Efavirenz / emtricitabine / tenofovir Side Effects

Not all side effects for efavirenz / emtricitabine / tenofovir may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to efavirenz / emtricitabine / tenofovir: oral tablet

In addition to its needed effects, some unwanted effects may be caused by efavirenz / emtricitabine / tenofovir. In the event that any of these side effects do occur, they may require medical attention.

You should check with your doctor immediately if any of these side effects occur when taking efavirenz / emtricitabine / tenofovir:

Less common
  • Abdominal or stomach pain or tenderness
  • blistering, peeling, or loosening of the skin
  • body aches or pain
  • clay-colored stools
  • cough
  • dark urine
  • ear congestion
  • fever or chills
  • headache
  • itching
  • loss of voice
  • muscle aches
  • nausea and vomiting
  • severe skin rash
  • sore throat
  • swelling of the feet or lower legs
  • tightness of the chest
  • trouble concentrating
  • yellow eyes or skin

Some of the side effects that can occur with efavirenz / emtricitabine / tenofovir may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common
  • Diarrhea
  • dizziness
  • unusual tiredness or weakness
Less common
  • Abnormal dreams
  • decreased appetite
  • discouragement
  • feeling sad or empty
  • irritability
  • loss of appetite
  • loss of interest or pleasure
  • mild rash
  • pain or tenderness around the eyes and cheekbones
  • sleepiness
  • trouble sleeping
  • unusual drowsiness

For Healthcare Professionals

Applies to efavirenz / emtricitabine / tenofovir: oral tablet

General

The most common side effects reported with this drug were psychiatric disorders, nervous system disorders, and gastrointestinal disorders. During a clinical trial using the individual components, the most common side effects were diarrhea, nausea, headache, fatigue, dizziness, depression, insomnia, abnormal dreams, and rash.

In general, the most common side effects associated with efavirenz in combination with other antiretroviral drugs of at least moderate severity included rash, dizziness, nausea, headache, and fatigue; the most significant side effects were nervous system symptoms, psychiatric symptoms, and rash.

In general, the most common side effects associated with emtricitabine in combination with other antiretroviral drugs of mild to moderate severity included headache, diarrhea, nausea, and rash; mild and asymptomatic skin discoloration (hyperpigmentation on the palms and/or soles) occurred more often with emtricitabine than the control treatment.

In general, the most common side effects associated with tenofovir in combination with other antiretroviral drugs were mild to moderate gastrointestinal events, including nausea, diarrhea, vomiting, and flatulence.[Ref]

Metabolic

Elevated fasting cholesterol (greater than 240 mg/dL), elevated fasting triglycerides (greater than 750 mg/dL), altered serum glucose (less than 40 mg/dL or greater than 250 mg/dL), hyperglycemia (greater than 250 mg/dL), and elevated alkaline phosphatase (greater than 550 units/L) have been reported in up to 22%, 4%, up to 3%, up to 2%, and 1% of patients, respectively.

Hypercholesterolemia and hypertriglyceridemia have also been reported during postmarketing experience with efavirenz.

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with the use of nucleoside analogs.

Hypokalemia and hypophosphatemia may occur as a result of proximal renal tubulopathy.

Hypokalemia, lactic acidosis, and hypophosphatemia have also been reported during postmarketing experience with tenofovir.[Ref]

Very common (10% or more): Elevated fasting cholesterol (up to 22%)
Common (1% to 10%): Anorexia, elevated fasting triglycerides, altered serum glucose, hyperglycemia, elevated alkaline phosphatase
Uncommon (0.1% to 1%): Increased appetite

Efavirenz:
-Common (1% to 10%): Anorexia, hypertriglyceridemia
-Uncommon (0.1% to 1%): Hypercholesterolemia
-Postmarketing reports: Redistribution/accumulation of body fat (in areas such as back of neck, breasts, abdomen, retroperitoneum)

Emtricitabine:
-Common (1% to 10%): Hyperglycemia, hypertriglyceridemia

Tenofovir:
-Very common (10% or more): Hypophosphatemia
-Uncommon (0.1% to 1%): Hypokalemia
-Rare (less than 0.1%): Lactic acidosis

Combination antiretroviral therapy:
-Frequency not reported: Metabolic abnormalities (e.g., hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, hyperlactatemia), redistribution/accumulation of body fat (including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, "cushingoid appearance")[Ref]

