Side Effects > Sustiva

Sustiva Side Effects

Generic Name: efavirenz

Please note - some side effects for Sustiva may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Sustiva - for the Consumer

Sustiva

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Sustiva:

Abnormal dreams; changes in body fat; diarrhea; dizziness; drowsiness; headache; trouble concentrating; trouble sleeping.

Seek medical attention right away if any of these SEVERE side effects occur when using Sustiva:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bizarre behavior; change in personality, behavior, mood, or emotions; dark urine or pale stools; delusions; hallucinations; memory loss; mouth sores; paranoia; rash with or without fever; severe depression; suicidal thoughts or behaviors; unusual fatigue; vision changes; yellowing of the skin or eyes.

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Sustiva Side Effects - for the Professional

Sustiva

The most significant adverse reactions observed in patients treated with Sustiva are:

• psychiatric symptoms [see Warnings and Precautions (5.4)],
• nervous system symptoms [see Warnings and Precautions (5.5)],
• rash [see Warnings and Precautions (5.7)].

The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with Sustiva in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.

6.1 Clinical Trials Experience in Adults

Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.

Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of Sustiva-treated patients in two controlled clinical trials are presented in Table 3.

Table 3: Selected Treatment-Emergenta Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Sustiva-Treated Patients in Studies 006 and ACTG 364

	Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients			Study ACTG 364 NRTI-experienced, NNRTI- and Protease Inhibitor-Naive Patients
Adverse Reactions	Sustivab + ZDV/LAM (n=412)	Sustivab + Indinavir (n=415)	Indinavir + ZDV/LAM (n=401)	Sustivab + Nelfinavir + NRTIs (n=64)	Sustivab + NRTIs (n=65)	Nelfinavir + NRTIs (n=66)
	180 weeksc	102 weeksc	76 weeksc	71.1 weeksc	70.9 weeksc	62.7 weeksc
a Includes adverse events at least possibly related to study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364.
b Sustiva provided as 600 mg once daily.
c Median duration of treatment.
d Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364.
— = Not Specified.
ZDV = zidovudine, LAM = lamivudine.
Body as a Whole
Fatigue	8%	5%	9%	0	2%	3%
Pain	1%	2%	8%	13%	6%	17%
Central and Peripheral Nervous System
Dizziness	9%	9%	2%	2%	6%	6%
Headache	8%	5%	3%	5%	2%	3%
Insomnia	7%	7%	2%	0	0	2%
Concentration impaired	5%	3%	<1%	0	0	0
Abnormal dreams	3%	1%	0	—	—	—
Somnolence	2%	2%	<1%	0	0	0
Anorexia	1%	<1%	<1%	0	2%	2%
Gastrointestinal
Nausea	10%	6%	24%	3%	2%	2%
Vomiting	6%	3%	14%	—	—	—
Diarrhea	3%	5%	6%	14%	3%	9%
Dyspepsia	4%	4%	6%	0	0	2%
Abdominal pain	2%	2%	5%	3%	3%	3%
Psychiatric
Anxiety	2%	4%	<1%	—	—	—
Depression	5%	4%	<1%	3%	0	5%
Nervousness	2%	2%	0	2%	0	2%
Skin & Appendages
Rashd	11%	16%	5%	9%	5%	9%
Pruritus	<1%	1%	1%	9%	5%	9%

Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients.

Nervous System Symptoms

For 1008 patients treated with regimens containing Sustiva and 635 patients treated with a control regimen in controlled trials, Table 4 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and depersonalization [see Warnings and Precautions (5.5)]. The frequencies of specific central and peripheral nervous system symptoms are provided in Table 3.

Table 4: Percent of Patients with One or More Selected Nervous System Symptomsa,b

Percent of Patients with:	Sustiva 600 mg Once Daily (n=1008)	Control Groups (n=635)
	%	%
a  Includes events reported regardless of causality.
b  Data from Study 006 and three Phase 2/3 studies.
c  "Mild" = Symptoms which do not interfere with patient’s daily activities.
d  "Moderate" = Symptoms which may interfere with daily activities.
e  "Severe" = Events which interrupt patient’s usual daily activities.
Symptoms of any severity	52.7	24.6
Mild symptomsc	33.3	15.6
Moderate symptomsd	17.4	7.7
Severe symptomse	2.0	1.3
Treatment discontinuation as a result of symptoms	2.1	1.1

Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with Sustiva. In controlled trials, psychiatric symptoms observed at a frequency of >2% among patients treated with Sustiva or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%).

