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 1,000 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.
Efavirenz/emtricitabine/tenofovir disoproxil should not be used during pregnancy unless the clinical condition of the woman requires treatment with efavirenz/emtricitabine/tenofovir disoproxil.
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. Therefore efavirenz/emtricitabine/tenofovir disoproxil should not be used during breast-feeding.
It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.
Pregnancy should be avoided in women receiving efavirenz/emtricitabine/tenofovir disoproxil. Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz/emtricitabine/tenofovir disoproxil.
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.
No human data on the effect of efavirenz/emtricitabine/tenofovir disoproxil are available. Animal studies do not indicate harmful effects of efavirenz, emtricitabine or tenofovir disoproxil on fertility.
No studies on the effects on the ability to drive and use machines have been performed. However, dizziness has been reported during treatment with efavirenz, emtricitabine and tenofovir disoproxil. Efavirenz may also cause impaired concentration and/or somnolence. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving and operating machinery.
The combination of efavirenz, emtricitabine and tenofovir disoproxil has been studied in 460 patients either as the fixed-dose combination tablet efavirenz/emtricitabine/tenofovir disoproxil (study AI266073) or as the component products (study GS-01-934). Adverse reactions were generally consistent with those seen in previous studies of the individual components. The most frequently reported adverse reactions considered possibly or probably related to efavirenz/emtricitabine/tenofovir disoproxil among patients treated up to 48 weeks in study AI266073 were psychiatric disorders (16%), nervous system disorders (13%), and gastrointestinal disorders (7%).
Severe skin reactions such as Stevens-Johnson syndrome and erythema multiforme; neuropsychiatric adverse reactions (including severe depression, death by suicide, psychosis-like behaviour, seizures); severe hepatic events; pancreatitis and lactic acidosis (sometimes fatal) have been reported.
Rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have also been reported. Monitoring of renal function is recommended for patients receiving efavirenz/emtricitabine/tenofovir disoproxil.
Discontinuation of efavirenz/emtricitabine/tenofovir disoproxil therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis.
The administration of efavirenz/emtricitabine/tenofovir disoproxil with food may increase efavirenz exposure and may lead to an increase in the frequency of adverse reactions.
The adverse reactions from clinical study and post-marketing experience with efavirenz/emtricitabine/tenofovir disoproxil and the individual components of efavirenz/emtricitabine/tenofovir disoproxil in antiretroviral combination therapy are listed in the table below by body system organ class, frequency and the component(s) of efavirenz/emtricitabine/tenofovir disoproxil to which the adverse reactions are attributable. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000).
Treatment-emergent adverse reactions considered possibly or probably related to efavirenz/emtricitabine/tenofovir disoproxil reported in study AI266073 (over 48 weeks; n=203), which have not been associated with one of the individual components of efavirenz/emtricitabine/tenofovir disoproxil, include:
Common: anorexia
Uncommon: dry mouth, incoherent speech, increased appetite, libido decreased, myalgia
Adverse reactions associated with efavirenz/emtricitabine/tenofovir disoproxil listed by the component(s) of efavirenz/emtricitabine/tenofovir disoproxil to which the adverse reactions are attributable:
| Efavirenz/emtricitabine/tenofovir disoproxil | |||
|---|---|---|---|
| Efavirenz | Emtricitabine | Tenofovir disoproxil | |
| Blood and lymphatic system disorders | |||
| Common | neutropenia | ||
| Uncommon | anaemia1 | ||
| Immune system disorders | |||
| Common | allergic reaction | ||
| Uncommon | hypersensitivity | ||
| Metabolism and nutrition disorders | |||
| Very common | hypophosphataemia2 | ||
| Common | hypertriglyceridaemia3 | hyperglycaemia, hypertriglyceridaemia | |
| Uncommon | hypercholesterolaemia3 | hypokalaemia2 | |
| Rare | lactic acidosis | ||
| Psychiatric disorders | |||
| Common | depression (severe in 1.6%)3, anxiety3, abnormal dreams3, insomnia3 abnormal dreams, insomnia | abnormal dreams, insomnia | |
| Uncommon | suicide attempt3, suicide ideation3, psychosis3, mania3, paranoia3, hallucination3, euphoric mood3, affect lability3, confusional state3, aggression3, catatonia3 | ||
| Rare | completed suicide3,4, delusion3,4, neurosis3,4 | ||
| Nervous system disorders | |||
| Very common | headache | dizziness | |
| Common | cerebellar coordination and balance disturbances3, somnolence (2.0%)3, headache (5.7%)3, disturbance in attention (3.6%)3, dizziness (8.5%)3 | dizziness | headache |
| Uncommon | convulsions3, amnesia3, thinking abnormal3, ataxia3, coordination abnormal3, agitation3, tremor | ||
| Eye disorders | |||
| Uncommon | vision blurred | ||
| Ear and labyrinth disorders | |||
| Uncommon | tinnitus, vertigo | ||
| Vascular disorders | |||
| Uncommon | flushing | ||
| Gastrointestinal disorders | |||
| Very common | diarrhoea, nausea | diarrhoea, vomiting, nausea | |
| Common | diarrhoea, vomiting, abdominal pain, nausea | elevated amylase including elevated pancreatic amylase, elevated serum lipase, vomiting, abdominal pain, dyspepsia | abdominal pain, abdominal distension, flatulence |