Gastrointestinal

Common (1% to 10%): Diarrhea, nausea, elevated serum amylase, vomiting
Uncommon (0.1% to 1%): Dry mouth

Emtricitabine or tenofovir:
-Common (1% to 10%): Dyspepsia, abdominal pain, elevated pancreatic amylase, elevated serum lipase

Efavirenz:
-Common (1% to 10%): Dyspepsia, abdominal pain, diarrhea, vomiting, nausea
-Uncommon (0.1% to 1%): Pancreatitis
-Postmarketing reports: Constipation, malabsorption

Emtricitabine:
-Very common (10% or more): Diarrhea, nausea
-Common (1% to 10%): Elevated amylase (including elevated pancreatic amylase), elevated serum lipase, vomiting, abdominal pain, dyspepsia

Tenofovir:
-Very common (10% or more): Diarrhea, vomiting, nausea
-Common (1% to 10%): Abdominal pain, abdominal distension, flatulence
-Uncommon (0.1% to 1%): Pancreatitis
-Postmarketing reports: Increased amylase[Ref]

Elevated serum amylase (greater than 175 units/L) has been reported in up to 8% of patients.

Elevated pancreatic amylase (greater than 2 x ULN) and serum lipase (greater than 2 x ULN) have each been reported with emtricitabine or tenofovir in up to 3% of patients.

Pancreatitis and abdominal pain have also been reported during postmarketing experience with efavirenz and tenofovir.[Ref]

Psychiatric

Serious psychiatric side effects associated with efavirenz have included severe depression, suicidal ideation, nonfatal suicide attempts, aggression, paranoia, and mania.

Aggression, agitation, affect lability, psychosis, paranoia, and mania have also been reported during postmarketing experience with efavirenz.[Ref]

Common (1% to 10%): Depression, anxiety, insomnia
Uncommon (0.1% to 1%): Decreased libido

Efavirenz:
-Very common (10% or more): Insomnia (up to 16.3%)
-Common (1% to 10%): Depression, anxiety, severe depression, abnormal dreams, nervousness, hallucination
-Uncommon (0.1% to 1%): Suicidal ideation, nonfatal suicide attempts, aggression, paranoia, mania, psychosis, euphoric mood, affect/emotional lability, confusional state, agitation
-Frequency not reported: Depersonalization, delirium
-Postmarketing reports: Delusions, neurosis, psychosis-like behavior, completed suicide

Emtricitabine:
-Common (1% to 10%): Insomnia, abnormal dreams[Ref]

Nervous system

Common (1% to 10%): Dizziness, headache
Uncommon (0.1% to 1%): Incoherent speech

Emtricitabine or tenofovir:
-Common (1% to 10%): Paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy)

Efavirenz:
-Very common (10% or more): Nervous system symptoms (53%), dizziness (up to 28.1%)
-Common (1% to 10%): Impaired concentration, somnolence, cerebellar coordination and balance disturbances, headache, disturbance in attention
-Uncommon (0.1% to 1%): Convulsions, amnesia, abnormal thinking, ataxia, abnormal coordination, tremor, vertigo, tinnitus
-Frequency not reported: Stupor
-Postmarketing reports: Hypoesthesia, paresthesia, neuropathy

Emtricitabine:
-Very common (10% or more): Headache
-Common (1% to 10%): Dizziness

Tenofovir:
-Very common (10% or more): Dizziness
-Common (1% to 10%): Headache[Ref]

Nervous system symptoms of any grade and regardless of causality (53%) included dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, hallucinations, amnesia, agitation, euphoria, depersonalization, confusion, abnormal thinking, and stupor during clinical trials of efavirenz in combination with other antiretroviral agents. These symptoms were mild in 33.3%, moderate in 17.4%, and severe in 2% of patients; generally began the first or second day of therapy and often resolved after 2 to 4 weeks. Therapy was discontinued in 2.1% of patients due to these side effects.

Abnormal coordination, ataxia, cerebellar coordination and balance disturbances, convulsions, tremor, tinnitus, and vertigo have also been reported during postmarketing experience with efavirenz.[Ref]

Dermatologic

Rashes associated with efavirenz were usually mild-to-moderate maculopapular skin eruptions. The median time to onset of rash was 11 days. In most patients who continued therapy, the rash resolved within 1 month. Treatment was discontinued in 1.7% of patients due to rash.

