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Sustiva

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Sustiva

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SIDE EFFECTS

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.

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

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.

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 2.

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

Adverse Reactions Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
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
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%
aIncludes 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.
bSUSTIVA provided as 600 mg once daily.
cMedian duration of treatment.
dIncludes 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.

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 (see Laboratory Abnormalities).

Nervous System Symptoms

For 1008 patients treated with regimens containing SUSTIVA and 635 patients treated with a control regimen in controlled trials, Table 3 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]. The frequencies of specific central and peripheral nervous system symptoms are provided in Table 2.

Table 3: 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) %
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
aIncludes events reported regardless of causality.
bData 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.

Psychiatric Symptoms

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

Rash

In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1008 adults treated with regimens containing SUSTIVA and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for SUSTIVA-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for SUSTIVA and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for SUSTIVA-treated patients and 0.3% for control groups [see WARNINGS AND PRECAUTIONS].

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 4.

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

Variable Limit Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
SUSTIVAa+ ZDV/LAM
(n=412) b180 weeks
SUSTIVAa + Indinavir
(n=415) b102 weeks
Indinavir + ZDV/LAM
(n=401) 76 weeks
SUSTIVAa + Nelfinavir + NRTIs
(n=64) b71.1 weeks
SUSTIVAa + NRTIs
(n=65) b 70.9 weeks
Nelfinavir + NRTIs
(n=66) b 62.7 weeks
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 3 < 750/mm³ 10% 3% 5% 2% 3% 2%
aSUSTIVA 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.
dNonfasting.
ZDV = zidovudine, LAM = lamivudine, ULN = Upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase.

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].

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].

Clinical Trial Experience In Pediatric Patients

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.

Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received SUSTIVA in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash [see WARNINGS AND PRECAUTIONS].

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]

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. A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.

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

Read the Sustiva (efavirenz) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Drug-Drug Interactions

Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with SUSTIVA. Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations [see DOSAGE AND ADMINISTRATION]. Drug interactions with SUSTIVA are summarized in Table 5 [for pharmacokinetics data see CLINICAL PHARMACOLOGY, Tables 7 and 8]. This table includes potentially significant interactions, but is not all inclusive.

Table 5: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class: Drug Name Effect Clinical Comment
HIV antiviral agents
Protease inhibitor: Fosamprenavir calcium ↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established.
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: Atazanavir sulfate ↓ atazanavir* Treatment-naive patients: When coadministered with SUSTIVA, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and SUSTIVA 600 mg (once daily on an empty stomach, preferably at bedtime).
Treatment-experienced patients: Coadministration of SUSTIVA and atazanavir is not recommended.
Protease inhibitor: Indinavir ↓ indinavir* The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone.
Protease inhibitor: Lopinavir/ritonavir ↓ lopinavir* Dose increase of lopinavir/ritonavir is recommended for all patients. Lopinavir/ritonavir tablets should not be administered once daily in combination with SUSTIVA. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when coadministered with efavirenz in adult and pediatric patients.
Protease inhibitor: Ritonavir ↑ ritonavir*
↑ efavirenz*
When ritonavir 500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir.
Protease inhibitor: Saquinavir ↓ saquinavir* Appropriate doses of the combination of SUSTIVA and saquinavir/ritonavir with respect to safety and efficacy have not been established.
NNRTI: Other NNRTIs ↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial.
CCR5 co-receptor antagonist: Maraviroc ↓ maraviroc* Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.
Integrase strand transfer inhibitor: Raltegravir ↓ raltegravir* SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: Boceprevir ↓ boceprevir* Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: Telaprevir ↓ telaprevir*
↓ efavirenz*
Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz.
Hepatitis C antiviral agents
Protease inhibitor: Boceprevir ↓ boceprevir* Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: Telaprevir ↓ telaprevir*
↓ efavirenz*
Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant: Warfarin ↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by SUSTIVA.
Anticonvulsants: Carbamazepine ↓ carbamazepine*
↓ efavirenz*
There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.
Phenytoin Phenobarbital ↓ anticonvulsant
↓ efavirenz
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: Bupropion ↓ bupropion* The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
Sertraline ↓ sertraline* Increases in sertraline dosage should be guided by clinical response.
Antifungals:
Voriconazole
↓ voriconazole*
↑ efavirenz*
SUSTIVA and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of SUSTIVA-associated side effects. When voriconazole is coadministered with SUSTIVA,
voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation. SUSTIVA tablets should not be broken. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY Tables 8 and 9.]
Itraconazole ↓ itraconazole*
↓ hydroxyitraconazole*
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
Ketoconazole ↓ ketoconazole Drug interaction studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has the potential to decrease plasma concentrations of ketoconazole.
Posaconazole ↓ posaconazole* Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: Clarithromycin ↓ clarithromycin*
↑ 14-OH metabolite*
Plasma concentrations decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment of SUSTIVA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered (see Other Drugs, following table). Other macrolide antibiotics, such as erythromycin, have not been studied in combination with SUSTIVA.
Antimycobacterials: Rifabutin ↓ rifabutin* Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Rifampin ↓ efavirenz* If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended.
Antimalarials: Artemether/ lumefantrine ↓ artemether*
↓ dihydroartemisinin*
↓ lumefantrine*
Artemether/lumefantrine should be used cautiously with efavirenz because decreased artemether, dihydroartemisinin (active metabolite of artemether), and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine.
Calcium channel blockers: Diltiazem ↓ diltiazem*
↓ desacetyl diltiazem*
↓ N-monodesmethyl diltiazem*
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem.
Others (eg, felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to
the full prescribing information for the calcium channel
blocker).
HMG-CoA reductase inhibitors: Atorvastatin Pravastatin Simvastatin ↓ atorvastatin*
↓ pravastatin*
↓ simvastatin*
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal
contraceptives: Oral Ethinyl estradiol/ Norgestimate
↓ active metabolites of norgestimate* A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant Etonogestrel ↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A ↓ immunosuppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
Narcotic analgesic: Methadone ↓ methadone* Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of
methadone and signs of opiate withdrawal. Methadone dose
was increased by a mean of 22% to alleviate withdrawal
symptoms. Patients should be monitored for signs of
withdrawal and their methadone dose increased as required to
alleviate withdrawal symptoms.
* The interaction between SUSTIVA and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. This table is not all-inclusive.

Other Drugs

Based on the results of drug interaction studies [see CLINICAL PHARMACOLOGY, Tables 7 and 8], no dosage adjustment is recommended when SUSTIVA is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine, tenofovir disoproxil fumarate, and zidovudine.

Specific drug interaction studies have not been performed with SUSTIVA and NRTIs other than lamivudine and zidovudine. Clinically significant interactions would not be expected since the NRTIs are metabolized via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways.

Cannabinoid Test Interaction

Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been 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.

Read the Sustiva Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 6/5/2014
This monograph has been modified to include the generic and brand name in many instances.

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