Efavirenz / Emtricitabine / Tenofovir Disoproxil Fumarate (Mylan-Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate)

1. Health Canada Product Monograph — Efavirenz / Emtricitabine / Tenofovir Disoproxil Fumarate

• This medicine treats HIV-1 infection in adults, either used alone as a complete regimen or combined with other antiretroviral agents.
• It is not approved to treat chronic hepatitis B infection, even though two of its components are also active against hepatitis B virus.

• Efavirenz may cause fetal harm when taken during the first trimester, so pregnancy should be avoided while on this medicine and for 12 weeks after stopping it.
• A barrier method of contraception must always be used together with another method, such as hormonal contraception, since efavirenz can reduce the effectiveness of hormonal birth control.
• Women who could become pregnant should have a pregnancy test before starting this medicine.
• This medicine should only be used in pregnancy if the potential benefit outweighs the potential risk to the fetus, such as when there is no other treatment option.
• Rare reports of neural tube defects have been described in babies exposed to efavirenz-containing regimens in the first trimester, though a direct causal link has not been established.

• Mothers with HIV should not breastfeed while taking this medicine, primarily to avoid passing HIV to the infant.
• Efavirenz, emtricitabine, and tenofovir all pass into breast milk, and nursing infants may be at risk of developing viral resistance or other adverse effects.

• Clinical studies did not include enough patients aged 65 and older to know whether they respond differently than younger adults; dose selection should be cautious given the greater likelihood of reduced liver, kidney, or heart function in this age group.

• Safety and effectiveness have not been established in patients under 18 years of age, so this medicine is not recommended for pediatric use.

• The recommended dose is one tablet (600 mg efavirenz / 200 mg emtricitabine / 300 mg tenofovir) taken by mouth once daily on an empty stomach.
• Taking the dose at bedtime can improve tolerability of nervous system side effects such as dizziness or vivid dreams.
• Because this is a fixed-dose tablet whose individual components cannot be separated, it should not be used in patients with moderate to severe kidney impairment (creatinine clearance under 50 mL/min).
• This medicine is not recommended in patients with moderate or severe liver impairment, and should be used cautiously with careful monitoring in mild liver impairment.
• If a dose is missed and remembered the same day, it should be taken right away; never take more than one dose in a single day.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Overdose experience is limited; some patients who accidentally took twice the recommended efavirenz dose reported increased nervous system symptoms, involuntary muscle contractions, or vomiting.
• There is no specific antidote for efavirenz overdose.
• Activated charcoal may help remove unabsorbed efavirenz from the gut.
• Emtricitabine and tenofovir can be removed to some extent by hemodialysis, but efavirenz is highly protein-bound and is not expected to be significantly removed by dialysis.
• Management is supportive, with monitoring of vital signs and clinical status.

• Dizziness may occur, often within the first days of treatment.
• Vivid or abnormal dreams may occur.
• Nausea may occur.
• Diarrhea may occur.
• Headache may occur.
• Fatigue may occur.
• Trouble sleeping (insomnia) may occur.
• Drowsiness (somnolence) may occur.
• Skin rash may occur, usually within the first two weeks of treatment.
• Upper respiratory infections and sinus infections may occur more often.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Lactic acidosis and severe enlargement of the liver with fatty change, including fatal cases, have been reported with the tenofovir component.
• Serious liver problems, including liver failure, have occurred, sometimes in people without pre-existing liver disease.
• Severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur; treatment should be stopped immediately if severe rash develops with blistering, peeling, or fever.
• Serious psychiatric reactions, including severe depression, suicidal thoughts, aggressive behaviour, and, rarely, psychosis, have been reported.
• Seizures have occurred, more often in patients with a prior seizure history.
• Kidney problems, including acute kidney failure and Fanconi syndrome (a kidney condition causing loss of phosphate, glucose, and other substances in the urine), have been reported with the tenofovir component.
• Decreases in bone mineral density have been observed with long-term tenofovir use.
• Immune reconstitution inflammatory syndrome can occur as the immune system recovers, triggering inflammation from hidden infections or autoimmune conditions.
• Sudden worsening of hepatitis B has been reported in patients coinfected with HIV and hepatitis B after stopping this medicine, so liver function should be monitored closely for several months after discontinuation in these patients.
• Seek urgent medical attention for severe rash, yellowing of the skin or eyes, unusual muscle pain with weakness, difficulty breathing, or thoughts of self-harm.

