Drugs List

Therapeutic Indications

Uses

HIV infection-combined with other antiretrovirals

Contraindications

Children under 3 months
Infants weighing less than 3.5kg
Breastfeeding
Congestive cardiac failure with reduced left ventricular ejection fraction
Galactosaemia
Long QT syndrome
Severe bradycardia
Severe electrolyte imbalance
Severe hepatic impairment
Torsade de pointes

Precautions and Warnings

Children aged 3 months to 18 years
Elderly
Family history of long QT syndrome
Acute porphyria
Electrolyte imbalance
Glucose-galactose malabsorption syndrome
Hepatitis B
Hepatitis C
History of depression
History of hepatic impairment
History of psychiatric disorder
History of seizures
History of torsade de pointes
Lactose intolerance
Mild hepatic impairment
Pregnancy
Severe renal impairment

Correct electrolyte disorders before treatment
Treatment does not prevent risk of transmission of HIV
Advise ability to drive/operate machinery may be affected by side effects
Consider prophylactic antihistamines for high risk patients
Not all available products are licensed for all age groups
Treatment should be initiated by doctor experienced in HIV management
Some formulations contain lactose
Advise patient to take at bedtime to reduce adverse effects
Not to be used as a single agent or added on to a failing regime
Exclude pregnancy prior to initiation of treatment
Autoimmune disorders can occur many months after initiation of treatment
Blood lipid and glucose levels may increase requiring treatment
Consider monitoring ECG in patients at risk of QT prolongation
Consider monitoring hepatic enzymes
Monitor for depressive disorders/suicidal ideation-consider discontinuation
Monitor patients with hepatic impairment
Monitor serum electrolytes
Advise patient to report any new or worsening depression/suicidal ideation
Advise patient to seek medical advice if joint aches or pain occur
Advise patient to seek medical advice if movement becomes difficult
Inflammatory symptoms should be evaluated and treated appropriately
Risk of developing opportunistic infections
May affect results of some laboratory tests
Discontinue if hepatic function deteriorates in pts with hepatic impairment
Discontinue if severe skin reaction occurs
Interrupt therapy if hepatic transaminases > 5 times upper limit of normal
Bioavailability differs with preparations;caution on changing formulations
Advise patient not to take ginkgo unless advised by clinician
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Female: Two reliable methods of contraception should be used simultaneously

When any antiretroviral in combination regimen is interrupted due to suspected intolerance, consider also interrupting all antiretroviral medications in order to prevent resistance developing. Restart all medications at the same time when intolerance symptoms have resolved.

Discontinue efavirenz if severe rash with blistering, desquamation, mucosal involvement or fever occur. If stopping efavirenz consider stopping all antiretrovirals. Mild to moderate rash usually improves with continuation of treatment and antihistamines and/or corticosteroids may be used. Efavirenz is not recommended in patients who have had life-threatening cutaneous reaction e.g. Stevens-Johnson syndrome whilst taking another NNRTI.

Rash is more common in children; consider prophylaxis with an appropriate antihistamine before initiating treatment.

Immune reactivation may occur when combination antiretroviral therapy is initiated in HIV infected patients with severe immune deficiency. Inflammatory reactions to asymptomatic or residual opportunistic pathogens may arise. This may lead to aggravation of symptoms or other serious clinical conditions such as cytomegalovirus retinitis, mycobacterial infections or Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia. These reactions usually happen in the first few weeks or months after treatment commences and should be evaluated and treated appropriately.

Blood lipid and glucose levels may increase during antiretroviral therapy. This may be linked to disease control and lifestyle. Refer to established HIV treatment guidelines for monitoring and manage lipid and glucose level disorders as appropriate.

Patients with chronic hepatitis B or C who are treated with combination antiretroviral therapy have an increased risk of developing severe and potentially fatal hepatic adverse effects, and therefore should be closely monitored during treatment. The product literature relating to concurrent treatments for hepatitis B or C should be consulted.

Monitor liver enzymes in patients receiving other medications associated with liver toxicity.

Cases of osteonecrosis have been reported in patients with advanced HIV disease and/or long term exposure to combination antiretroviral therapy, although the aetiology of this condition is thought to be due to several factors including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index. Patients should be advised to seek medical advice if they experience joint aches or pains, joint stiffness or difficulty in movement.

The Drug Database for Acute Porphyria considers efavirenz as probably porphyrinogenic.

