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
Crixivan Side Effects, and Drug Interactions - Indinavir Sulfate
Crixivan Side Effects, and Drug Interactions - Indinavir Sulfate
SIDE EFFECTS
Clinical Trials in Adults
Nephrolithiasis/urolithiasis, 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 1.8% in the control arms. Of the patients
treated with CRIXIVAN who developed nephrolithiasis/urolithiasis, 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/Urolithiasis.)
Asymptomatic hyperbilirubinemia (total bilirubin ³2.5
mg/dL), reported predominantly as elevated indirect bilirubin, has occurred
in approximately 14% of patients treated with CRIXIVAN. In <1% this was
associated with elevations in ALT or AST.
Hyperbilirubinemia and nephrolithiasis/urolithiasis occurred more frequently
at doses exceeding 2.4 g/day compared to doses £2.4
g/day.
Clinical adverse experiences reported in ³2%
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 5.
| Table 5 Clinical Adverse
Experiences Reported in ³2% of Patients |
| Adverse
Experience |
Study 028
Considered Drug-Related and of Moderate or Severe Intensity |
Study ACTG 320
of Unknown Drug Relationship and of Severe or Life-threatening Intensity |
| CRIXIVAN |
CRIXIVAN
plus Zidovudine |
Zidovudine |
CRIXIVAN
plus
Zidovudine
plus
Lamivudine |
Zidovudine
plus
Lamivudine |
Percent
(n= 332) |
Percent
(n= 332) |
Percent
(n= 332) |
Percent
(n=571) |
Percent
(n=575) |
| Body as a Whole |
| Abdominal pain |
16.6 |
16.0 |
12.0 |
1.9 |
0.7 |
| Asthenia/ fatigue |
2.1 |
4.2 |
3.6 |
2.4 |
4.5 |
| Fever |
1.5 |
1.5 |
2.1 |
3.8 |
3.0 |
| Malaise |
2.1 |
2.7 |
1.8 |
0 |
0 |
| Digestive System |
| Nausea |
11.7 |
31.9 |
19.6 |
2.8 |
1.4 |
| Diarrhea |
3.3 |
3.0 |
2.4 |
0.9 |
1.2 |
| Vomiting |
8.4 |
17.8 |
9.0 |
1.4 |
1.4 |
| Acid regurgitation |
2.7 |
5.4 |
1.8 |
0.4 |
0 |
| Anorexia |
2.7 |
5.4 |
3.0 |
0.5 |
0.2 |
| Appetite increase |
2.1 |
1.5 |
1.2 |
0 |
0 |
| Dyspepsia |
1.5 |
2.7 |
0.9 |
0 |
0 |
| Jaundice |
1.5 |
2.1 |
0.3 |
0 |
0 |
| Hemic and Lymphatic System |
| Anemia |
0.6 |
1.2 |
2.1 |
2.4 |
3.5 |
| Musculoskeletal System |
| Back pain |
8.4 |
4.5 |
1.5 |
0.9 |
0.7 |
| Nervous System/ Psychiatric |
| Headache |
5.4 |
9.6 |
6.0 |
2.4 |
2.8 |
| Dizziness |
3.0 |
3.9 |
0.9 |
0.5 |
0.7 |
| Somnolence |
2.4 |
3.3 |
3.3 |
0 |
0 |
| Skin and Skin Appendage |
| Pruritus |
4.2 |
2.4 |
1.8 |
0.5 |
0 |
| Rash |
1.2 |
0.6 |
2.4 |
1.1 |
0.5 |
| Respiratory System |
| Cough |
1.5 |
0.3 |
0.6 |
1.6 |
1.0 |
| Difficulty breathing/ dyspnea/ shortness of breath |
0 |
0.6 |
0.3 |
1.8 |
1.0 |
| Urogenital System |
| Nephrolithiasis/ urolithiasis* |
8.7 |
7.8 |
2.1 |
2.6 |
0.3 |
| Dysuria |
1.5 |
2.4 |
0.3 |
0.4 |
0.2 |
| Special Senses |
|
Taste perversion
|
2.7 |
8.4 |
1.2 |
0.2 |
0 |
* 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 6.
