Crixivan Side Effects

Please note - some side effects for Crixivan may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Crixivan - for the Consumer

Crixivan

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Crixivan:

Bad taste in the mouth; diarrhea; dizziness; drowsiness; headache; nausea; tiredness; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Crixivan:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); back, flank, or side pain; bloody or cloudy urine; change in the amount of urine; changes in appetite; chest pain; chills; confusion; dark urine; fast or irregular heartbeat; fever; flushed face; heartburn; ingrown toenails; joint or muscle aches; mental or mood changes; numbness of the mouth; one-sided numbness or weakness; pain while urinating; pale stools; red, swollen, or blistered skin; severe dizziness or fainting; severe or persistent stomach pain or upset; speech problems; swelling of the feet, hands, lower legs, or stomach; unusual hair loss; unusual paleness; unusual tiredness; unusually dry skin; vision changes; weight changes; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Crixivan Side Effects - for the Professional

Crixivan

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.

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

		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
Adverse Experience		Percent (n=332)	Percent (n=332)	Percent (n=332)	Percent (n=571)	Percent (n=575)
* Including renal colic, and flank pain with and without hematuria
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

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			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)
* Upper limit of the normal range.
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

Post-Marketing Experience

Body As A Whole: redistribution/accumulation of body fat.

Cardiovascular System: cardiovascular disorders including myocardial infarction and angina pectoris; cerebrovascular disorder.

Digestive System: liver function abnormalities; hepatitis including reports of hepatic failure; pancreatitis; jaundice; abdominal distention; dyspepsia.

Hematologic: increased spontaneous bleeding in patients with hemophilia; acute hemolytic anemia.

Endocrine/Metabolic: new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia.

Hypersensitivity: anaphylactoid reactions; urticaria; vasculitis.

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, pyelonephritis with or without bacteremia; 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, crystalluria; dysuria.

Laboratory Abnormalities

Increased serum triglycerides; increased serum cholesterol.

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Side Effects by Body System - for Healthcare Professionals

Renal

Renal side effects have included nephrolithiasis/urolithiasis, characterized by renal colic and flank pain with or without hematuria, in 12.4% (ranging from 4.7% to 34.4% in individual studies) of patients receiving indinavir at the usual dose during clinical trials; 2.8% of these developed hydronephrosis and 4.5% underwent stent placements. Increased creatinine greater than 3 times ULN occurred in 0.2% of patients receiving indinavir combined with zidovudine plus lamivudine. Capillary necrosis and pyuria have also been reported. Nephrolithiasis/urolithiasis (sometimes resulting in renal insufficiency or acute renal failure), interstitial nephritis (occasionally with indinavir crystal deposits), pyelonephritis (with or without bacteremia), renal insufficiency, and renal failure have been reported during postmarketing experience.

The incidence of nephrolithiasis/urolithiasis is increased with doses greater than 2.4 g/day.

According to the manufacturer, indinavir was identified as a component of the kidney stones from 8 of 12 patients in whom nephrolithiasis developed. It is not known whether an additional risk is incurred with the concomitant use of crystalluria-inducing medications such as sulfonamides.

During postmarketing experience, the interstitial nephritis continued in some patients after stopping indinavir.

Hepatic

Hepatic side effects have included asymptomatic hyperbilirubinemia (total bilirubin greater than or equal to 2.5 mg/dL) in 14% of patients and frequency was increased at doses greater than 2.4 g/day. Less than 1% of these patients had concomitant elevations in ALT or AST. Elevated ALT greater than 5 times ULN (5%), AST greater than 5 times ULN (3.7%), total serum bilirubin greater than 2.5 times ULN (11.9%), and serum amylase greater than 2 times ULN (2.1%) have also been reported. Hepatitis, hepatic failure, hepatic cytolysis, pancreatitis (including at least one case with lactic acidosis), jaundice, liver function abnormalities, increased serum triglycerides, and cirrhosis have been reported in postmarketing experience with indinavir.

Gastrointestinal

Gastrointestinal side effects have included nausea (12%), diarrhea (3.3%), vomiting (8.4%), acid regurgitation (3%), anorexia (3%), increased appetite (2.1%), dyspepsia (1.5%), jaundice (1.5%), and dry mouth/lips. Nausea and vomiting may increase substantially (up to 32%) when combined with zidovudine and other nucleoside analog reverse transcriptase inhibitors. Abdominal distention and dyspepsia have been reported in postmarketing experience with indinavir.

