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Clinical Trials In Adults

Nephrolithiasis/urolithiasis, including flank pain with or without hematuria (including microscopic hematuria), has been reported in approximately 12.4% (301/2429; range across individual trials: 4.7% to 34.4%) of patients receiving CRIXIVAN at the recommended dose in clinical trials with a median follow-up of 47 weeks (range: 1 day to 242 weeks; 2238 patient-years follow-up). The cumulative frequency of nephrolithiasis events increases with duration of exposure to CRIXIVAN; however, the risk over time remains relatively constant. Of the patients treated with CRIXIVAN who developed nephrolithiasis/urolithiasis in clinical trials during the double-blind phase, 2.8% (7/246) were reported to develop hydronephrosis and 4.5% (11/246) underwent stent placement. Following the acute episode, 4.9% (12/246) of patients discontinued therapy. (See WARNINGS and DOSAGE AND ADMINISTRATION, Nephrolithiasis/Urolithiasis.)

Asymptomatic hyperbilirubinemia (total bilirubin ≥ 2.5 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 ≥ 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 10.

Table 10: Clinical Adverse Experiences Reported in ≥ 2% 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 Percent
(n=332)
CRIXIVAN plus Zidovudine Percent
(n=332)
Zidovudine Percent
(n=332)
CRIXIVAN plus Zidovudine plus Lamivudine Percent
(n=571)
Zidovudine plus Lamivudine 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 11.

Table 11: Selected Laboratory Abnormalities of Severe or Life-threatening Intensity Reported in Studies 028 and ACTG 320

  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 Percent
(n=329)
CRIXIVAN plus Zidovudine Percent
(n=320)
Zidovudine Percent
(n=330)
CRIXIVAN plus Zidovudine plus Lamivudine Percent
(n=571)
Zidovudine plus Lamivudine 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, 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; vasculitis.

Musculoskeletal System: arthralgia, periarthritis.

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, pyelonephritis with or without bacteremia (see WARNINGS); interstitial nephritis sometimes with indinavir crystal deposits; in some patients, the interstitial nephritis did not resolve following discontinuation of CRIXIVAN; renal insufficiency; renal failure; leukocyturia (see PRECAUTIONS), crystalluria; dysuria.

Laboratory Abnormalities

Increased serum triglycerides; increased serum cholesterol.