Table 6
Selected Laboratory Abnormalities of Severe or Life-threatening Intensity
Reported in Studies 028 and ACTG 320 |
| |
Study 028 |
Study ACTG 320 |
| CRIXIVAN |
CRIXIVAN plus
Zidovudine |
Zidovudine |
CRIXIVAN
plus
Zidovudine
plus
Lamivudine |
Zidovudine
plus
Lamivudine |
Percent
(n=329) |
Percent
(n=320) |
Percent
(n=330) |
Percent
(n=571) |
Percent
(n=575) |
| Hematology |
Decreased hemoglobin
<7.0 g/dL |
0.6 |
0.9 |
3.3 |
2.4 |
3.5 |
Decreased platelet count
<50 THS/mm3 |
0.9 |
0.9 |
1.8 |
0.2 |
0.9 |
Decreased neutrophils
<0.75 THS/mm3 |
2.4 |
2.2 |
6.7 |
5.1 |
14.6 |
| Blood chemistry |
Increased ALT
>500% ULN* |
4.9 |
4.1 |
3.0 |
2.6 |
2.6 |
Increased AST
>500% ULN |
3.7 |
2.8 |
2.7 |
3.3 |
2.8 |
Total serum bilirubin
>250% ULN |
11.9 |
9.7 |
0.6 |
6.1 |
1.4 |
Increased serum amylase
>200% ULN |
2.1 |
1.9 |
1.8 |
0.9 |
0.3 |
Increased glucose
>250 mg/dL |
0.9 |
0.9 |
0.6 |
1.6 |
1.9 |
Increased creatinine
>300% ULN |
0 |
0 |
0.6 |
0.2 |
0 |
* Upper limit of the normal range.
Post-Marketing Experience
Body As A Whole: redistribution/accumulation of body fat
(see PRECAUTIONS: General -
Fat Redistribution).
Cardiovascular System: cardiovascular disorders including
myocardial infarction and angina pectoris; cerebrovascular disorder.
Digestive System: liver function abnormalities; hepatitis
including reports of hepatic failure (see WARNINGS);
pancreatitis; jaundice; abdominal distention; dyspepsia.
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; urticaria.
Musculoskeletal System: arthralgia.
Nervous System/Psychiatric: oral paresthesia; depression.
Skin and Skin Appendage: rash including erythema multiforme
and Stevens-Johnson Syndrome; hyperpigmentation; alopecia; ingrown toenails
and/or paronychia; pruritus.
Urogenital System: nephrolithiasis/urolithiasis; in some
cases resulting in renal insufficiency or acute renal failure (see WARNINGS);
interstitial nephritis sometimes with indinavir crystal deposits; in some
patients, the interstitial nephritis did not resolve following discontinuation
of CRIXIVAN; crystalluria; dysuria.
Laboratory Abnormalities
Increased serum triglycerides; increased serum cholesterol.
DRUG INTERACTIONS
Delavirdine
Due to an increase in indinavir plasma concentrations (preliminary results),
a dosage reduction of indinavir should be considered when CRIXIVAN and
delavirdine are coadministered. (See DOSAGE
AND ADMINISTRATION: Concomitant Therapy, Delavirdine;
CLINICAL PHARMACOLOGY: Drug Interactions
- Drugs Requiring Dose Modification - Delavirdine.)
Efavirenz
Due to a decrease in the plasma concentrations of indinavir, a dosage
increase of indinavir is recommended when CRIXIVAN and efavirenz are coadministered.
No adjustment of the dose of efavirenz is necessary when given with indinavir.
(See DOSAGE AND ADMINISTRATION: Concomitant
Therapy, Efavirenz; CLINICAL PHARMACOLOGY:
Drug Interactions - Drugs Requiring Dose Modification -
Efavirenz.)
Itraconazole
Itraconazole is an inhibitor of P-450 3A4 that increases plasma concentrations
of indinavir. Therefore, a dosage reduction of indinavir is recommended
when CRIXIVAN and itraconazole are coadministered (see DOSAGE
AND ADMINISTRATION: Concomitant Therapy, Itraconazole; CLINICAL
PHARMACOLOGY: Drug Interactions - Drugs Requiring Dose Modification
- Itraconazole).
Ketoconazole
Ketoconazole is an inhibitor of P-450 3A4 that increases plasma concentrations
of indinavir. Therefore, a dosage reduction of indinavir is recommended
when CRIXIVAN and ketoconazole are coadministered (see DOSAGE
AND ADMINISTRATION: Concomitant Therapy, Ketoconazole; CLINICAL
PHARMACOLOGY: Drug Interactions - Drugs Requiring Dose Modification
- Ketoconazole).
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; CLINICAL
PHARMACOLOGY: Drug Interactions - Drugs Requiring Dose Modification,
Rifabutin.)
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:
Drug Interacitons - Drugs That Should Not Be Coadministered With CRIXIVAN).
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 CYP3A4 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
may result.
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