Rash

For 1008 adults and 57 pediatric patients treated with regimens containing Sustiva and 635 patients treated with a control regimen in controlled trials, the frequency of rash by NCI grade and the discontinuation rates as a result of rash in clinical studies are provided in Table 5 [see Warnings and Precautions (5.7)].

Table 5: Percent of Patients with Treatment-Emergent Rasha,b

Percent of Patients with:	Description of Rash Gradec	Sustiva 600 mg Once Daily Adults (n=1008)	Sustiva Pediatric Patients (n=57)	Control Groups Adults (n=635)
		%	%	%
a  Includes events reported regardless of causality.
b  Data from Study 006 and three Phase 2/3 studies.
c  NCI Grading System.
Rash of any grade	—	26.3	45.6	17.5
Grade 1 rash	Erythema, pruritus	10.7	8.8	9.8
Grade 2 rash	Diffuse maculopapular rash, dry desquamation	14.7	31.6	7.4
Grade 3 rash	Vesiculation, moist desquamation, ulceration	0.8	1.8	0.3
Grade 4 rash	Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, necrosis requiring surgery, exfoliative dermatitis	0.1	3.5	0.0
Treatment discontinuation as a result of rash	—	1.7	8.8	0.3

As seen in Table 5, rash is more common in pediatric patients and more often of higher grade (ie, more severe) [see Warnings and Precautions (5.7)].

Experience with Sustiva in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with Sustiva. Nine of these patients developed mild-to-moderate rash while receiving therapy with Sustiva, and two of these patients discontinued because of rash.

Laboratory Abnormalities

Selected Grade 3-4 laboratory abnormalities reported in ≥2% of Sustiva-treated patients in two clinical trials are presented in Table 6.

Table 6: Selected Grade 3-4 Laboratory Abnormalities Reported in ≥2% of Sustiva-Treated Patients in Studies 006 and ACTG 364

		Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients			Study ACTG 364 NRTI-experienced, NNRTI- and Protease Inhibitor-Naive Patients
Variable	Limit	Sustivaa + ZDV/LAM (n=412)	Sustivaa + Indinavir (n=415)	Indinavir + ZDV/LAM (n=401)	Sustivaa + Nelfinavir + NRTIs (n=64)	Sustivaa + NRTIs (n=65)	Nelfinavir + NRTIs (n=66)
		180 weeksb	102 weeksb	76 weeksb	71.1 weeksb	70.9 weeksb	62.7 weeksb
a  Sustiva provided as 600 mg once daily.
b  Median duration of treatment.
c  Isolated elevations of GGT in patients receiving Sustiva may reflect enzyme induction not associated with liver toxicity.
d  Nonfasting.
ZDV = zidovudine, LAM = lamivudine, ULN = Upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase.
Chemistry
ALT	>5 x ULN	5%	8%	5%	2%	6%	3%
AST	>5 x ULN	5%	6%	5%	6%	8%	8%
GGTc	>5 x ULN	8%	7%	3%	5%	0	5%
Amylase	>2 x ULN	4%	4%	1%	0	6%	2%
Glucose	>250 mg/dL	3%	3%	3%	5%	2%	3%
Triglyceridesd	≥751 mg/dL	9%	6%	6%	11%	8%	17%
Hematology
Neutrophils	<750/mm3	10%	3%	5%	2%	3%	2%

Patients Coinfected with Hepatitis B or C

Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with Sustiva-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among these coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the Sustiva arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the Sustiva arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with Sustiva-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders [see Warnings and Precautions (5.8)].

Lipids

Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving Sustiva. In patients treated with Sustiva + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with Sustiva + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients treated with Sustiva + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with Sustiva + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of Sustiva on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown [see Warnings and Precautions (5.10)].