| Uncommon | pancreatitis | pancreatitis | |
| Hepatobiliary disorders | |||
| Common | elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT), elevated gamma- glutamyltransferase (GGT) | elevated serum AST and/or elevated serum ALT, hyperbilirubinaemia | increased transaminases |
| Uncommon | hepatitis acute | ||
| Rare | hepatic failure3,4 | hepatic steatosis, hepatitis | |
| Skin and subcutaneous tissue disorders | |||
| Very common | rash (moderate-severe, 11.6%, all grades, 18%)3 | rash | |
| Common | pruritus | vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin discolouration (increased pigmentation)1 | |
| Uncommon | Stevens-Johnson syndrome, erythema multiforme3, severe rash (<1%) | angioedema4 | |
| Rare | photoallergic dermatitis | angioedema | |
| Musculoskeletal and connective tissue disorders | |||
| Very common | elevated creatine kinase | ||
| Uncommon | rhabdomyolysis2, muscular weakness2 | ||
| Rare | osteomalacia (manifested as bone pain and infrequently contributing to fractures)2,4, myopathy2 | ||
| Renal and urinary disorders | |||
| Uncommon | increased creatinine, proteinuria, proximal renal tubulopathy including Fanconi syndrome | ||
| Rare | renal failure (acute and chronic), acute tubular necrosis, nephritis (including acute interstitial nephritis)4, nephrogenic diabetes insipidus | ||
| Reproductive system and breast disorders | |||
| Uncommon | gynaecomastia | ||
| General disorders and administration site conditions | |||
| Very common | asthenia | ||
| Common | fatigue | pain, asthenia | |
1 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients.
2 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil in the absence of this condition.
3 See Description of selected adverse reactions for more details.
4 This adverse reaction was identified through post-marketing surveillance for either efavirenz, emtricitabine or tenofovir disoproxil. The frequency category was estimated from a statistical calculation based on the total number of patients treated with efavirenz in clinical studies (n=3,969) or exposed to emtricitabine in randomised controlled clinical studies (n=1,563) or exposed to tenofovir disoproxil in randomised controlled clinical studies and the expanded access programme (n=7,319).
In clinical studies of efavirenz, rashes were usually mild-to-moderate maculopapular skin eruptions that occurred within the first two weeks of initiating therapy with efavirenz. In most patients rash resolved with continuing therapy with efavirenz within one month. Efavirenz/emtricitabine/tenofovir disoproxil can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids is recommended when efavirenz/emtricitabine/tenofovir disoproxil is restarted.
Patients with a history of psychiatric disorders appear to be at greater risk of serious psychiatric adverse reactions listed in the efavirenz column of the table above.
Nervous system symptoms are common with efavirenz, one of the components of efavirenz/emtricitabine/tenofovir disoproxil. In clinical controlled studies of efavirenz, nervous system symptoms of moderate to severe intensity were experienced by 19% (severe 2%) of patients, and 2% of patients discontinued therapy due to such symptoms. They usually begin during the first one or two days of efavirenz therapy and generally resolve after the first two to four weeks. They may occur more frequently when efavirenz/emtricitabine/tenofovir disoproxil is taken concomitantly with meals possibly due to increased efavirenz plasma levels. Dosing at bedtime seems to improve the tolerability of these symptoms.
Hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, as reported post-marketing, were sometimes characterised by a fulminant course, progressing in some cases to transplantation or death.
As efavirenz/emtricitabine/tenofovir disoproxil may cause renal damage, monitoring of renal function is recommended. Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medicinal products) are at increased risk of experiencing incomplete recovery of renal function despite tenofovir disoproxil discontinuation.
Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as severe hepatic impairment (CPT, Class C), or patients receiving concomitant medicinal products known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown.
Insufficient safety data are available for children below 18 years of age.
Efavirenz/emtricitabine/tenofovir disoproxil is not recommended in this population.
Efavirenz/emtricitabine/tenofovir disoproxil has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased hepatic or renal function, therefore caution should be exercised when treating elderly patients with efavirenz/emtricitabine/tenofovir disoproxil.
Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended in any patient with mild renal impairment treated with efavirenz/emtricitabine/tenofovir disoproxil.
Only a limited number of patients were co-infected with HBV (n=13) or HCV (n=26) in study GS-01-934. The adverse reaction profile of efavirenz, emtricitabine and tenofovir disoproxil in patients co-infected with HIV/HBV or HIV/HCV was similar to that observed in patients infected with HIV without co-infection. However, as would be expected in this patient population, elevations in AST and ALT occurred more frequently than in the general HIV infected population.
In HIV infected patients co-infected with HBV, clinical and laboratory evidence of hepatitis may occur after discontinuation of treatment.
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