Other

Other side effects have included abdominal pain (17%), taste perversion (2.7%), asthenia/fatigue (2.1%), fever (1.5%), and malaise (2.1%). Angiolipomatosis has been reported in postmarketing experience with indinavir.

Dermatologic

Dermatologic side effects have included rash (1.2%), pruritus (4.2%), dry skin, and leukocytoclastic vasculitis. Rash (including Stevens-Johnson syndrome and erythema multiforme), nail and skin hyperpigmentation, ingrown toenails and/or paronychia, pruritus, and alopecia have been reported during postmarketing experience.

Genitourinary

Genitourinary side effects have included nephrolithiasis/urolithiasis (including renal colic and flank pain with and without hematuria; 8.7%), dysuria (1.5%), hematuria, nocturia, proteinuria, urinary frequency, and urinary tract infection. Indinavir-induced neuropathy may result in erectile dysfunction. Leukocyturia, crystalluria, and dysuria have been reported during postmarketing experience.

Hematologic

Cases of acute spontaneous bleeding in hemophiliacs may be associated with protease inhibitors in general.

Hematologic side effects have included decreased hemoglobin (0.6%), anemia, (0.6%), decreased platelets (0.9%), decreased neutrophils (2.4%), and increased platelets. Lymphadenopathy, spleen disorder, and hemolytic anemia have also been reported but rarely. Increased spontaneous bleeding in hemophiliacs and acute hemolytic anemia have been reported during postmarketing experience.

Metabolic

In a 1997 postmarketing report, the average time to onset of protease inhibitor (PI)-related hyperglycemic event was 76 days. However, some cases occurred as early as 4 days after the initiation of therapy. The disorder was serious in 32 out of 83 cases, which included 27 hospitalizations and 5 incidents of diabetic ketoacidosis.

The underlying mechanism for the development of PI-related hyperglycemia has not been identified. It has been proposed that since PIs are peptidomimetic inhibitors, they may inhibit the conversion of proinsulin to insulin via the calcium-dependent endopeptidases. Peripheral insulin resistance may be involved, since impaired glucose tolerance has been reported in PI-treated subjects in one study. Patients receiving PI therapy should have blood glucose levels measured periodically.

Metabolic side effects have included increased blood glucose (0.9%) and insulin resistance. New-onset diabetes mellitus, hyperglycemia, exacerbation of existing diabetes, and increased serum cholesterol have been reported during postmarketing experience.

Musculoskeletal

Indinavir deposition in synovial fluid may have resulted in monoarthritis in a patient. Intraarticular indinavir levels of 1.36 mcg/mL were measured in the patient's knee joint.

Musculoskeletal side effects have included back pain (8.4%), acute monoarthritis, enthesopathies, adhesive capsulitis, myalgia, muscle cramps, muscle weakness, stiffness, and muscle pain. Arthralgia has been reported during postmarketing experience.

Nervous system

Nervous system side effects have included headache (5.4%), dizziness (3%), and somnolence (2.4%). Agitation, bruxism, dream abnormality, dysesthesia, fasciculation, hypesthesia, neuralgia, peripheral neuropathy, tremor, vertigo, epidural lipomatosis, sensory loss, syncope, and peripheral paresthesia have also been reported. Oral paresthesia has been reported during postmarketing experience.

Respiratory

Respiratory side effects have included cough (1.5%), dyspnea, halitosis, pharyngitis, rales/rhonchi, respiratory distress, and upper respiratory infections.

Cardiovascular

Cardiovascular side effects have included myocardial infarction, angina pectoris, hypertension, and cerebrovascular disorder during postmarketing experience.

Hypersensitivity

Hypersensitivity side effects have included anaphylactoid reactions, urticaria, and vasculitis during postmarketing experience.

Psychiatric

Psychiatric side effects have included anxiety and neurosis. Depression has been reported during postmarketing experience.

Other

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement, peripheral wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving protease inhibitors, including indinavir. The mechanism and long-term consequences of these events are currently unknown and a causal relationship has not been established.

Ocular

Ocular side effects have included blurred vision, eye pain, eye swelling, and orbital edema.

Endocrine

Endocrine side effects have included galactorrhea and hyperprolactinemia.

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