Pregnancy and Lactation

Pregnancy

Use efavirenz with caution in pregnancy. First trimester exposure should be avoided where possible.

Efavirenz should generally be avoided in pregnancy particularly during the first trimester due to reports of neural tube defects, and given only if no other options are available. Generally guidance states that HIV combination therapy should be continuous to prevent emergence of resistant viral strains, however the US Department of Health and Human Services guidelines recommend avoiding efavirenz in pregnancy particularly during the first trimester due to neural tube defects occurring. Briggs suggests data do not support efavirenz as being a major teratogen. If indicated the drug should not be withheld because of pregnancy.

There is limited information concerning efavirenz administration during human pregnancy. Post-marketing experience of 206 pregnancies exposed to efavirenz during the first trimester showed no specific malformation patterns. A small number of cases of neural tube defects, including meningomyelocele, have been reported but causality has not been established. The Antiretroviral Pregnancy Registry as of July 2013 reported one neural tube defect in a total of 766 live births from an initial 904 pregnancies. The rates of neural tube defects were reported to be within the general population range.

Efavirenz has shown teratogenic effects during studies in primates and embryotoxicity has been observed in rats, suggesting a potential for risk in humans. It is not known if efavirenz crosses the placenta however, animal studies and the low molecular weight (about 316) suggest that transfer occurs. Dandy Walker syndrome has also been reported after first trimester exposure.

Briggs recommends the use of zidovudine during the intrapartum period regardless of current regimen, as this may prevent vertical transmission of HIV to the newborn.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Efavirenz is contraindicated in breastfeeding. It is recommended that HIV infected women should not breastfeed their infants in order to avoid transmission of HIV.

Insufficient evidence exists for the safety of efavirenz in breastfeeding. The molecular weight (about 316) is low enough that excretion into the breast milk is expected. Due to insufficient data, risk to the infant cannot be excluded.

Studies in lactating rats demonstrated that efavirenz is excreted in milk achieving much higher concentrations than in the maternal plasma.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Abnormal thinking
Aggression
Agitation
Amnesia
Anxiety
Ataxia
Attention disturbances
Autoimmune hepatitis
Blurred vision
Catatonia
Cerebellar dysfunction
Confusion
Convulsions
Delusions
Depression
Diarrhoea
Dizziness
Dream abnormalities
Elevated amylase levels
Emotional lability
Erythema multiforme
Euphoria
Fatigue
Flushing
Gamma glutamyl transferase (GGT) increased
Graves' disease
Gynaecomastia
Hallucinations
Headache
Hepatic failure
Hepatitis
Hypercholesterolaemia
Hypersensitivity reactions
Hypertriglyceridaemia
Immune Reactivation/Reconstitution Syndrome
Impaired co-ordination
Impaired concentration
Increase in serum ALT/AST
Insomnia
Maculopapular rash
Mania
Metabolic disorders
Nausea
Nervous system effects
Neurosis
Osteonecrosis
Pancreatitis
Paranoia
Photoallergic reactions
Pruritus
Psychiatric disorders
Psychosis-like reactions
Rash
Sleep disturbances
Somnolence
Stevens-Johnson syndrome
Suicidal tendencies
Tinnitus
Tremor
Vertigo
Vomiting

Presentation

Oral formulations containing efavirenz.

Drugs List

Therapeutic Indications

Uses

HIV infection-combined with other antiretrovirals

Dosage

Adults

Children

Additional Dosage Information

Contraindications

Children under 3 months
Infants weighing less than 3.5kg
Breastfeeding
Congestive cardiac failure with reduced left ventricular ejection fraction
Galactosaemia
Long QT syndrome
Severe bradycardia
Severe electrolyte imbalance
Severe hepatic impairment
Torsade de pointes

Precautions and Warnings

Children aged 3 months to 18 years
Elderly
Family history of long QT syndrome
Acute porphyria
Electrolyte imbalance
Glucose-galactose malabsorption syndrome
Hepatitis B
Hepatitis C
History of depression
History of hepatic impairment
History of psychiatric disorder
History of seizures
History of torsade de pointes
Lactose intolerance
Mild hepatic impairment
Pregnancy
Severe renal impairment

