efavirenz/lamivudine/tenofovir disoproxil fumarate

Efavirenz

Absorption: 50% absorbed when ingested following a high-fat meal.

Distribution: Unknown.

Protein Binding: >99%.

Metabolism/Excretion: Mostly metabolized by the liver by the CYP3A and CYP2B6 isoenzymes. 16–61% excreted in feces as unchanged drug, 14–34% excreted in urine (primarily as metabolites).

Half-Life: Following single dose: 52–76 hr. Following multiple doses: 40–55 hr.

Lamivudine

Absorption: 86% absorbed after oral administration.

Distribution: Unknown.

Metabolism/Excretion: Mostly excreted unchanged in urine; <5% metabolized by the liver.

Half-Life: 5–7 hr.

Tenofovir Disoproxil Fumarate

Absorption: Tenofovir disoproxil fumarate is a prodrug, which is split into tenofovir, the active component; absorption enhanced by food.

Distribution: Unknown.

Metabolism/Excretion: 70–80% excreted unchanged in urine by glomerular filtration and active tubular secretion.

Half-Life: 17 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
Efavirenz (PO)	rapid	3–5 hr	24 hr
Lamivudine (PO)	unknown	0.9 hr	24 hr
Tenofovir (PO)	unknown	2 hr	24 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Concurrent use of elbasvir and grazoprevir;
Coinfection with hepatitis B virus (HBV) (hepatitis may recur after discontinuation of lamivudine or tenofovir) (lamivudine dose not appropriate for patients coinfected with HBV);
Concurrent or recent use of nephrotoxic medications;
Concurrent use with ribavirin and/or interferon alfa (↑ risk of hepatic decompensation);
Moderate or severe hepatic impairment;
CCr <50 mL/min;
OB: May cause fetal harm during 1st trimester of pregnancy;
Lactation: Breastfeeding not recommended for women with HIV.

Use Cautiously in:

Mental illness, substance abuse, or use of psychiatric medications (↑ risk of psychiatric symptoms);
Seizures disorders (↑ risk of seizures);
Rep: Women of reproductive potential;
Pedi: Children with a prior history of antiretroviral exposure or history of pancreatitis ( risk of pancreatitis);
Pedi: Children 40 kg (Symfi) or 35 kg (Symfi Lo) (safety and effectiveness not established);
Geri: Cautious initial dosing in older adults due to incidence of renal, hepatic, or cardiac dysfunction.

Adv. Reactions/Side Effects ⬆ ⬇

CV: QT interval prolongation

Derm: rash, ERYTHEMA MULTIFORME, STEVENS-JOHNSON SYNDROME (SJS)

Endo: Graves' disease

F and E: diarrhea

GI: ↑amylase, ↑liver enzymes, abdominal pain, autoimmune hepatitis, dyspepsia, HEPATOMEGALY WITH STEATOSIS, HEPATOTOXICITY, LACTIC ACIDOSIS, nausea, PANCREATITIS, vomiting

GU: ACUTE RENAL FAILURE/FANCONI SYNDROME, hematuria

Hemat: neutropenia

Metab: fat redistribution, hyperlipidemia

MS: ↑creatine kinase, pain, ↓bone mineral density, arthralgia, muscle weakness, myalgia, osteomalacia, polymyositis

Neuro: depression, headache, abnormal dreams, aggressive behavior, anxiety, ataxia, catatonia, delusions, dizziness, drowsiness, encephalopathy, fatigue, Guillain-Barré syndrome, hallucinations, impaired concentration, insomnia, manic episodes, nervousness, paranoia, peripheral neuropathy, psychoses, sedation, SEIZURES, SUICIDAL THOUGHTS/BEHAVIORS

Misc: fever, immune reconstitution syndrome

Interactions ⬆ ⬇

Drug-drug:

May lead to loss of virologic response to elbasvir/grazoprevir; concurrent use contraindicated.
Nephrotoxic drugs, including acyclovir, aminoglycosides, cidofovir, ganciclovir, NSAIDs, valacyclovir, or valganciclovir, may ↑ risk of nephrotoxicity; avoid recent or concurrent use.
May ↑ risk of hepatic decompensation with ribavirin or interferon alfa; avoid concurrent use.
Concurrent use with other QT interval prolonging medications may ↑ risk of QT interval prolongation or torsades de pointes.
May alter the effects of warfarin.
Concurrent use with carbamazepine may ↓ levels of carbamazepine and efavirenz; use alternative anticonvulsant agent.
Concurrent use with phenytoin or phenobarbital may ↓ levels of phenytoin, carbamazepine, and efavirenz.
May ↓ levels of bupropion and sertraline; may need to ↑ antidepressant dose.
May ↓ posaconazole levels; avoid concurrent use.
May ↓ itraconazole or ketoconazole levels; use alternative antifungal agent.
May ↓ clarithromycin levels; consider using alternative antibiotic that does not cause QT interval prolongation.
May ↓ rifabutin levels; ↑ daily dose of rifabutin by 50%.
Rifampin may ↓ levels; ↑ dose of efavirenz.
May ↓ artemether/lumefantrine levels; consider alternative antimalarial that does not cause QT interval prolongation.
May ↓ atovaquone/proguanil levels; concurrent use not recommended.
May ↓ levels of calcium channel blockers; may need to ↑ calcium channel blocker dose.
May ↓ levels of atorvastatin, pravastatin, and simvastatin.
May ↓ therapeutic effects of pibrentasvir/glecaprevir, velpatasvir/sofosbuvir, and velpatasvir/sofosbuvir/voxilaprevir; concurrent use not recommended.
Ledipasvir/sofosbuvir may ↑ tenofovir levels.
May ↓ the effectiveness of progestin-containing hormonal contraceptives (e.g., etonogestrel, norelgestromin, levonorgestrel); additional barrier contraceptive should be used.
May ↓ levels of cyclosporine, tacrolimus, and sirolimus; may need to adjust dose of immunosuppressant.
May ↓ methadone levels.
Medications containing sorbitol may ↓ lamivudine levels.

