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
Viramune Side Effects, and Drug Interactions - Nevirapine
Viramune Side Effects, and Drug Interactions - Nevirapine
SIDE EFFECTS
Adults:
Clinical practice has shown that the most serious adverse reactions
associated with VIRAMUNE are clinical hepatitis/hepatic failure, Stevens-Johnson
syndrome, toxic epider-mal necrolysis, and hypersensitivityreactions. Clinical
hepatitis/hepatic failure maybe isolated orassociated with signs of hypersensitivitywhich
mayinclude severe rash orrash accompanied byfever, general malaise, fatigue,
muscle orjoint aches, blisters, oral lesions, conjunctivitis, facial edema,
and/orhepatitis, eosinophilia, granulocytopenia, lym-phadenopathy, and renal
dysfunction.
Severe and life-threatening hepatotoxicity, and fatal fulminant
hepatitis have been reported in patients treated with VIRAMUNE. Hepatic adverse
events have been reported to occurmore frequentlyduring the first 18 weeks of
treatment, but such events may occurat anytime during treatment.
In controlled clinical trials, clinical hepatic events regardless
of severityoccurred in 4.0% (range 2.5% to 11.0%) of patients who received VIRAMUNE
and 1.2% of patients in control groups. Transaminase elevations (ALTorAST>
5X ULN) were observed in 8.8% of patients receiving VIRAMUNE and 6.2% of patients
in control groups in clinical trials. (See WARNINGS)
The most common clinical toxicityof VIRAMUNE is rash. Severe
orlife-threatening rash occurred in approximately2% of VIRAMUNE-treated patients,
most frequentlywithin the first 6 weeks of therapy. (See Table 5) Rashes are
usuallymild to moderate, maculopapu-larerythematous cutaneous eruptions, with
orwithout pruritus, located on the trunk, face and extremities. Women tend to
be at higherriskfordevelopment of VIRAMUNE associated rash.
|
Table 5: Riskof Rash (%) in Adult Placebo Controlled
Trials 1 – Regardless of Causality
|
| |
VIRAMUNE n=1374%
|
Placebo n=1331%
|
|
Through 6 weeks of treatment2
|
|
Rash events of all grades3
|
14.8
|
5.9
|
|
Grade 1
|
Erythema, pruritus
|
8.5
|
4.2
|
|
Grade 2
|
Diffuse maculopapularrash, drydesquamation
|
4.8
|
1.6
|
|
Grade 3 or4
|
Grade 3: vesiculation, moist desquamation, ulceration;
Grade 4: erythema multiforme, Stevens Johnson syndrome, toxic epidermal
necrolysis, necrosis requiring surgery, exfoliative dermatitis
|
1.5
|
0.1
|
|
Through 52 weeks of treatment2
|
|
|
|
Rash events of all grades3
|
24.0
|
14.9
|
|
Grade 1
|
See above
|
15.5
|
10.8
|
|
Grade 2
|
See above
|
7.1
|
3.9
|
|
Grade 3 or4
|
See above
|
1.7
|
0.2
|
|
Proportion of Patients who Discontinued Treatment Due
to Rash
|
| |
4.3
|
1.2
|
|
1 Trials 1037, 1038, 1046 and 1090
|
|
2 % based on Kaplan-Meierprobabilityestimates
|
|
3 NCI grading system
|
Treatment related, adverse experiences of moderate orsevere
intensityobserved in >2% of patients receiving VIRAMUNE in placebo-controlled
trials are shown in Table 6.
