Efavirenz-Lamivudine-Tenofovir DF

Efavirenz-Lamivudine-Tenofovir DF is a combination medication used for the treatment of HIV infection.

• Efavirenz-Lamivudine-Tenofovir DF is available under the following different brand names: Symfi, Symfi Lo.

Common side effects of Efavirenz-Lamivudine-Tenofovir DF include:

• headache,
• dizziness,
• depression,
• thinking problems,
• nausea,
• diarrhea,
• sleep problems (insomnia),
• pain,
• weakness,
• tiredness,
• cough,
• stuffy nose,
• sinus pain,
• rash, and
• changes in the shape or location of body fat (especially in the arms, legs, face, neck, breasts and waist)

Serious side effects of Efavirenz-Lamivudine-Tenofovir DF include:

• hives,
• difficulty breathing,
• swelling of the face, lips, tongue, or throat,
• fever,
• sore throat,
• burning in the eyes,
• skin pain,
• red or purple skin rash that spreads and causes blistering and peeling,
• severe dizziness,
• drowsiness,
• trouble concentrating,
• strange dreams,
• confusion,
• thinking problems,
• hallucinations (may occur months or years after starting the medication),
• fast or pounding heartbeats,
• fluttering in the chest,
• sudden dizziness,
• problems with the balance or coordination,
• new or worsening bone pain,
• pain in your arms, legs, hands, or feet,
• unusual muscle pain,
• stomach pain,
• vomiting,
• irregular heart rate,
• dizziness,
• feeling cold,
• weakness,
• tiredness,
• severe pain in the upper stomach spreading to the back,
• nausea,
• unusual thoughts of fear, paranoia, sadness or hopelessness,
• thoughts of self-harm,
• swelling around the midsection,
• upper stomach pain,
• unusual tiredness,
• loss of appetite,
• dark urine,
• clay-colored stools,
• yellowing of the skin or eyes (jaundice),
• fever,
• night sweats,
• swollen glands,
• cold sores,
• cough,
• wheezing,
• diarrhea,
• weight loss,
• trouble speaking or swallowing,
• problems with balance or eye movement,
• prickly feeling,
• swelling in the neck or throat (enlarged thyroid),
• menstrual changes, and
• impotence

Rare side effects of Efavirenz-Lamivudine-Tenofovir DF include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors;
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult and pediatric dosage

Tablet

• 400 mg/300 mg/300 mg (Symfi Lo)
• 600 mg/300 mg/300 mg (Symfi)

HIV Infection

Adult dosage

• 1 tablet (efavirenz 400 mg/lamivudine 300 mg/tenofovir DF 300 mg) orally during bedtime OR
• 1 tablet (efavirenz 600 mg/lamivudine 300 mg/tenofovir DF 300 mg) orally during bedtime

Pediatric dosage

Symfi Lo

• Weight below 35 kg: Safety and efficacy not established
• Weight above 35 kg: 1 tablet (efavirenz 400 mg/lamivudine 300 mg/tenofovir 300 mg) orally during bedtime

Symfi

• Weight below 40 kg: Safety and efficacy not established
• Weight above 40 kg: 1 tablet (efavirenz 600 mg/lamivudine 300 mg/tenofovir DF 300 mg) orally during bedtime

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Efavirenz-Lamivudine-Tenofovir DF has severe interactions with the following drugs:
  • carbamazepine
  • cariprazine
  • cobimetinib
  • dienogest/estradiol valerate
  • doravirine
  • dronedarone
  • elbasvir/grazoprevir
  • elvitegravir/cobicistat/emtricitabine/tenofovir DF
  • emtricitabine
  • ergonovine
  • etravirine
• Efavirenz-Lamivudine-Tenofovir DF has serious interactions with at least 207 other drugs.
• Efavirenz-Lamivudine-Tenofovir DF has moderate interactions with at least 346 other drugs.
• Efavirenz-Lamivudine-Tenofovir DF has minor interactions with at least 101 other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all your products. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• Documented hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, toxic skin eruptions) to any components contained in the formulation
• Coadministration with elbasvir and grazoprevir

Effects of drug abuse

None

Short-Term Effects

• See “What Are Side Effects Associated with Using Efavirenz-Lamivudine-Tenofovir DF?”