Route/Dosage ⬆ ⬇

PO (Adults and Children ≥40 kg): Symfi: 1 tablet (efavirenz 600 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg) once daily.
PO (Adults and Children ≥35 kg): Symfi Lo: 1 tablet (efavirenz 400 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg) once daily.

Availability ⬆ ⬇

(Generic available)

Tablets (Symfi): efavirenz 600 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
Tablets (Symfi Lo): efavirenz 400 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg

Assessment ⬆ ⬇

Assess patient for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.
Assess patient for CNS and psychiatric symptoms (dizziness, impaired concentration, somnolence, abnormal dreams, insomnia, suicidal thoughts and behaviors) during therapy. Symptoms usually begin during 1st or 2nd day of therapy and resolve after 2–4 wk. Administration at bedtime may minimize symptoms. Concurrent use with alcohol or psychoactive agents may cause additive CNS symptoms.
Assess for rash, especially during 1st mo of therapy. Onset is usually within 2 wk and resolves with continued therapy within 1 mo. May range from mild maculopapular with erythema and pruritus to exfoliative dermatitis and SJS. Occurs more often and may be more severe in children. If rash is severe or accompanied by blistering, desquamation, mucosal involvement, or fever, therapy must be discontinued immediately. Symfi may be reinstated concurrently with antihistamines or corticosteroids in patients discontinuing due to rash.
Monitor for signs and symptoms of pancreatitis (abdominal pain with or without nausea and vomiting) during therapy. Discontinue therapy immediately if symptoms occur.
Monitor for seizures during therapy. Institute seizure precautions.
Assess bone mineral density in adult and pediatric patients with a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. May supplement with calcium and vitamin D.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.
- Monitor viral load and CD4 count before and routinely during therapy to determine response.
- Assess for HBV. Symfi and Symfi Lo are not approved for administration in patients with HIV and HBV. If therapy is discontinued, may cause severe exacerbation of HBV. Monitor liver function in coinfected patients for several months after stopping therapy.
- Monitor liver function tests prior to, during and following therapy. May cause ↑ LDL cholesterol, total cholesterol, and triglyceride concentrations. Lactic acidosis may occur with hepatic toxicity causing hepatic steatosis; may be fatal, especially in women. Discontinue therapy if symptoms occur.
- Calculate serum creatinine, CCr, urine glucose, and urine protein prior to and periodically during therapy and when clinically indicated. In patients with chronic kidney disease, assess serum creatinine, CCr, serum phosphorus, urine glucose, and urine protein prior to and periodically during therapy. May cause hypophosphatemia in patients with renal impairment.
- May cause ↑ lipids. Monitor total cholesterol and triglycerides before starting and periodically during therapy.
- May cause hyperglycemia and glycosuria.

Implementation ⬆ ⬇

PO: Administer once daily on an empty stomach, preferably at bedtime to minimize drowsiness.

Patient/Family Teaching ⬆ ⬇

Instruct patient on the importance of taking medication as directed, even if feeling better. Do not take more than prescribed amount and do not stop taking without consulting health care professional. Discontinuing therapy may lead to severe exacerbations. Take missed doses as soon as remembered unless almost time for next dose; do not double doses. Advise patient to read Patient Information prior to starting therapy and with each Rx refill in case of changes. Caution patient not to share or trade Symfi or Symfi Lo with others.
Inform patient of importance of HBV testing before starting antiretroviral therapy.
Inform patient that Symfi and Symfi Lo do not cure AIDS and may reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Caution patient to use a condom and avoid sharing needles or donating blood to prevent spreading HIV to others.
May cause dizziness, impaired concentration, or drowsiness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
Instruct patient to notify health care professional immediately if rash or suicidal thoughts or behaviors occur.
Advise patient to notify health care professional immediately if symptoms of lactic acidosis (nausea, vomiting, unusual or unexpected stomach discomfort; unusual muscle pain; difficulty breathing; feeling cold, especially in arms and legs; dizziness; fast or irregular heartbeat; and weakness or tiredness) liver problems (yellow skin or whites of eyes, dark urine, light-colored stools, loss of appetite, nausea, stomach pain) or signs of immune reconstitution syndrome (signs and symptoms of an infection or inflammation) occur.
Advise patient to notify health care professional if bone pain (bone pain that does not go away or worsening bone pain; pain in arms, legs, hands, or feet; broken bones; muscle pain or weakness). May be symptoms of a bone or kidney problem.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
Inform patient of risk of developing late-onset neurotoxicity (ataxia, encephalopathy); may occur months to years after starting therapy.
Rep: May cause fetal harm; may cause neural tube defects if administered during 1st trimester. Advise females of reproductive potential taking oral contraceptives to use a nonhormonal method of birth control during therapy and for at least 12 wk following discontinuation and to avoid breastfeeding. Advise patient to notify health care professional if they become pregnant while taking Symfi or Symfi Lo. Encourage patients who become pregnant during therapy to join Antiretroviral Pregnancy Registry that monitors pregnancy outcomes in women exposed to efavirenz during pregnancy. Enroll patient by calling 1-800-258-4263.
Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