|
Table 6: Percentage of Patients with Moderate or Severe
Drug Related Events in Adult Placebo Controlled Trials
|
| |
Trial 10901
|
Trials 1037, 1038, 10462
|
| |
VIRAMUNE(n=1121)
|
Placebo(n=1128)
|
VIRAMUNE(n=253)
|
Placebo(n=203)
|
| |
|
|
|
|
|
Median exposure (weeks)
|
58
|
52
|
28
|
28
|
|
Anyadverse event
|
14.5%
|
11.1%
|
31.6%
|
13.3%
|
|
Rash
|
5.1
|
1.8
|
6.7
|
1.5
|
|
Abnormal LFTs
|
1.2
|
0.9
|
6.7
|
1.5
|
|
Nausea
|
0.5
|
1.1
|
8.7
|
3.9
|
|
Granulocytopenia
|
1.8
|
2.8
|
0.4
|
0
|
|
Headache
|
0.7
|
0.4
|
3.6
|
0.5
|
|
Fatigue
|
0.2
|
0.3
|
4.7
|
3.9
|
|
Diarrhea
|
0.2
|
0.8
|
2.0
|
0.5
|
|
Abdominal pain
|
0.1
|
0.4
|
2.0
|
0
|
|
Myalgia
|
0.2
|
0
|
1.2
|
2.0
|
|
1 Background therapyincluded 3TC forall patients
and combinations of NRTIs and PIs. Patients had CD4+ cell counts <200
cells/mm3.
|
|
2 Background therapyincluded ZDV and ZDV+ddI;
VIRAMUNE monotherapywas administered in some patients. Patients had CD4+
cell count > 200 cells/mm3.
|
Laboratory Abnormalities: Liverfunction test abnormalities
(AST, ALT) were observed more frequentlyin patients receiving VIRAMUNE than
in controls. (Table 7) Asymptomatic elevations in GGToccurfrequentlybut are
not a contraindication to continue VIRAMUNE therapyin the absence of elevations
in otherliverfunction tests. Otherlaboratoryabnor-malities (bilirubin, anemia,
neutropenia, thrombocytopenia) were observed with similar frequencies in clinical
trials comparing VIRAMUNE and control regimens. (SeeTable 7)
|
Table 7: Percentage of Adult Patients with Laboratory
Abnormalities
|
| |
Trial 10901
|
Trials 1037, 1038, 10462
|
| |
VIRAMUNE
|
Placebo
|
VIRAMUNE
|
Placebo
|
|
Laboratory Abnormality
|
n=1121
|
n=1128
|
n=253
|
n=203
|
|
Blood Chemistry
|
|
|
|
|
|
SGPT(ALT) >250 U/L
|
5.3%
|
4.4%
|
14.0%
|
4.0%
|
|
SGOT(AST) >250 U/L
|
3.7
|
2.5
|
7.6
|
1.5
|
|
Bilirubin >2.5 mg/dL
|
1.7
|
2.2
|
1.7
|
1.5
|
|
Hematology
|
|
|
|
|
|
Hemoglobin <8.0 g/dL
|
3.2
|
4.1
|
0
|
0
|
|
Platelets <50,000/mm3
|
1.3
|
1.0
|
0.4
|
1.5
|
|
Neutrophils <750/mm3
|
13.3
|
13.5
|
3.6
|
1.0
|
|
1 Background therapyincluded 3TC forall patients
and combinations of NRTIs and PIs. Patients had CD4+ cell counts <200
cells/mm3.
|
|
2 Background therapyincluded ZDV and ZDV+ddI;
VIRAMUNE monotherapywas administered in some patients. Patients had CD4+
cell count > 200 cells/mm3.
|
Because clinical hepatitis has been reported in VIRAMUNE-treated
patients, intensive clinical and laboratorymonitoring, including liverfunction
tests, is essential at baseline and during the first 18 weeks of treatment.
Monitoring should continue at frequent intervals thereafter, depending on the
patient’s clinical status. (See WARNINGS)
Post Marketing Surveillance: In addition to the adverse
events identified during clinical trials, the following events have been reported
with the use of VIRAMUNE in clinical practice: Bodyas a Whole: fever, somnolence,
drug withdrawal (See PRECAUTIONS: Drug
Interactions), redistribution/accumulation of bodyfat (see PRECAUTIONS,
Fat redistribution). Gastrointestinal: vomiting Liverand Biliary: jaundice,
fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure Hematology:
anemia, eosinophilia, neutropenia Musculoskeletal: arthralgia Neurologic: paraesthesia
Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous
eruptions, ulcerative stomatitis and urticaria have all been reported. In addition,
hypersensitivitysyndrome and hypersensitivityreactions with rash associated
with constitutional findings such as fever, blistering, oral lesions, conjunctivitis,
facial edema, muscle orjoint aches, general malaise, fatigue orsignificant hepatic
abnormalities (See WARNINGS) plus one ormore
of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathyand/orrenal
dysfunction have been reported with the use of VIRAMUNE.