There was limited experience using efavirenz in patients who previously discontinued other nonnucleoside reverse transcriptase inhibitors due to rash. In 19 such patients formerly on nevirapine, about half developed a mild to moderate rash; 2 of those patients discontinued efavirenz because of the rash.

Erythema multiforme, pruritus, photoallergic dermatitis, and Stevens-Johnson syndrome have also been reported during postmarketing experience with efavirenz. Rash has also been reported during postmarketing experience with tenofovir.[Ref]

Common (1% to 10%): Rash event (including rash, exfoliative rash, generalized rash, macular rash, maculopapular rash, pruritic rash, vesicular rash)

Emtricitabine or tenofovir:
-Common (1% to 10%): Rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, allergic reaction)

Efavirenz:
-Very common (10% or more): Skin rash of any grade (up to 26.3%), grade 2 rash (diffuse maculopapular rash, dry desquamation; 14.7%), grade 1 rash (erythema, pruritus; 10.7%)
-Common (1% to 10%): Pruritus
-Uncommon (0.1% to 1%): Grade 3 rash (vesiculation, moist desquamation, ulceration), grade 4 rash (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, necrosis requiring surgery, exfoliative dermatitis)
-Rare (less than 0.1%): Photoallergic dermatitis
-Frequency not reported: Nail disorders, skin discoloration, leukocytoclastic vasculitis

Emtricitabine:
-Common (1% to 10%): Vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin discoloration (palmar-plantar hyperpigmentation)
-Postmarketing reports: Angioedema

Tenofovir:
-Very common (10% or more): Rash
-Rare (less than 0.1%): Angioedema[Ref]

Other

Common (1% to 10%): Fatigue
Frequency not reported: Increased body weight

Emtricitabine or tenofovir:
-Common (1% to 10%): Fever, pain, back pain

Efavirenz:
-Common (1% to 10%): Pain, fatigue
-Uncommon (0.1% to 1%): Flushing
-Frequency not reported: False-positive urine cannabinoid test results
-Postmarketing reports: Contraceptive failure (with an implantable hormonal contraceptive), asthenia

Emtricitabine:
-Common (1% to 10%): Pain, asthenia

Tenofovir:
-Very common (10% or more): Asthenia
-Frequency not reported: Higher 1,25 vitamin D levels[Ref]

False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected patients receiving efavirenz.

Flushing and asthenia have also been reported during postmarketing experience with efavirenz and tenofovir, respectively.[Ref]

Respiratory

Common (1% to 10%): Sinusitis, upper respiratory tract infections, nasopharyngitis

Emtricitabine or tenofovir:
-Common (1% to 10%): Increased cough, pneumonia, rhinitis

Efavirenz:
-Postmarketing reports: Dyspnea

Tenofovir:
-Postmarketing reports: Dyspnea[Ref]

Hepatic

Elevated AST (greater than 180 units/L in males and 170 units/L in females) and ALT (greater than 215 units/L in males and 170 units/L in females) have been reported in 3% and 2% of patients, respectively.

AST and ALT elevations were reported more often in patients who were coinfected with hepatitis B or C than in patients without coinfection.

Elevated bilirubin (greater than 2.5 times the upper limit of normal [2.5 x ULN]) has been reported with emtricitabine or tenofovir in up to 3% of patients.

Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and hepatitis B after discontinuation of emtricitabine or tenofovir and were associated with liver failure and liver decompensation in some of the emtricitabine-treated patients.

Some of the postmarketing reports of hepatic failure with efavirenz occurred in patients with no preexisting liver disease or other identifiable risk factors.

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with nucleoside analogs.

Hepatic steatosis and hepatitis have also been reported during postmarketing experience with tenofovir.[Ref]

Common (1% to 10%): Elevated AST, elevated ALT

Emtricitabine or tenofovir:
-Common (1% to 10%): Elevated bilirubin
-Frequency not reported: Severe acute exacerbations of hepatitis B

Efavirenz:
-Common (1% to 10%): Elevated ALT, elevated AST, elevated GGT
-Uncommon (0.1% to 1%): Acute hepatitis
-Postmarketing reports: Hepatic enzyme increase, hepatic failure (a few reports were characterized by a fulminant course, with some cases progressing to transplantation or death), hepatitis

