efavirenz/lamivudine/tenofovir DF (Rx)

Brand and Other Names:Symfi, Symfi Lo
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

efavirenz/lamivudine/tenofovir DF (ie, tenofovir disoproxil fumarate)

tablet

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

HIV Infection

Indicated as a complete antiretroviral (ART) regimen for HIV-1 infection

Combination consists of 2 nucleo(t)side reverse transcriptase inhibitors (NRTIs) (ie, lamivudine and tenofovir) and 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) (ie, efavirenz)

1 tablet (efavirenz 400 mg/lamivudine 300 mg/tenofovir DF 300 mg) PO qHS OR

1 tablet (efavirenz 600 mg/lamivudine 300 mg/tenofovir DF 300 mg) PO qHS

Also see administration

Dosage Modifications

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment necessary
  • Moderate-to-severe (Child-Pugh B or C): Not recommended

Renal impairment

  • CrCl ≥50 mL/min: No dosage adjustment necessary
  • CrCl <50 mL/min or end-stage renal disease (ESRD) requiring hemodialysis: Not recommended because drug is a fixed-dose combination tablet and dose cannot be adjusted

Dosing Considerations

Testing prior to initiation and during treatment

  • Prior to initiation of efavirenz/lamivudine/tenofovir DF, test patients for hepatitis B virus (HBV)
  • Assess serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein in all patients as clinically appropriate
  • Monitor hepatic function

Dosage Forms & Strengths

efavirenz/lamivudine/tenofovir DF (ie, tenofovir disoproxil fumarate)

tablet

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

HIV Infection

Indicated as a complete antiretroviral (ART) regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and children (weight dependent)

Combination consists of 2 nucleo(t)side reverse transcriptase inhibitors (NRTIs) (ie, lamivudine and tenofovir) and 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) (ie, efavirenz)

Also see administration

Symfi Lo

  • <35 kg: Safety and efficacy not established
  • ≥35 kg: 1 tablet (efavirenz 400 mg/lamivudine 300 mg/tenofovir 300 mg) PO qHS

Symfi

  • <40 kg: Safety and efficacy not established
  • ≥40 kg: 1 tablet (efavirenz 600 mg/lamivudine 300 mg/tenofovir DF 300 mg) PO qHS

Dosage Modifications

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment necessary
  • Moderate-to-severe (Child-Pugh B or C): Not recommended

Renal impairment

  • CrCl ≥50 mL/min: No dosage adjustment necessary
  • CrCl <50 mL/min or end-stage renal disease (ESRD) requiring hemodialysis: Not recommended because drug is a fixed-dose combination tablet and dose cannot be adjusted

Dosing Considerations

Testing prior to initiation and during treatment

  • Prior to initiation of efavirenz/lamivudine/tenofovir DF, test patients for hepatitis B virus (HBV)
  • Assess serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein in all patients as clinically appropriate
  • Monitor hepatic function

Clinical trials did not include sufficient number of patients aged ≥65 yr to determine if they respond differently from younger individuals

Exercise caution when administering lamivudine in elderly patients because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy

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Interactions

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            Adverse Effects

            Listed adverse reactions are Grade 2-4 unless specified

            >10%

            Rash (18%)

            Headache (14%)

            Pain (13%)

            Diarrhea (11%)

            Depression (11%)

            Grade 3-4 laboratory abnormalities

            • Fasting cholesterol >250 mg/dL (19%)
            • Creatine kinase (males: >990 U/L; females >845 U/L) (12%)

            1-10%

            Fever (8%)

            Abdominal pain (7%)

            Asthenia (6%)

            Anxiety (6%)

            Arthralgia (5%)

            Insomnia (5%)

            Pneumonia (5%)

            Myalgia (3%)

            Dizziness (3%)

            Lipodystrophy (1%)

            Peripheral neuropathy (1%)

            Grade 3-4 laboratory abnormalities

            • Serum amylase >175 U/L (9%)
            • AST elevated (5%)
            • ALT elevated (4%)
            • Hematuria >100 RBC/HPF (7%)
            • Neutrophils <750 mg/dL (3%)
            • Fasting triglycerides >750 mg/dL (1%)

            Postmarketing Reports

            Efavirenz

            • Body as a whole: Allergic reactions, asthenia, redistribution/accumulation of body fat
            • Central and peripheral nervous system: Abnormal coordination, ataxia, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo
            • Endocrine: Gynecomastia
            • Gastrointestinal: Constipation, malabsorption
            • Cardiovascular: Flushing, palpitations
            • Liver and biliary system: Hepatic enzyme increase, hepatic failure, hepatitis
            • Metabolic and nutritional: Hypercholesterolemia, hypertriglyceridemia
            • Musculoskeletal: Arthralgia, myalgia, myopathy
            • Psychiatric: Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia
            • Respiratory: Dyspnea
            • Skin and appendages: Erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome
            • Special senses: Abnormal vision, tinnitus

            Lamivudine

            • Body as a whole: Redistribution/accumulation of body fat
            • Endocrine and metabolic: Hyperglycemia
            • General: Weakness
            • Hemic and lymphatic: Anemia (including pure red blood cell aplasia and severe anemias progressing on therapy)
            • Hepatic and pancreatic: Lactic acidosis and hepatic steatosis, posttreatment exacerbation of hepatitis B
            • Hypersensitivity: Anaphylaxis, urticaria
            • Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis
            • Skin: Alopecia, pruritus

            Tenofovir DF

            • Immune system disorders: Allergic reaction, including angioedema
            • Metabolism and nutrition disorders: Lactic acidosis, hypokalemia, hypophosphatemia
            • Respiratory, thoracic, and mediastinal disorders: Dyspnea
            • Gastrointestinal disorders: Pancreatitis, increased amylase, abdominal pain
            • Renal and urinary disorders: Renal insufficiency, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria
            • Hepatobiliary disorders: Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)
            • Skin and subcutaneous tissue disorders: Rash
            • Musculoskeletal and connective-tissue disorders: Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy
            • General disorders and administration site conditions: Asthenia
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            Warnings

            Black Box Warnings

            Severe acute exacerbations of hepatitis B reported in patients coinfected with HBV and HIV-1 and who have discontinued lamivudine or tenofovir DF, 2 components of Symfi Lo

            Closely monitor hepatic function in these patients and initiate antihepatitis B treatment if necessary

            Contraindications

            Documented hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, toxic skin eruptions) to any components contained in the formulation

            Coadministration with elbasvir and grazoprevir

            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) 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

            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

            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
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            Pregnancy & Lactation

            Pregnancy

            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

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Tenofovir: NRTI; following hydrolysis and phosphorylation, inhibits HIV-1 reverse transcriptase by competing with AMP as substrate

            Lamivudine: NRTI; following phosphorylation, inhibits HIV reverse transcriptase by viral DNA chain termination; cytosine analog

            Efavirenz: NNRTI; activity against HIV-1 by binding to reverse transcriptase and consequently blocking the RNA-dependent and DNA-dependent DNA polymerase activities including HIV-1 replication; it does not require intracellular phosphorylation for antiviral activity

            Absorption

            Efavirenz

            • Peak plasma time: 3-5 hr
            • Steady-state plasma concentration reached in 6-10 days

            Lamivudine

            • Peak plasma concentration: 1.5 mcg/mL (2 mg/kg BID)
            • Bioavailability: 87% (oral solution)
            • Peak plasma concentration
              • CrCl >60 mL/min, single 300-mg dose: 2.6 mcg/mL
              • CrCl 10-30 mL/min, single 300-mg dose: 3.6 mcg/mL
              • CrCl <10 mL/min, single 300-mg dose: 6 mcg/mL
            • AUC
              • CrCl >60 mL/min, single 300-mg dose: 11 mcg•hr/mL
              • CrCl 10-30 mL/min, single 300-mg dose: 48 mcg•hr/mL
              • CrCl <10 mL/min, single 300-mg dose: 157 mcg•hr/mL

            Tenofovir DF

            • Peak plasma time: 1 hr
            • Bioavailability: ~25% (fasted)
            • Peak plasma concentration
              • Fasted; single 300-mg dose: 296 ng/mL
              • CrCl >80 mL/min, single 300-mg dose: 0.34 mcg/mL
              • CrCl >80 mL/min, single 300-mg dose: 0.34 mcg/mL
              • CrCl 50-80 mL/min, single 300-mg dose: 0.33 mcg/mL
              • CrCl 30-49 mL/min, single 300-mg dose: 0.37 mcg/mL
              • CrCl 12-29 mL/min, single 300-mg dose: 0.6 mcg/mL
            • AUC
              • Fasted; single 300-mg dose: 2287 ng•hr/mL
              • CrCl >80 mL/min, single 300-mg dose: 2.18 mcg•hr/mL
              • CrCl 50-80 mL/min, single 300-mg dose: 3.06 mcg•hr/mL
              • CrCl 30-49 mL/min, single 300-mg dose: 6.01 mcg•hr/mL
              • CrCl 12-29 mL/min, single 300-mg dose: 15.98 mcg•hr/mL

            Distribution

            Efavirenz

            • Protein bound: ~99.5-99.75% (human plasma proteins, predominantly albumin)

            Lamivudine

            • Protein bound: <36%

            Tenofovir DF

            • Protein bound: <7% (0.01-25 mcg/mL)

            Metabolism

            Efavirenz

            • In vitro studies suggest CYP3A and CYP2B6 are major isozymes responsible for efavirenz metabolism; also shown to induce CYP enzymes, resulting in induction of its own metabolism

            Tenofovir DF

            • Not by CYP; converted intracellularly by hydrolysis to tenofovir, then phosphorylated to active tenofovir diphosphate

            Excretion

            Efavirenz

            • Half-life: 52-76 hr (single doses); 40-55 hr (multiple doses)
            • Excretion: Feces (16-68%)

            Lamivudine

            • Excretion, trans-sulfoxide metabolite: Urine (5.2%)
            • Majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion
            • Half-life: 5-7 hr

            Tenofovir DF

            • Excretion: Urine (~70-80% [unchanged drug])
            • Half-life: ~17 hr
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            Administration

            Oral Administration

            Oral use only

            Take on an empty stomach, preferably at bedtime; dosing at bedtime may improve tolerability of neurologic symptoms

            Missed dose

            • Missed dose: Take dose as soon as possible
            • If it is almost time for next dose, skip missed dose and take next dose at your regular time

            Storage

            Tablets: Store below 30°C (86°F)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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