Correct electrolyte disorders before treatment
Treatment does not prevent risk of transmission of HIV
Advise ability to drive/operate machinery may be affected by side effects
Consider prophylactic antihistamines for high risk patients
Not all available products are licensed for all age groups
Treatment should be initiated by doctor experienced in HIV management
Some formulations contain lactose
Advise patient to take at bedtime to reduce adverse effects
Not to be used as a single agent or added on to a failing regime
Exclude pregnancy prior to initiation of treatment
Autoimmune disorders can occur many months after initiation of treatment
Blood lipid and glucose levels may increase requiring treatment
Consider monitoring ECG in patients at risk of QT prolongation
Consider monitoring hepatic enzymes
Monitor for depressive disorders/suicidal ideation-consider discontinuation
Monitor patients with hepatic impairment
Monitor serum electrolytes
Advise patient to report any new or worsening depression/suicidal ideation
Advise patient to seek medical advice if joint aches or pain occur
Advise patient to seek medical advice if movement becomes difficult
Inflammatory symptoms should be evaluated and treated appropriately
Risk of developing opportunistic infections
May affect results of some laboratory tests
Discontinue if hepatic function deteriorates in pts with hepatic impairment
Discontinue if severe skin reaction occurs
Interrupt therapy if hepatic transaminases > 5 times upper limit of normal
Bioavailability differs with preparations;caution on changing formulations
Advise patient not to take ginkgo unless advised by clinician
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Female: Two reliable methods of contraception should be used simultaneously

When any antiretroviral in combination regimen is interrupted due to suspected intolerance, consider also interrupting all antiretroviral medications in order to prevent resistance developing. Restart all medications at the same time when intolerance symptoms have resolved.

Discontinue efavirenz if severe rash with blistering, desquamation, mucosal involvement or fever occur. If stopping efavirenz consider stopping all antiretrovirals. Mild to moderate rash usually improves with continuation of treatment and antihistamines and/or corticosteroids may be used. Efavirenz is not recommended in patients who have had life-threatening cutaneous reaction e.g. Stevens-Johnson syndrome whilst taking another NNRTI.

Rash is more common in children; consider prophylaxis with an appropriate antihistamine before initiating treatment.

Immune reactivation may occur when combination antiretroviral therapy is initiated in HIV infected patients with severe immune deficiency. Inflammatory reactions to asymptomatic or residual opportunistic pathogens may arise. This may lead to aggravation of symptoms or other serious clinical conditions such as cytomegalovirus retinitis, mycobacterial infections or Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia. These reactions usually happen in the first few weeks or months after treatment commences and should be evaluated and treated appropriately.

Blood lipid and glucose levels may increase during antiretroviral therapy. This may be linked to disease control and lifestyle. Refer to established HIV treatment guidelines for monitoring and manage lipid and glucose level disorders as appropriate.

Patients with chronic hepatitis B or C who are treated with combination antiretroviral therapy have an increased risk of developing severe and potentially fatal hepatic adverse effects, and therefore should be closely monitored during treatment. The product literature relating to concurrent treatments for hepatitis B or C should be consulted.

Monitor liver enzymes in patients receiving other medications associated with liver toxicity.

Cases of osteonecrosis have been reported in patients with advanced HIV disease and/or long term exposure to combination antiretroviral therapy, although the aetiology of this condition is thought to be due to several factors including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index. Patients should be advised to seek medical advice if they experience joint aches or pains, joint stiffness or difficulty in movement.

The Drug Database for Acute Porphyria considers efavirenz as probably porphyrinogenic.

Pregnancy and Lactation

Pregnancy

Use efavirenz with caution in pregnancy. First trimester exposure should be avoided where possible.

Efavirenz should generally be avoided in pregnancy particularly during the first trimester due to reports of neural tube defects, and given only if no other options are available. Generally guidance states that HIV combination therapy should be continuous to prevent emergence of resistant viral strains, however the US Department of Health and Human Services guidelines recommend avoiding efavirenz in pregnancy particularly during the first trimester due to neural tube defects occurring. Briggs suggests data do not support efavirenz as being a major teratogen. If indicated the drug should not be withheld because of pregnancy.

There is limited information concerning efavirenz administration during human pregnancy. Post-marketing experience of 206 pregnancies exposed to efavirenz during the first trimester showed no specific malformation patterns. A small number of cases of neural tube defects, including meningomyelocele, have been reported but causality has not been established. The Antiretroviral Pregnancy Registry as of July 2013 reported one neural tube defect in a total of 766 live births from an initial 904 pregnancies. The rates of neural tube defects were reported to be within the general population range.