Emtricitabine:
-Common (1% to 10%): Elevated serum AST and/or elevated serum ALT, hyperbilirubinemia
-Frequency not reported: Liver failure, liver decompensation

Tenofovir:
-Common (1% to 10%): Increased transaminases
-Rare (less than 0.1%): Hepatic steatosis, hepatitis
-Frequency not reported: Lactic acidosis/severe hepatomegaly with steatosis
-Postmarketing reports: Elevated liver enzymes (primarily AST, ALT, GGT)[Ref]

Hematologic

Decreased neutrophils (less than 750/mm3) has been reported in 3% of patients.[Ref]

Common (1% to 10%): Decreased neutrophils
Frequency not reported: Increased hemoglobin

Emtricitabine:
-Common (1% to 10%): Neutropenia
-Uncommon (0.1% to 1%): Anemia[Ref]

Musculoskeletal

Elevated creatine kinase (greater than 990 units/L in males and 845 units/L in females) has been reported in up to 9% of patients.

Rhabdomyolysis, osteomalacia, muscular weakness, and myopathy may occur as a result of proximal renal tubulopathy.

Rhabdomyolysis, osteomalacia, muscular weakness, and myopathy have also been reported during postmarketing experience with tenofovir.[Ref]

Common (1% to 10%): Elevated creatine kinase
Uncommon (0.1% to 1%): Myalgia

Emtricitabine or tenofovir:
-Common (1% to 10%): Arthralgia, myalgia

Emtricitabine:
-Very common (10% or more): Elevated creatine kinase

Efavirenz:
-Postmarketing reports: Arthralgia, myalgia, myopathy

Tenofovir:
-Uncommon (0.1% to 1%): Rhabdomyolysis, muscular weakness
-Rare (less than 0.1%): Myopathy, osteomalacia (manifested as bone pain and infrequently contributing to fractures)
-Frequency not reported: Decreased bone mineral density, increased biochemical markers of bone metabolism

Combination antiretroviral therapy:
-Frequency not reported: Osteonecrosis[Ref]

Genitourinary

Common (1% to 10%): Hematuria
Uncommon (0.1% to 1%): Glycosuria

Tenofovir:
-Uncommon (0.1% to 1%): Proteinuria
-Postmarketing reports: Polyuria[Ref]

Hematuria (greater than 75 red blood cells/high power field) and glycosuria (3+ or greater) have been reported in up to 3% and less than 1% of patients, respectively.

Proteinuria has also been reported during postmarketing experience with tenofovir.[Ref]

Renal

Tenofovir:
-Uncommon (0.1% to 1%): Increased creatinine
-Rare (less than 0.1%): Renal failure (acute and chronic), acute tubular necrosis, proximal renal tubulopathy (including Fanconi syndrome), nephrogenic diabetes insipidus
-Frequency not reported: New onset or worsening renal impairment
-Postmarketing reports: Renal insufficiency, nephritis (including acute interstitial nephritis)[Ref]

Rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, and hypophosphatemia may occur as a result of proximal renal tubulopathy.

Renal failure, acute renal failure, Fanconi syndrome, proximal renal tubulopathy, increased creatinine, acute tubular necrosis, and nephrogenic diabetes insipidus have also been reported during postmarketing experience with tenofovir.[Ref]

Immunologic

Frequency not reported: Immune reconstitution/reactivation syndrome, autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome)

Efavirenz:
-Postmarketing reports: Immune reconstitution syndrome

Emtricitabine:
-Postmarketing reports: Immune reconstitution syndrome

Tenofovir:
-Postmarketing reports: Immune reconstitution syndrome[Ref]

Hypersensitivity

Efavirenz:
-Uncommon (0.1% to 1%): Hypersensitivity
-Postmarketing reports: Allergic reactions

Emtricitabine:
-Common (1% to 10%): Allergic reaction

Tenofovir:
-Postmarketing reports: Allergic reaction (including angioedema)[Ref]

Cardiovascular

Efavirenz:
-Frequency not reported: QT interval prolongation, torsades de pointes
-Postmarketing reports: Palpitations[Ref]

Endocrine

Efavirenz:
-Uncommon (0.1% to 1%): Gynecomastia

Tenofovir:
-Frequency not reported: Higher serum parathyroid hormone levels[Ref]

Gynecomastia has also been reported during postmarketing experience with efavirenz.[Ref]

Ocular

Efavirenz:
-Uncommon (0.1% to 1%): Blurred vision
-Postmarketing reports: Abnormal vision[Ref]

Blurred vision has also been reported during postmarketing experience with efavirenz.[Ref]

References

1. "Product Information. Sustiva (efavirenz)." DuPont Pharmaceuticals, Wilmington, DE.

