A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Sustiva Side Effects, and Drug Interactions - Efavirenz
Sustiva Side Effects, and Drug Interactions - Efavirenz
SIDE EFFECTS
The most significant adverse events observed in patients treated
with SUSTIVA are nervous system symptoms, psychiatric symptoms, and rash. Unless
otherwise specified, the analyses described below included 1008 patients treated
with regimens containing SUSTIVA and 635 patients treated with a control regimen
in controlled trials.
Nervous System Symptoms: Fifty-three percent of patients
receiving SUSTIVA reported central nervous system symptoms (see WARNINGS:
Nervous System Symptoms). Table 6 lists the frequency of the symptoms of
different degrees of severity and gives the discontinuation rates in clinical
trials 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.
The frequencies of specific central and peripheral nervous system symptoms are
provided in Table 8.
|
Table 6: 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
|
|
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
|
|
d "Moderate" = Symptoms which may
interfere with daily activities.
|
|
e "Severe" = Events which interrupt
patient’s
|
Psychiatric Symptoms: Serious psychiatric adverse experiences
have been reported in patients treated with SUSTIVA. In controlled trials, the
frequency of specific serious psychiatric symptoms among patients who received
SUSTIVA or control regimens, respectively, were severe depression (2.4%, 0.9%),
suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0), aggressive
behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions
(0.2%, 0.3%) (see WARNINGS: Psychiatric
Symptoms). Additional psychiatric symptoms observed at a frequency of >2%
among patients treated with SUSTIVA or control regimens, respectively, in controlled
clinical trials were depression (19%, 16%), anxiety (13%, 9%), and nervousness
(7%, 2%).
Skin Rash: Rashes are usually mild-to-moderate maculopapular
skin eruptions that occur within the first 2 weeks of initiating therapy with
SUSTIVA. In most patients, rash resolves with continuing SUSTIVA therapy within
one month. SUSTIVA can be reinitiated in patients interrupting therapy because
of rash. Use of appropriate antihistamines and/or corticosteroids may be considered
when SUSTIVA is restarted. SUSTIVA should be discontinued in patients developing
severe rash associated with blistering, desquamation, mucosal involvement, or
fever. The frequency of rash by NCI grade and the discontinuation rates as a
result of rash are provided in Table 7.
|
Table 7: 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) %
|
|
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 discontinuationas a result of rash
|
--
|
1.7
|
8.8
|
0.3
|
|
a Includes events reported regardless of causality.
b Data from Study 006 and three Phase 2/3 studies.
|
|
c NCI Grading System.
|
As seen in Table 7, rash is more common in pediatric patients
and more often of higher grade (ie, more severe) (see PRECAUTIONS:
General).
Experience with SUSTIVA (efavirenz) 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.
A few cases of pancreatitis have been described, 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 ADVERSE
REACTIONS: Laboratory Abnormalities).
Selected clinical adverse experiences of moderate or severe
intensity observed in ³2% of SUSTIVA-treated of patients
in two controlled clinical trials are presented in Table 8.
|
Table 8: Selected Treatment-Emergenta Adverse Events
of Moderate or Severe Intensity Reported in ³2%
of SUSTIVA-Treated Patients in Studies 006 and ACTG 364
|
|
Adverse Events
|
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) 180 weeksc
|
SUSTIVAb + Indinavir (n=415) 102 weeksc
|
Indinavir + ZDV/LAM (n=401) 76 weeksc
|
SUSTIVAb + Nelfinavir + NRTIs (n=64) 71.1 weeksc
|
SUSTIVAb + NRTIs (n=65) 70.9 weeksc
|
Nelfinavir + NRTIs (n=66) 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
|
5%
|
3%
|
<1%
|
0
|
0
|
0
|
|
impaired
|
|
|
|
|
|
|
|
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
|
|
Rash
|
11%
|
16%
|
5%
|
9%
|
5%
|
9%
|
|
Pruritus
|
<1%
|
1%
|
1%
|
9%
|
5%
|
9%
|
|
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.
|
|
— = Not Specified.
|
|
ZDV = zidovudine, LAM = lamivudine.
|
Clinical adverse experiences observed in ³10%
of 57 pediatric patients aged 3 to 16 years who received SUSTIVA (efavirenz)
capsules, nelfinavir, and one or more NRTIs 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 also PRECAUTIONS: Skin Rash
and Pediatric Use).