Long-Term Effects

See “What Are Side Effects Associated with Using Efavirenz-Lamivudine-Tenofovir DF?”

Cautions

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, reported with the use of nucleoside analogs and other ARTs; suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity
• Not approved for chronic hepatitis B virus (HBV) infection and the safety and efficacy have not been established in patients coinfected with HBV and HIV-1; if treatment with Epivir-HBV, tenofovir DF, or a tenofovir AF-containing product is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment (see Black Box Warnings and Dosing Considerations)
• Risk of serious psychiatric events (eg, depression, suicidality, paranoia, manic episodes); immediate medical evaluation recommended for serious psychiatric symptoms such as severe depression or suicidal ideation; there have been occasional postmarketing reports of death by suicide, delusions, psychosis like behavior and catatonia; a causal relationship to the use of efavirenz cannot be determined from these reports (see Adverse Effects)
• CNS symptoms reported (eg, dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, hallucinations); nervous system symptoms (NSSs) are frequent and usually begin 1-2 days after initiating therapy and resolve in 2-4 weeks; dosing at bedtime may improve tolerability; NSSs are not predictive of onset of psychiatric symptoms
• Risk of rash; rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, rash resolves within 1 month
• Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman (see Pregnancy)
• Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, reported in patients treated with efavirenz; reports included patients with underlying hepatic disease, including coinfection with hepatitis B or C, and patients without preexisting hepatic disease or other identifiable risk factors; monitoring of liver enzymes before and during treatment is recommended for all patients; consider discontinuing treatment in patients with persistent elevations of serum transaminases to greater than 5x ULN; discontinue treatment if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensations
• Hepatic decompensation, some fatal, reported in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon and ribavirin-based regimens; monitor for treatment-associated toxicities; discontinue therapy, as medically appropriate, and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both
• Immune reconstitution syndrome reported in HIV-infected patients treated with combination ART; during initial phase of combination ART, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (eg, Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), tuberculosis), and further evaluation and treatment may be necessary
• Autoimmune disorders (eg, Grave disease, polymyositis, and Guillain-Barré syndrome, autoimmune hepatitis) reported to occur in the immune reconstitution setting; however, time to onset varies and can occur many months after initiation of treatment
• In HIV-infected patients, redistribution/accumulation of body fat (eg, central obesity, dorsocervical fat enlargement [buffalo hump], peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance) observed in patients receiving combination ART
• Treatment with efavirenz has resulted in increases in total cholesterol and triglycerides; perform cholesterol and triglyceride testing before initiating efavirenz therapy and at periodic intervals during therapy
• Convulsions observed in patients receiving efavirenz, generally in the presence of known medical history of seizures; exercise caution in any patient with a history of seizures
• In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, lamivudine should be used with caution
• Late-onset neurotoxicity
  • Ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning therapy
  • Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased drug levels despite standard dosing therapy
  • Evaluate promptly patients presenting with signs and symptoms of serious neurologic adverse experiences to assess the possibility that these events may be related to therapy, and whether discontinuation is warranted
  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, reported with use of nucleoside analogs and other antiretrovirals; female sex and obesity may be risk factors for development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues
• Bone effects of tenofovir
  • In clinical trials, tenofovir DF was associated with slightly greater decreases in bone mineral density and increases in biochemical markers of bone metabolism
  • Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, reported
  • Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients
  • Effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults and pediatric subjects 2 years and older are unknown
  • Long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, effects of long-duration exposure in younger children unknown
  • Consider assessment of BMD for adult and pediatric patients who have history of pathologic bone fracture or other risk factors for osteoporosis or bone loss; if bone abnormalities are suspected obtain appropriate consultation
• New onset or worsening renal impairment
  • Renal impairment (eg, cases of acute renal failure and Fanconi syndrome [eg, renal tubular injury with severe hypophosphatemia]) reported with the use of tenofovir DF
  • Assess estimated CrCl in all patients prior to initiating therapy and as clinically appropriate during therapy with tenofovir DF; in patients at risk of renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to initiation of tenofovir disoproxil fumarate and periodically during tenofovir DF therapy
  • Cases of acute renal failure after initiation of high-dose or multiple nonsteroidal anti-inflammatory drugs (NSAIDs) reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF; some patients required hospitalization and renal replacement therapy
• Drug interactions overview
  • Coadministration of Symfi Lo and other ARTs for HIV-1 should be avoided since Symfi Lo is a complete HIV infection
  • Concomitant use with other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effects, possible development of resistance, or possible increased effects/toxicities of concomitant drugs
  • Since tenofovir is primarily eliminated by the kidneys, coadministration of Efavirenz-Lamivudine-Tenofovir DF with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs; avoid Efavirenz-Lamivudine-Tenofovir DF with concurrent or recent use of a nephrotoxic agent (eg, high-dose or multiple NSAIDs); consider alternatives to NSAIDs, if needed, in patients at risk for renal dysfunction
  • QTc prolongation observed with the use of efavirenz; consider alternatives to efavirenz-containing products when coadministered with a drug with a known risk of torsade de pointes or with patients at higher risk of torsade de pointes
  • Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels
  • False-positive urine cannabinoid test results reported with some screening assays in uninfected and HIV-infected subjects receiving efavirenz; confirmation of positive screening tests for cannabinoids by a more specific method is recommended Efavirenz has been shown in vivo to induce CYP3A and CYP2B6; efavirenz coadministered with CYP3A or CYP2B6 substrates may result in decreased plasma concentrations
  • Drugs that induce CYP3A activity (eg, rifampin, rifabutin) would be expected to increase the clearance of efavirenz, resulting in lowered plasma concentrations; this may lead to loss of virologic response and possibly resistance
  • Lamivudine is predominantly eliminated in the urine by active organic cationic secretion; coadministration with drugs eliminated via organic cationic transport system (eg, trimethoprim) may interact with lamivudine
  • Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures; when possible, avoid use of sorbitol-containing medicines with lamivudine