Pediatric Patients:
Safetywas assessed in trial BI 882 in which patients were followed
fora mean duration of 33.9 months (range: 6.8 months to 5.3 years, including
long-term follow-up in 29 of these patients in trial BI 892). The most frequentlyreported
adverse events related to VIRAMUNE in pediatric patients were similarto those
observed in adults, with the exception of granulocytopenia, which was more commonlyobserved
in children. Serious adverse events were assessed in ACTG 245, a double-blind,
placebo-controlled trial of VIRAMUNE (n = 305) in which pediatric patients received
combination treatment with VIRAMUNE. In this trial two patients were reported
to experience Stevens-Johnson syndrome orStevens-Johnson/toxic epidermal necrolysis
transition syndrome. Cases of allergic reaction, including one case of anaphylaxis,
were also reported.
Table 8 summarizes the marked laboratoryabnormalities occurring
in pediatric patients in Trial BI 882 and in follow-up Trial BI 892.
|
Table 8: Number of Pediatric Patients (%) with Laboratory
Abnormalities In Trials BI 882 and BI 892 Combined
|
| |
No. (%) of Patients
|
| |
n=37
|
|
Blood Chemistry
|
|
|
Increased ALT(>250 U/L)
|
4 (11)
|
|
Increased AST(>250 U/L)
|
5 (14)
|
|
Increased GGT(>450 U/L)
|
4 (11)
|
|
Increased total bilirubin (>2.5 mg/dL)
|
1 (3)
|
|
Increased alkaline phosphatase (>2x ULN)
|
19 (51)
|
|
Increased amylase (>2x ULN)
|
6 (16)
|
|
Hematology
|
|
|
Decreased Hg (<8.0 g/dL)
|
7 (19)
|
|
Decreased platelets (<50,000/mm3)
|
4 (11)
|
|
Decreased neutrophils (<750/mm3)
|
14 (38)
|
|
Increased MCV (>100 F/L)
|
13 (35)
|
DRUG INTERACTIONS
Nevirapine is principallymetabolized bythe livervia the cytochrome
P450 isoenzymes, 3A4 and 2B6. Nevirapine is known to be an inducerof these enzymes.
As a result, drugs that are metabolized bythese enzyme systems mayhave lowerthan
expected plasma levels when co-administered with nevirapine.
The specific pharmacokinetic changes that occurwith co-administration
of nevirapine and otherdrugs are listed in CLINICAL PHARMACOLOGY, Table 1. Clinical
comments about possible dosage modifications based on these pharmacokinetic
changes are listed in Table 3. The data in Tables 1 and 3 are based on the results
of drug interaction studies conducted in HIV-1 seropositive subjects unless
otherwise indicated.
In addition to established drug interactions, there maybe potential
pharmacokinetic interactions between nevirapine and otherdrug classes that are
metabolized bythe cytochrome P450 system. These potential drug interactions
are listed in Table 4. Although specific drug interaction studies in HIV-1 seropositive
subjects have not been conducted forthe classes of drugs listed in Table 4,
additional clinical monitoring may be warranted when co-administering these
drugs.
The in vitro interaction between nevirapine and the
antithrombotic agent warfarin is complex. As a result, when giving these drugs
concomitantly, plasma warfarin levels maychange with the potential forincreases
in coagulation time. When warfarin is co-administered with nevirapine, anticoagulation
levels should be monitored frequently.
|
Table 3: Established Drug Interactions: Alteration
in Dose or Regimen May Be Recommended Based on Drug Interaction Studies
(See CLINICAL PHARMACOLOGY, Table 1 for Magnitude
of Interaction)
|
|
Drug Name
|
Effect on Concentration
of Nevirapine or
Concomitant Drug
|
Clinical Comment
|
|
Clarithromycin
|
¯ Clarithromycin
|
Clarithromycin exposure was significantlydecreased bynevirapine;
however, 14-OH metabolite concentrations were increased. Because clarithromycin
active metabolite has reduced activityagainst Mycobacterium avium-intracellulare
complex, overall activityagainst this pathogen maybe altered. Alternatives
to clarithromycin, such as azithromycin, should be considered.