Postmarketing Experience
Body as a Whole- allergic reactions, asthenia, redistribution/accumulation
of body fat (see PRECAUTIONS: Fat Redistribution)
Central and Peripheral Nervous System- abnormal coordination, ataxia,
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, nail disorders, skin discoloration,
Stevens-Johnson syndrome
Special Senses- abnormal vision, tinnitus
Laboratory Abnormalities
Selected Grade 3-4 laboratory abnormalities reported in ³2%
of SUSTIVA-treated patients in two clinical trials are presented in Table 9.
|
Table 9: Selected Grade 3-4 Laboratory Abnormalites
Reported in ³2% 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) 180 weeksb
|
SUSTIVAa + Indinavir (n=415) 102 weeksb
|
Indinavir + ZDV/LAM (n=401) 76 weeksb
|
SUSTIVAa + Nelfinavir + NRTIs (n=64) 71.1
weeksb
|
SUSTIVAa + NRTIs (n=65) 70.9 weeksb
|
Nelfinavir + NRTIs (n=66) 62.7 weeksb
|
|
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
|
³751 mg/dL
|
9%
|
6%
|
6%
|
11%
|
8%
|
17%
|
|
Hematology Neutrophils
|
<750/mm3
|
10%
|
3%
|
5%
|
2%
|
3%
|
2%
|
|
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.
|
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 co-infected 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 co-infected 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 PRECAUTIONS:
General).
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 ³240
mg/dL and ³300 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 were not well characterized
since samples were taken from nonfasting patients. The clinical significance
of these findings is unknown (see PRECAUTIONS:
General).
Cannabinoid Test Interaction: Efavirenz does
not bind to cannabinoid receptors. False-positive urine cannabinoid test results
have been observed in non-HIV-infected volunteers receiving SUSTIVA when the
Microgenics CEDIA® DAU Multi-Level THC assay was used for screening.
Negative results were obtained when more specific confirmatory testing was performed
with gas chromatography/mass spectrometry.
Of the three assays analyzed (Microgenics CEDIA DAU Multi-Level
THC assay, Cannabinoid Enzyme Immunoassay [Diagnostic Reagents, Inc.], and AxSYM®
Cannabinoid Assay), only the Microgenics CEDIA DAU Multi-Level THC assay
showed false-positive results. The other two assays provided true-negative results.
The effects of SUSTIVA on cannabinoid screening tests other than these three
are unknown. The manufacturers of cannabinoid assays should be contacted for
additional information regarding the use of their assays with patients receiving
efavirenz.
DRUG INTERACTIONS
(see also CONTRAINDICATIONS
and CLINICAL PHARMACOLOGY: Drug Interactions)
Efavirenz has been shown in vivo to induce CYP3A4. Other
compounds that are substrates of CYP3A4 may have decreased plasma concentrations
when coadministered with SUSTIVA (efavirenz). In vitro studies have demonstrated
that efavirenz inhibits 2C9, 2C19, and 3A4 isozymes in the range of observed
efavirenz plasma concentrations. Coadministration of efavirenz with drugs primarily
metabolized by these isozymes may result in altered plasma concentrations of
the coadministered drug. Therefore, appropriate dose adjustments may be necessary
for these drugs.
