ADVERSE REACTIONS
The most significant adverse reactions observed in patients treated with SUSTIVA are:
- psychiatric symptoms [see Warnings and Precautions ],
- nervous system symptoms [see Warnings and Precautions ],
- rash [see Warnings and Precautions ].
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.
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 | 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 |
|---|
| 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 (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 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 ]. 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 ].
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 ].
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 ].
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
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 ] 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 and Adverse Reactions (6.1, Table 5) ].
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
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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