|
|
14-OH clarithromycin
|
|
Efavirenz
|
¯ Efavirenz
|
Appropriate doses forthis combination are not established.
|
|
Ethinyl estradiol and Norethindrone
|
¯ Ethinyl estradiol
|
Oral contraceptives and otherhormonal methods of birth
control should not be used as the sole method of contraception in women
taking nevirapine, since nevirapine maylowerthe plasma levels of these
medications. An alternative oradditional method of contraception is recommended.
|
|
¯ Norethindrone
|
|
Fluconazole
|
Nevirapine
|
Because of the riskof increased exposure to nevirapine,
caution should be used in concomitant administration, and patients should
be monitored closelyfornevirapine-associated adverse events.
|
|
Indinavir
|
¯ Indinavir
|
Appropriate doses forthis combination are not established,
but an increase in the dosage of indinavirmaybe required.
|
|
Ketoconazole
|
¯ Ketoconazole
|
Nevirapine and ketoconazole should not be administered
concomitantlybecause decreases in ketoconazole plasma concentrations mayreduce
the efficacy of the drug.
|
|
Lopinavir/Ritonavir
|
¯Lopinavir
|
A dose increase of lopinavir/ritonavirto 533/133 mg twice
dailywith food is recommended in combination with nevirapine.
|
|
Methadone
|
¯ Methadonea
|
Methadone levels maybe decreased; increased dosages maybe
required to prevent symptoms of opiate withdrawal. Methadone maintained
patients beginning nevirapine therapyshould be monitored forevidence of
withdrawal and methadone dose should be adjusted accordingly.
|
|
Nelfinavir
|
¯NelfinavirM8 Metabolite
|
The appropriate dose fornelfinavirin combination with
nevirapine, with respect to safetyand efficacy, has not been established.
|
|
¯NelfinavirCmin
|
|
Rifabutin
|
Rifabutin
|
Rifabutin and its metabolite concentrations were moderatelyincreased.
Due to high intersubject variability, however, some patients mayexperience
large increases in rifabutin exposure and may be at higherriskforrifabutin
toxicity. Therefore, caution should be used in concomitant administration.
|
|
Rifampin
|
¯ Nevirapine
|
Nevirapine and rifampin should not be administered concomitantlybecause
decreases in nevirapine plasma concentrations mayreduce the efficacy of
the drug. Physicians needing to treat patients co-infected with tuberculosis
and using a nevirapine containing regimen mayuse rifabutin instead.
|
|
Saquinavir
|
¯Saquinavir
|
Appropriate doses forthis combination are not established,
but an increase in the dosage of saquinavirmaybe required.
|
|
a Based on reports of narcotic withdrawal
syndrome in patients treated with nevirapine and methadone concurrently,
and evidence of decreased plasma concentrations of methadone.
|
|
Table 4: Potential Drug Interactions: Use With
Caution, Dose Adjustment of Co-administered Drug May Be Needed due to
Possible Decrease in Clinical Effect
|
|
Examples of Drugs in Which Plasma Concentrations May
Be Decreased By Co-administration With Nevirapine
|
|
Drug Class
|
Examples of Drugs
|
|
Antiarrhythmics
|
Amiodarone, disopyramide, lidocaine
|
|
Anticonvulsants
|
Carbamazepine, clonazepam, ethosuximide
|
|
Antifungals
|
Itraconazole
|
|
Calcium channel blockers
|
Diltiazem, nifedipine, verapamil
|
|
Cancerchemotherapy
|
Cyclophosphamide
|
|
Ergot alkaloids
|
Ergotamine
|
|
Immunosuppressants
|
Cyclosporin, tacrolimus, sirolimus
|
|
Motilityagents
|
Cisapride
|
|
Opiate agonists
|
Fentanyl
|
|
Examples of Drugs in Which Plasma Concentrations May
Be Increased By Co-administration With Nevirapine
|
|
Antithrombotics
|
Warfarin
|
| |
Potential effect on anticoagulation.
|
| |
Monitoring of anticoagulation levels is
|
| |
recommended.
|
Fat redistribution: Redistribution/accumulation
of bodyfat including central obesity, dorsocervical fat enlargement (buffalo
hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid
appearance" have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currentlyunknown.
A causal relationship has not been established.
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