• Use with caution in patients with underlying liver disease, including hepatitis B or C coinfection, due to the risk of worsening liver function.
• Use with caution in patients with a history of seizures or who take other medicines that lower the seizure threshold.
• Use with caution in patients with a history of psychiatric illness, and monitor closely for new or worsening depression, anxiety, or unusual thoughts.
• Use with caution in patients with risk factors for kidney disease, and check kidney function before starting and periodically during treatment.
• Use with caution in patients with a history of bone fracture or osteoporosis risk, since tenofovir can reduce bone mineral density.
• Use with caution in patients switching from a protease-inhibitor-based regimen, since virologic response may be lower and closer monitoring is warranted.
• Avoid concurrent use of other nephrotoxic drugs, such as aminoglycosides, amphotericin B, or vancomycin, because of the added kidney risk from tenofovir.
• Alert patients to the added risk of central nervous system effects when this medicine is combined with alcohol or other psychoactive drugs.

• Contraindicated in patients with known hypersensitivity to efavirenz, emtricitabine, tenofovir disoproxil fumarate, or any ingredient in the tablet.
• Contraindicated with certain antiarrhythmics, such as bepridil, due to the risk of serious heart rhythm problems.
• Contraindicated with the hepatitis C combination elbasvir/grazoprevir, due to a significant loss of effectiveness of that treatment.
• Contraindicated with voriconazole, since each drug significantly changes the blood levels of the other.
• Contraindicated with certain antihistamines (astemizole, terfenadine) and the GI motility drug cisapride, due to the risk of serious heart rhythm problems.
• Contraindicated with ergot-derived migraine medicines, due to the risk of severe vasospasm and reduced blood flow to the extremities.
• Contraindicated with the sedatives midazolam and triazolam, due to the risk of prolonged sedation or slowed breathing.
• Contraindicated with the antipsychotic pimozide, due to the risk of serious heart rhythm problems.
• Contraindicated with St. John's wort, since it can significantly lower efavirenz levels and lead to loss of viral control.

• Other HIV protease inhibitors, including atazanavir and indinavir, can have significantly altered blood levels when combined with this medicine, and some combinations are not recommended.
• Certain hepatitis C antiviral regimens, including glecaprevir/pibrentasvir, can have reduced effectiveness when combined with this medicine and are not recommended together.
• Rifampin lowers efavirenz levels and generally requires an increased efavirenz dose; rifabutin levels are reduced and usually require an increased rifabutin dose.
• Methadone levels can drop significantly, sometimes causing withdrawal symptoms, so the methadone dose may need to be increased.
• Warfarin levels can be increased or decreased, so more frequent monitoring of blood clotting tests is needed.
• Immunosuppressants such as cyclosporine, tacrolimus, and sirolimus can have reduced blood levels, requiring closer monitoring and possible dose adjustment.
• Sertraline levels can be reduced, sometimes requiring a higher sertraline dose.
• Hormonal contraceptives can have reduced effectiveness, so a reliable barrier method must always be used in addition.
• Other enzyme-inducing or enzyme-affected drugs metabolized through the same liver pathways as efavirenz may need dose adjustment; a pharmacist should review the full medication list before starting this medicine.

• This medicine should be taken on an empty stomach; taking it with a high-fat meal significantly increases efavirenz absorption and can worsen nervous system side effects such as dizziness and vivid dreams.

• Take this medicine once daily on an empty stomach, ideally at bedtime, to help reduce dizziness, vivid dreams, and other nervous system side effects.

• Store at 15°C to 30°C in the original container, tightly closed.
• Do not use if the seal over the bottle opening is broken or missing.

• This medicine is a three-drug combination that treats HIV-1 infection and must be taken every day, on an empty stomach, exactly as prescribed, without missing doses.
• Taking it at bedtime can make dizziness, vivid dreams, and other nervous system effects easier to tolerate.
• Tell your healthcare professional about every other medicine you take, including birth control, since this medicine has many significant drug interactions and can make hormonal contraceptives less effective.