Pregnancy and Lactation

• Advise pregnant women of the potential risk to a fetus
• Owing to the potential teratogenic effects, avoid pregnancy in women receiving Symfi Lo
• Females of reproductive potential should undergo pregnancy testing before initiation
• An ART pregnancy registry has been established (1-800-258-4263); prospective pregnancy data from the Antiviral Pregnancy Registry (APR) not sufficient to adequately assess risk of birth defects or miscarriage
• Retrospective case reports of neural tube defects in infants whose mothers were exposed to efavirenz-containing regimens in the first trimester of pregnancy; similar malformations observed in studies conducted in monkeys at doses similar to the human dose; fetal and embryonic toxicities occurred in rats at a dose 10 times less than the human exposure at recommended clinical dose; owing to the potential risk of neural tube defects, do not use in the first trimester of pregnancy
• Lamivudine produced embryonic toxicity in rabbits at a dose that produced similar human exposures as the recommended clinical dose; relevance of animal findings to human pregnancy registry data is not known; there are no adequate and well-controlled studies with tenofovir DF in pregnant women; tenofovir DF should be used during pregnancy only if clearly needed
• Contraception
  • Females of reproductive potential should use effective contraception during and for 12 weeks after discontinuing treatment, owing to the long half-life of efavirenz
  • Always use barrier contraception in combination with other methods of contraception
  • Hormonal methods that contain progesterone may have decreased effectiveness
• Lactation
  • The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection
  • Efavirenz has been shown to pass into human breast milk; no information available on the effects of efavirenz on the breastfed infant or the effects of efavirenz on milk production
  • Lamivudine is excreted into human milk
  • Samples of breast milk obtained from five HIV-1-infected mothers in the first postpartum week show that tenofovir is excreted in human milk at low levels; impact of this exposure in breastfed infants is unknown and the effects of tenofovir DF on milk production is unknown
  • Owing to the potential for HIV transmission (in HIV-negative infants), developing viral resistance (in HIV-positive infants), and adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed