SIDE EFFECTS
Clinical Trials
Nephrolithiasis, including flank pain with or without
hematuria (including microscopic hematuria), has been
reported in approximately 9.3% (193/2071) of patients
receiving CRIXIVAN in clinical trials at the recommended
dose, compared to 2.1% in the control arms. Of the patients
treated with CRIXIVAN who developed nephrolithiasis, 3.1%
(6/193) were reported to develop hydronephrosis and 3.1%
(6/193) underwent stent placement. Following the acute
episode, 3.6% (7/193) of patients discontinued therapy.
(See WARNINGS and DOSAGE AND ADMINISTRATION, Nephrolithiasis)
Asymptomatic hyperbilirubinemia (total bilirubin ³2.5
mg/dL), reported predominantly as elevated indirect bilirubin,
has occurred in approximately 10% of patients treated
with CRIXIVAN. In <1% this was associated with elevations
in ALT or AST.
Hyperbilirubinemia and nephrolithiasis occurred more
frequently at doses exceeding 2.4 g/day compared to doses
£2.4 g/day.
Clinical adverse experiences reported in ³ 2% of patients
treated with CRIXIVAN alone, CRIXIVAN in combination with
zidovudine or zidovudine plus lamivudine, zidovudine alone,
or zidovudine plus lamivudine are presented in Table 4.
Table 4.
Clinical Adverse Experiences Reported in ³2%
of Patients
Studies 028 and 033* Considered Drug-Related and of Moderate
or Severe Intensity
| Adverse
Experience |
CRIXIVAN
Percent
(n=196)
|
CRIXIVAN
Plus Zidovudine Percent (n=196)
|
Zidovudine
Percent (n=195)
|
| Body
as a Whole |
|
| Abdominal
pain |
8.7
|
8.2
|
5.1
|
| Asthenia/fatigue |
3.6
|
9.2
|
7.7
|
| Fever
|
0.5
|
0.5
|
0
|
| Malaise |
0.5
|
2.0
|
1.5
|
| Digestive
System |
|
| Nausea |
11.7
|
32.1
|
14.4
|
| Diarrhea |
4.6
|
4.1
|
2.1
|
| Vomiting |
4.1
|
12.2
|
4.6
|
| Acid
regurgitation |
2.0
|
2.0
|
0.5
|
| Anorexia |
0.5
|
2.0
|
3.1
|
| Dry
mouth |
0.5
|
0
|
2.1
|
| Musculoskeletal
System |
|
| Back
pain |
2.0
|
1.0
|
1.5
|
| Nervous
System/Psychiatric |
|
| Headache |
5.6
|
11.7
|
5.1
|
| Insomnia |
3.1
|
1.5
|
0
|
| Dizziness |
1.0
|
3.6
|
0.5
|
| Somnolence |
1.0
|
1.5
|
3.6
|
| Respiratory
System |
|
| Cough |
0
|
0
|
0
|
| Difficulty
breathing/ dyspnea/shortness of breath |
0
|
0.5
|
0.5
|
| Urogenital
System |
|
| Nephrolithiasis** |
3.1
|
1.5
|
0
|
| Special
Senses |
|
|
|
| Taste
perversion |
2.6
|
3.6
|
2.1
|
Study ACTG 320 of Unknown Drug Relationship and of
Severe or Life-threatening Intensity
| Adverse
Experience |
CRIXIVAN plus Zidovudine plus Lamivudine
Percent (n=571)
|
Zidovudine plus Lamivudine Percent (n=575)
|
| Body
as a Whole |
|
| Abdominal
pain |
1.9
|
0.7
|
| Asthenia/fatigue |
2.4
|
4.5
|
| Fever |
3.8
|
3.0
|
| Malaise |
0
|
0
|
| Digestive
System |
|
| Nausea |
2.8
|
1.4
|
| Diarrhea |
0.9
|
1.2
|
| Vomiting |
1.4
|
1.4
|
| Acid
regurgitation |
0.4
|
0
|
| Anorexia |
0.5
|
0.2
|
| Dry
mouth |
0
|
0
|
| Musculoskeletal
System |
|
| Back
pain |
0.9
|
0.7
|
| Nervous
System/ Psychiatric |
|
| Headache |
2.4
|
2.8
|
| Insomnia |
0.2
|
0
|
| Dizziness |
0.5
|
0.7
|
| Somnolence |
0
|
0
|
| Respiratory
System |
|
| Cough |
1.6
|
1.0
|
Difficulty
breathing/ dyspnea/
shortness of breath
|
1.8
|
1.0
|
| Urogenital
System |
|
| Nephrolithiasis** |
2.6
|
0.3
|
| Special
Senses |
|
| Taste
perversion |
0.2
|
0
|
*Includes, from Protocol 028, 224 patients
with 12-week data and
from Protocol 033, 263 patients with a minimum
of 12-week data as well as 100 patients with less than 12-week data.
**Including renal colic, and flank pain with
and without hematuria
In Phase I and II controlled trials, the following adverse
events were reported significantly more frequently by those
randomized to the arms containing CRIXIVAN than by those
randomized to nucleoside analogues: rash, upper respiratory
infection, dry skin, pharyngitis, taste perversion.
Selected laboratory abnormalities of severe or life-threatening
intensity reported in patients treated with CRIXIVAN alone,
CRIXIVAN in combination with zidovudine or zidovudine plus
lamivudine, zidovudine alone, or zidovudine plus lamivudine
are presented in Table 5.
Table 5.
Selected Laboratory Abnormalities of Severe or
Life-threatening Intensity Reported in Studies 028
and ACTG 320
Study 028
| |
CRIXIVAN Percent (n=329)
|
CRIXIVAN plus Zidovudine Percent (n=321)
|
Zidovudine Percent (n=330)
|
| Hematology |
|
| Decreased
hemoglobin < 7.0 g/dL |
0.6
|
0.9
|
3.0
|
| Decreased
platelet count < 50 THS/mm3 |
0.9
|
1.2
|
2.4
|
| Decreased
neutrophils < 0.75 THS/mm3 |
2.1
|
2.5
|
7.9
|
| Blood
chemistry |
|
| Increased
ALT > 500% ULN* |
5.5
|
5.9
|
5.2
|
| Increased
AST > 500% ULN |
4.0
|
2.8
|
3.6
|
| Total
serum bilirubin > 250% ULN |
12.5
|
10.6
|
1.5
|
| Increased
serum amylase > 200% ULN |
2.1
|
2.8
|
2.1
|
| Increased
glucose > 250 mg/dL |
0.9
|
1.2
|
0.6
|
| Increased
creatinine > 300% ULN |
0
|
0
|
0.6
|
Study ACTG 320
| |
CRIXIVAN plus Zidovudine plus Lamivudine
Percent (n=571)
|
Zidovudine plus Lamivudine Percent (n=575)
|
| Hematology |
|
| Decreased
hemoglobin < 7.0 g/dL |
2.4
|
3.5
|
| Decreased
platelet count < 50 THS/mm3 |
0.2
|
0.9
|
| Decreased
neutrophils < 0.75 THS/mm3 |
5.1
|
14.6
|
| Blood
chemistry |
|
| Increased
ALT > 500% ULN* |
2.6
|
2.6
|
| Increased
AST > 500% ULN |
3.3
|
2.8
|
| Total
serum bilirubin > 250% ULN |
6.1
|
1.4
|
| Increased
serum amylase > 200% ULN |
0.9
|
0.3
|
| Increased
glucose > 250 mg/dL |
1.6
|
1.9
|
| Increased
creatinine > 300% ULN |
0.2
|
0
|
*Upper limit of the normal range
Post-Marketing Experience
Body As A Whole: redistribution/accumulation
of body fat in areas such as the back of the neck, abdomen,
and retroperitoneum.
Digestive System: liver function
abnormalities; hepatitis including reports of hepatic
failure (see WARNINGS).
Hematologic: increased spontaneous
bleeding in patients with hemophilia (see PRECAUTIONS);
acute hemolytic anemia (see WARNINGS).
Endocrine/Metabolic: new onset
diabetes mellitus, exacerbation of pre-existing diabetes
mellitus, hyperglycemia (see WARNINGS).
Hypersensitivity: anaphylactoid
reactions.
Skin and Skin Appendage: rash
including erythema multiforme and Stevens-Johnson Syndrome;
hyperpigmentation; alopecia.
Urogenital System: nephrolithiasis;
in some cases resulting in renal insufficiency or acute
renal failure (see WARNINGS); crystalluria; interstitial
nephritis.
Laboratory Abnormalities Increased serum triglycerides.
DRUG INTERACTIONS
Rifampin
Rifampin is a potent inducer of P-450 3A4 that markedly
diminishes plasma concentrations of indinavir. Therefore,
CRIXIVAN and rifampin should not be coadministered (see
CLINICAL PHARMACOLOGY, Drugs That Should Not Be Coadministered
With CRIXIVAN.)
Rifabutin
When rifabutin and CRIXIVAN are coadministered, there
is an increase in the plasma concentrations of rifabutin
and a decrease in the plasma concentrations of indinavir.
A dosage reduction of rifabutin and a dosage increase
of CRIXIVAN are necessary when rifabutin is coadministered
with CRIXIVAN. The suggested dose adjustments are expected
to result in rifabutin concentrations at least 50% higher
than typically observed when rifabutin is administered
alone at its usual dose (300 mg/day) and indinavir concentrations
which may be slightly less than typically observed when
indinavir is administered alone at its usual dose (800
mg every 8 hours). (See DOSAGE AND ADMINISTRATION, Concomitant
Therapy, Rifabutin)
Ketoconazole
Due to an increase in the plasma concentrations of indinavir,
a dosage reduction of indinavir should be considered when
CRIXIVAN and ketoconazole are coadministered (see DOSAGE
AND ADMINISTRATION, Concomitant Therapy, Ketoconazole)
Other
If CRIXIVAN and didanosine are administered concomitantly,
they should be administered at least one hour apart on
an empty stomach; a normal (acidic) gastric pH may be
necessary for optimum absorption of indinavir, whereas
acid rapidly degrades didanosine which is formulated with
buffering agents to increase pH (consult the manufacturer's
product circular for didanosine).
Interactions between indinavir and less potent C.P.A. inducers
than rifampin, such as phenobarbital, phenytoin, carbamazepine,
and dexamethasone have not been studied. These agents should
be used with caution if administered concomitantly with
indinavir because decreased indinavir plasma concentrations
St. John's Wort may lower blood levels of indinavir leading to
treatment failure. (Lancet - Feb 2000)
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in mice and rats.
In mice, no increased incidence of any tumor type was
observed. The highest dose tested in rats was 640 mg/kg/day;
at this dose a statistically significant increased incidence
of thyroid adenomas was seen only in male rats. At that
dose, daily systemic exposure in rats was approximately
1.3 times higher than daily systemic exposure in humans.
No evidence of mutagenicity or genotoxicity was observed
in in vitro microbial mutagenesis (Ames) tests, in vitro
alkaline elution assays for DNA breakage, in vitro and
in vivo chromosomal aberration studies, and in vitro mammalian
cell mutagenesis assays. No treatment-related effects
on mating, fertility, or embryo survival were seen in
female rats and no treatment-related effects on mating
performance were seen in male rats at doses providing
systemic exposure comparable to or slightly higher than
that with the clinical dose. In addition, no treatment-related
effects were observed in fecundity or fertility of untreated
females mated to treated males.
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