2. "Product Information. Viread (tenofovir)." Gilead Sciences, Foster City, CA.

3. Frampton JE, Croom KF "Efavirenz/Emtricitabine/Tenofovir disoproxil fumarate: triple combination tablet." Drugs 66 (2006): 1501-12

4. Cerner Multum, Inc. "Australian Product Information." O 0

5. "Product Information. Atripla (efavirenz / emtricitabine / tenofovir)." Bristol-Myers Squibb, Princeton, NJ.

6. HHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Office of AIDS Research Advisory Council (OARAC). NIH. National Institutes of Health "Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available from: URL: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf." ([2015 Apr 8]):

7. "A once-daily combination tablet (Atripla) for HIV." Med Lett Drugs Ther 48 (2006): 78-9

8. "Product Information. Emtriva (emtricitabine)." Gilead Sciences, Foster City, CA.

9. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

10. Arribas JR "Efavirenz/Emtricitabine/Tenofovir disoproxil fumarate triple combination tablet: a viewpoint by jose R. Arribas." Drugs 66 (2006): 1513-4

11. Peyriere H, Mauboussin JM, Rouanet I, Fabre J, Reynes J, HillaireBuys D "Management of sudden psychiatric disorders related to efavirenz." Aids 15 (2001): 1323-4

12. Welch KJ, Morse A "Association between Efavirenz and Selected Psychiatric and Neurological Conditions." J Infect Dis 185 (2002): 268-9

13. Carlan SJ, Bouldin S, Blust D, OBrien WF "Safety and efficacy of misoprostol orally and vaginally: A randomized trial." Obstet Gynecol 98 (2001): 107-12

14. Puzantian T "Central nervous system adverse effects with efavirenz: case report and review." Pharmacotherapy 22 (2002): 930-3

15. de La Garza CL, Paoletti-Duarte S, Garcia-Martin C, Gutierrez-Casares JR "Efavirenz-induced psychosis." AIDS 15 (2001): 1911-2

16. Domingo P, Barcelo M "Efavirenz-induced leukocytoclastic vasculitis." Arch Intern Med 162 (2002): 355-6

17. Colebunders R, Vanwolleghem T, Meurrens P, Moerman F "Efavirenz-associated Stevens-Johnson syndrome." Infection 32 (2004): 306-7

18. Treudler R, Husak R, Raisova M, Orfanos CE, Tebbe B "Efavirenz-induced photoallergic dermatitis in HIV." AIDS 15 (2001): 1085-6

19. Callens S, De Schacht C, Huyst V, Colebunders R "Pancreatitis in an HIV-infected person on a tenofovir, didanosine and stavudine containing highly active antiretroviral treatment." J Infect 47 (2003): 188-9

20. Perazella MA "Drug-induced renal failure: update on new medications and unique mechanisms of nephrotoxicity." Am J Med Sci 325 (2003): 349-62

21. Castillo R, Pedalino RP, El-Sherif N, Turitto G "Efavirenz-associated QT prolongation and Torsade de Pointes arrhythmia." Ann Pharmacother 36 (2002): 1006-8

22. Mercie P, Viallard JF, Thiebaut R, Faure I, Rispal P, Leng B, Pellegrin JL "Efavirenz-associated breast hypertrophy in HIV-infected patients." Aids 15 (2001): 126-9

23. Caso JA, Prieto Jde M, Casas E, Sanz J "Gynecomastia without lipodystrophy syndrome in HIV-infected men treated with efavirenz." AIDS 15 (2001): 1447-8

24. Qazi NA, Morlese JF, King DM, Ahmad RS, Gazzard BG, Nelson MR "Gynaecomastia without lipodystrophy in HIV-1-seropositive patients on efavirenz: an alternative hypothesis." AIDS 16 (2002): 506-7

25. Caso JAA, Prieto JD, Casas E, Sanz J "Gynecomastia without lipodystrophy syndrome in HIV-infected men treated with efavirenz." Aids 15 (2001): 1447-8

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