4 count

Specific cases may require

• Blood glucose
• Blood potassium
• Urine glucose concentrations
• Blood lipids

Dosing

• It is recommended that Efavirenz/Emtricitabine/Tenofovir disoproxil fumarate be taken on an empty stomach since food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions
• In order to improve the tolerability to efavirenz with respect to undesirable effects on the nervous system, bedtime dosing is recommended

Missed dose 

• If a patient misses a dose within 12 hours of the time it is usually taken, the patient should take the tablet as soon as possible and resume the normal dosing schedule
• If a patient misses a dose by more than 12 hours and it is almost time for the next dose, the patient should not take the missed dose and simply resume the usual dosing schedule
• If the patient vomits within 1 hour of taking the dose, another tablet should be taken
• If the patient vomits more than 1 hour after taking the dose he/she does not need to take another dose

Coadministration with rifampicin

• If Efavirenz/Emtricitabine/Tenofovir disoproxil fumarate is co-administered with rifampicin to patients weighing 50 kg or more, an additional 200 mg/day (800 mg total) of efavirenz may be considered

Efavirenz
Efavirenz, a selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1, diffuses into the cell where it binds adjacent to the active site of reverse transcriptase. Thus a conformational change in the enzyme is produced and its function is inhibited. Efavirenz is a non-competitive inhibitor of HIV-1 reverse transcriptase (RT) with respect to template, primer or nucleoside triphosphates, with a small component of competitive inhibition. Efavirenz does not inhibit HIV-2 RT and human cellular DNA polymerases alpha, beta, gamma and delta.

Tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate is a nucleotide analogue reverse transcriptase inhibitor (nRTIs), which inhibits reverse transcriptase, an enzyme crucial to viral production in HIV-infected people. Tenofovir diphosphate inhibits the activity of HIV-1 RT through competition with the natural substrate deoxyadenosine 5'-triphosphate. After incorporation into DNA, the DNA chain is terminated.

Emtricitabine
Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and an analogue of cytidine. It competitively inhibits HIV-1 reverse transcriptase, the enzyme that copies HIV RNA into new viral DNA, resulting in chain termination.

COMBINATION PREPARATIONS

Efavirenz/  Tenofovir disoproxil fumarate/ Emtricitabine

Tablet 600mg/300mg/200mg

• Atenef (Sonke)
• Atreslawin (Zentiva) originator
• Atripla (MSD) originator
• Atroiza (Mylan)
• Citenvir (Novagen)
• Eftenem (Specpharm)
• Heftenam (Hetero Drugs South Africa)
• Hetripco (Hetero Drugs South Africa)
• Odimune (Cipla)
• Rizene (Adcock)
• Tabex (Hetero Drugs South Africa)
• Teerenz (Strides Pharma SA)
• Teevir (Mylan) originator
• Trenvir (Cipla)
• Tribuss (Pharmacare)
• Triemta (Macleods Pharma)
• Triolar (Macleods)
• Trionce (Emcure)
• Tripavir (Macleods Pharma)
• Triploco (Adcock)
• Trivage (Macleods Pharma)
• Trivenz (Adcock)
• Truno 600/200/300 (Aurobindo)
• Virastiva (Innovata)
• Virtem (Emcure pharmaceuticals)