Efavirenz has shown teratogenic effects during studies in primates and embryotoxicity has been observed in rats, suggesting a potential for risk in humans. It is not known if efavirenz crosses the placenta however, animal studies and the low molecular weight (about 316) suggest that transfer occurs. Dandy Walker syndrome has also been reported after first trimester exposure.

Briggs recommends the use of zidovudine during the intrapartum period regardless of current regimen, as this may prevent vertical transmission of HIV to the newborn.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Efavirenz is contraindicated in breastfeeding. It is recommended that HIV infected women should not breastfeed their infants in order to avoid transmission of HIV.

Insufficient evidence exists for the safety of efavirenz in breastfeeding. The molecular weight (about 316) is low enough that excretion into the breast milk is expected. Due to insufficient data, risk to the infant cannot be excluded.

Studies in lactating rats demonstrated that efavirenz is excreted in milk achieving much higher concentrations than in the maternal plasma.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Counselling

Advise patients to take the daily dose at bedtime to improve the tolerability of nervous system symptoms.

Advise patients to take on an empty stomach to prevent adverse reactions occurring. When administered with food, increased plasma levels of efavirenz are observed and this may lead to an increased incidence of adverse effects.

Capsule contents may be administered with a small amount of food (1 to 2 teaspoons). Patients and carers should be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. It is recommended to hold the capsule vertically with the cap facing upwards and to pull the cap away from the body of the capsule and to mix the contents with food in a small container. The mixture should then be administered as soon as possible (within 30 minutes of mixing). Following administration, a small amount (2 teaspoons) of food should be added to the mixing container and stirred to disperse any remaining drug residue and this must also be given to the patient. No additional food is to be consumed within 2 hours of administration.

Advise patient to avoid grapefruit products.

Advise patient to avoid St John's Wort.

Advise patient to avoid ginkgo unless advised by clinician.

Advise patient to report any new or worsening depression or suicidal ideation.

Advise patient to seek medical advice if joint aches or pains occur or if movement becomes difficult.

Inform patients nervous system symptoms involving CNS depression are reported frequently. These tend to start in the first two days of treatment and resolve after the first 2 to 4 weeks. These are not predictive of the less frequent psychiatric symptoms.

Advise patient their ability to drive and operate machinery may be affected by the side effects.

Side Effects

Abdominal pain
Abnormal thinking
Aggression
Agitation
Amnesia
Anxiety
Ataxia
Attention disturbances
Autoimmune hepatitis
Blurred vision
Catatonia
Cerebellar dysfunction
Confusion
Convulsions
Delusions
Depression
Diarrhoea
Dizziness
Dream abnormalities
Elevated amylase levels
Emotional lability
Erythema multiforme
Euphoria
Fatigue
Flushing
Gamma glutamyl transferase (GGT) increased
Graves' disease
Gynaecomastia
Hallucinations
Headache
Hepatic failure
Hepatitis
Hypercholesterolaemia
Hypersensitivity reactions
Hypertriglyceridaemia
Immune Reactivation/Reconstitution Syndrome
Impaired co-ordination
Impaired concentration
Increase in serum ALT/AST
Insomnia
Maculopapular rash
Mania
Metabolic disorders
Nausea
Nervous system effects
Neurosis
Osteonecrosis
Pancreatitis
Paranoia
Photoallergic reactions
Pruritus
Psychiatric disorders
Psychosis-like reactions
Rash
Sleep disturbances
Somnolence
Stevens-Johnson syndrome
Suicidal tendencies
Tinnitus
Tremor
Vertigo
Vomiting

Effects on Laboratory Tests

Cannabinoid test interaction
Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected volunteers who received efavirenz. The manufacturers suggest confirmatory testing by a more specific method such as gas chromatography/mass spectrometry should be used in such cases.

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: December 2015

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press https://www.medicinescomplete.com [Accessed on April 11, 2014].

Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications https://www.medicinescomplete.com [Accessed on April 11, 2014].

Summary of Product Characteristics: Sustiva 50mg, 100mg and 200mg Hard Capsules. Bristol Myers Squibb. Revised October 2018.
Summary of Product Characteristics: Sustiva 600mg Film-Coated Tablets. Bristol Myers Squibb. Revised October 2018.

The Drug Database for Acute Porphyria (NAPOS)
Available at: https://www.drugs-porphyria.com/languages/UnitedKingdom/index2.php?l=gbr
Efavirenz. Last revised: July 2 2015
Last accessed: December 17 2015