Drugs which induce CYP3A4 activity (eg, phenobarbital, rifampin,
rifabutin) would be expected to increase the clearance of efavirenz resulting
in lowered plasma concentrations. Drug interactions with SUSTIVA are summarized
in Table 5.
|
Table 5a: Drugs That Should Not Be Coadministered
With SUSTIVA
|
|
Drug Class
|
Drugs Within Class Not To Be Coadministered With SUSTIVA
|
|
Antihistamines Benzodiazepines GI Motility Agents Anti-Migraine
Antifungal
|
astemizole midazolam, triazolam
cisapride ergot derivatives voriconazole
|
|
Established Drug Interactions
|
|
|
Drug Name
|
Effect
|
Clinical Comment
|
|
Atazanavir
|
¯atazanavir
|
When coadministered with SUSTIVA in treatment-naive patients,
the recommended dose of atazanavir is 300 mg with ritonavir 100 mg and
SUSTIVA 600 mg (all once daily). Dosing recommendations for SUSTIVA and
atazanavir in treatment-experienced patients have not been established.
|
|
Established Drug Interactions (continued)
|
|
Drug Name
|
Effect
|
Clinical Comment
|
|
Clarithromycin
|
¯clarithromycin concentration
|
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.
|
|
|
14-OH metabolite
concentration
|
|
Indinavir
|
¯indinavir concentration
|
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.
|
|
Lopinavir/ritonavir
|
¯lopinavir concentration
|
A dose increase of lopinavir/ritonavir to 533/133 mg
(4 capsules or 6.5 mL) twice daily taken with food is recommended when
used in combination with SUSTIVA.
|
|
Methadone
|
¯methadone concentration
|
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.
|
|
Ethinyl estradiol
|
ethinyl estradiol
concentration
|
Plasma concentrations increased by SUSTIVA (efavirenz);
clinical significance unknown. Because the potential interaction of efavirenz
with oral contraceptives has not been fully characterized, a reliable
method of barrier contraception should be used in addition to oral contraceptives.
|
|
Rifabutin
|
¯rifabutin concentration
|
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 concentration
|
Clinical significance of reduced efavirenz concentrations
unknown.
|
|
Ritonavir
|
ritonavir concentration
|
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.
|
|
|
efavirenz concentration
|
|
|
Saquinavir
|
¯saquinavir
concentration
|
Should not be used as sole protease inhibitor in combination
with SUSTIVA.
|
|
Sertraline
|
¯sertraline concentration
|
Increases in sertraline dose should be guided by clinical
response.
|
|
Other Potentially Clinically Significant Drug or Herbal
Product Interactions With SUSTIVAb
|
|
Anticoagulants: Warfarin
|
Plasma concentrations and effects potentially increased
or decreased by SUSTIVA.
|
|
Anticonvulsants: Phenytoin Phenobarbital Carbamazepine
|
Potential for reduction in anticonvulsant and/or efavirenz
plasma levels; periodic monitoring of anticonvulsant plasma levels should
be conducted.
|
|
Antifungals: Itraconazole Ketoconazole
|
Drug interaction studies with SUSTIVA and these imidazole
and triazole antifungals have not been conducted. SUSTIVA has the potential
to decrease plasma concentrations of itraconazole and ketoconazole.
|
|
Anti-HIV protease inhibitors: Saquinavir/ritonavir combination
|
No pharmacokinetic data are available.
|
|
Amprenavir
|
SUSTIVAhas the potential to decrease serum concentrations
of amprenavir.
|
|
Non-nucleoside reverse transcriptase inhibitors
|
No studies have been performed with other NNRTIs.
|
|
St. John’s wort (Hypericum perforatum)
|
Expected to substantially decrease plasma levels of efavirenz;has
not been studied in combination with SUSTIVA.
|
|
a See Tables 1 and 2.
|
|
b This table is not all-inclusive.
|
Other Drugs: Based on the results of drug interaction
studies(see Tables 1 and 2), no dosage adjustment is recommended when SUSTIVA
(efavirenz) is given with the following: aluminum/magnesium hydroxide antacids,
azithromycin, cetirizine, famotidine, fluconazole, lamivudine, lorazepam, nelfinavir,
paroxetine, 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.
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