6.2 Clinical Trial Experience in Pediatric Patients

Clinical adverse experiences observed in ≥10% of 57 pediatric patients aged 3 to 16 years who received Sustiva capsules, nelfinavir, and one or more NRTIs in Study ACTG 382 [see Use In Specific Populations (8.4)] were rash (46%), diarrhea/loose stools (39%), fever (21%), cough (16%), dizziness/lightheaded/fainting (16%), ache/pain/discomfort (14%), nausea/vomiting (12%), and headache (11%). The incidence of nervous system symptoms was 18% (10/57). One patient experienced Grade 3 rash, two patients had Grade 4 rash, and five patients (9%) discontinued because of rash [see Warnings and Precautions (5.7) and Adverse Reactions (6.1, Table 5)].

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Sustiva. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat [see Warnings and Precautions (5.12)]

Central and Peripheral Nervous System: abnormal coordination, ataxia, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor

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

Respiratory: dyspnea

Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome

Special Senses: abnormal vision, tinnitus

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Side Effects by Body System

General

The most significant side effects associated with efavirenz have included nervous system symptoms, psychiatric symptoms, and rash. The most common side effects of at least moderate severity have included rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting in greater than 5% of patients treated with efavirenz in combination with lamivudine-zidovudine or indinavir.

Nervous system

Nervous system symptoms generally begin the first or second day of therapy and often resolve after 2 to 4 weeks. Dosing at bedtime may improve the tolerability of these effects.

Nervous system side effects of moderate or severe intensity have included dizziness (up to 9%), headache (up to 8%), insomnia (up to 7%), impaired concentration (up to 5%), abnormal dreams (up to 3%), and somnolence (up to 2%). Nervous system symptoms of any grade and regardless of causality (52.7%) included dizziness (28.1%), insomnia (16.3%), impaired concentration (8.3%), somnolence (7%), abnormal dreams (6.2%), hallucinations (1.2%), 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. Therapy was discontinued in 2.1% of patients due to these side effects. Vivid dreams, nightmares, and impaired attention span have also been reported. Abnormal coordination, ataxia, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, and tinnitus have been reported during postmarketing experience.

Psychiatric

Psychiatric side effects have included depression (moderate or severe intensity: up to 5%; any severity: up to 19%), anxiety (moderate or severe intensity: up to 4%; any severity: up to 13%), and nervousness (moderate or severe intensity: up to 2%; any severity; up to 7%). Psychiatric side effects classified as serious during controlled trials included severe depression (2.4%), suicidal ideation (0.7%), nonfatal suicide attempts (0.5%), aggressive behavior (0.4%), paranoid reactions (0.4%), and manic reactions (0.2%). One percent of patients discontinued or interrupted efavirenz treatment due to one or more of these side effects. Obsessive disorder, irritability, and mood changes have also been reported. Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, and suicide have been reported during postmarketing experience.

Psychiatric symptoms generally begin the first or second day of therapy and often resolve after 2 to 4 weeks. Dosing at bedtime may improve the tolerability of these effects.

Dermatologic

The median time to onset of rash in adults was 11 days. In most patients, the rash resolved within one month despite continued use of the drug. Patients who discontinue efavirenz therapy because of rash may be reinstated with the use of appropriate antihistamines and/or corticosteroids. The drug should be withdrawn if severe rash develops, such as that associated with blistering, desquamation, mucosal involvement, or fever.

There is limited experience with the use of efavirenz in patients who have previously discontinued other nonnucleoside reverse transcriptase inhibitors (NNRTIs) due to rash. In 19 such patients formerly on nevirapine, approximately half developed a mild to moderate rash, and two of them discontinued efavirenz because of the rash.

Dermatologic side effects of moderate or severe intensity have included rash (includes erythema multiforme, rash, erythematous rash, follicular rash, maculopapular rash, petechial rash, pustular rash, urticaria, macules, papules, erythema, redness, inflammation, allergic rash, welts, hives, and itchy; up to 16%) and pruritus (up to 9%). Skin rash of any grade (26.3%) included Grade 1 rash (erythema, pruritus; 10.7%), Grade 2 rash (diffuse maculopapular rash, dry desquamation; 14.7%), Grade 3 rash (vesiculation, moist desquamation, ulceration; 0.8%), and Grade 4 rash (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, necrosis requiring surgery, exfoliative dermatitis; 0.1%) during clinical trials. Treatment was discontinued in 1.7% of patients due to rash. Nail disorders, skin discoloration, and leukocytoclastic vasculitis have also been reported. Erythema multiforme, photoallergic dermatitis, and Stevens-Johnson syndrome have been reported during postmarketing experience.

Gastrointestinal

Gastrointestinal side effects of moderate or severe intensity have included diarrhea (up to 14%), nausea (up to 10%), vomiting (up to 6%), dyspepsia (up to 4%), abdominal pain (up to 3%), and anorexia (up to 2%). Pancreatitis has been reported, although causality was not determined. Burning mouth syndrome has also been reported. Constipation and malabsorption have been reported during postmarketing experience.

A 42-year-old HIV-positive woman's saquinavir in her highly active antiretroviral therapy was replaced with efavirenz to increase compliance. Two weeks following efavirenz initiation, the patient reported severe and constant burning in her tongue, gums, and oral mucosa and was diagnosed with burning mouth syndrome (BMS). Efavirenz therapy was discontinued and the BMS resolved within a week.

Hepatic

Isolated elevations of GGT in patients receiving efavirenz may reflect the enzyme inducing effects of the drug not associated with liver toxicity.

Hepatic side effects have included increased ALT (greater than 5 times ULN; up to 8%), AST (greater than 5 times ULN; up to 8%), and GGT (greater than 5 times ULN; up to 8%). During clinical trials, elevations in ALT and AST to greater than five times ULN occurred in 20% and 13%, respectively, of patients seropositive for hepatitis B and/or C treated with efavirenz. Treatment was discontinued in 3% of coinfected patients due to liver or biliary system disorders. Hepatic failure, hepatic enzyme increase, and hepatitis have been reported during postmarketing experience.

Hematologic

Hematologic side effects have included neutropenia (less than 750/mm3) in up to 10% of patients. Hemolytic anemia has been reported rarely.

Other

Other side effects of moderate or severe intensity have included pain (up to 13%) and fatigue (up to 8%). Elevated amylase (greater than 2 times ULN; up to 6%), asymptomatic increases in serum amylase levels, and vitamin D deficiency have been reported. Contraceptive failure (with an implantable hormonal contraceptive) and asthenia have been reported during postmarketing experience.

Metabolic

Metabolic side effects have included increased nonfasting triglycerides (greater than or equal to 751 mg/dL; up to 11%) and increased glucose (greater than 250 mg/dL; up to 5%). Increased nonfasting serum cholesterol (up to 54%) and HDL (up to 35%) have been reported, although the clinical significance of these elevations is unknown. Redistribution and accumulation of body fat including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. Hypercholesterolemia and hypertriglyceridemia have been reported during postmarketing experience.

Cardiovascular

Cardiovascular side effects have included flushing and palpitations during postmarketing experience. QT interval prolongation and torsades de pointes have been reported.

Hypersensitivity

Hypersensitivity side effects have included skin rash, eosinophilia, and systemic involvement (lymphadenopathy, interstitial nephritis, pneumonia, pulmonary infiltration, hepatitis, fever, rigor, myalgia, and arthralgias). Allergic reactions have been reported during postmarketing experience.

Musculoskeletal

Musculoskeletal side effects have included arthralgia, myalgia, and myopathy during postmarketing experience. Osteomalacia due to efavirenz-induced vitamin D deficiency has been reported.

Immunologic

Immunologic side effects have included immune reconstitution syndrome in patients treated with combination antiretroviral therapy, including efavirenz.

Genitourinary

Analysis of a 3 mm stone, eliminated by a 47-year-old HIV-1-infected male patient, showed a stone consisting of 60% efavirenz metabolites.

Genitourinary side effects have included rare cases of renal colic and urolithiasis.

Respiratory

Respiratory side effects have included dyspnea during postmarketing experience.

Endocrine

Endocrine side effects have included gynecomastia during postmarketing experience.

Ocular

Ocular side effects have included abnormal vision during postmarketing experience.

Renal

Renal side effects have included at least one report of podocyte damage.

Other

False positive urine drug screening test results for tetrahydrocannabinol and benzodiazepines have been reported in HIV-infected patients receiving efavirenz. False positive cannabinoid test results have been observed with the CEDIA (Cloned Enzyme Donor ImmunoAssay) DAU Multilevel THC assay and the InstaCheck multidrug Screen Panel. The Triage 8 and the Drug Screen Multi 5 have shown false-positive results for benzodiazepines and tetrahydrocannabinol.

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