Side Effects of Crixivan (indinavir)

Crixivan (indinavir) is a type of antiviral medication called a protease inhibitor used to treat infections with the human immunodeficiency virus (HIV). 

During infection with HIV, the HIV virus multiplies within the body's cells. Viruses are released from the cells and spread throughout the body where they infect other cells. In this manner, HIV infection is perpetuated among new cells that the body produces continually. During the production of the viruses, new proteins are made. 

Some of the proteins are structural proteins, that, is, proteins that form the body of the virus. Other proteins are enzymes which manufacture DNA and other components for the new viruses. Protease is the enzyme that forms the new structural proteins and enzymes. 

Crixivan blocks the activity of protease and results in the formation of defective viruses that are unable to infect the body's cells. As a result, the number of viruses in the body (the viral load) decreases. Crixivan does not prevent the transmission of HIV among individuals, and it does not cure HIV infections or AIDS. 

Common side effects of Crixivan include

• abdominal pain,
• weakness,
• nausea,
• diarrhea,
• vomiting,
• headache,
• insomnia,
• abnormal taste sensation, and
• redistribution or accumulation of body fat.

Serious side effects of Crixivan include

• anemia,
• liver failure,
• kidney stones,
• increased blood cholesterol, and
• worsening of diabetes.

Drug interactions of Crixivan include triazolam, midazolam, alprazolam, pimozide, lovastatin, simvastatin, ergot derivatives, and amiodarone because of the risk of serious adverse effects resulting from Crixivan increasing the blood levels of these drugs.

• Crixivan increases blood concentrations of stavudine, alfuzosin, oral contraceptives, and clarithromycin. Increased blood levels may result in more frequent side effects.
• Crixivan decreases the blood concentration of didanosine in the body and can thereby reduce the effectiveness of didanosine.
• Crixivan also may inhibit the break-down of the cholesterol-lowering drugs lovastatin, simvastatin, and atorvastatin. This may increase the risk of muscle breakdown (rhabdomyolysis) that may be seen when these drugs accumulate in the body.
• Ketoconazole, itraconazole, delavirdine, and clarithromycin can increase blood levels of Crixivan and result in more frequent or severe side effects from Crixivan. Rifampin, rifabutin, St. John's wort, and efavirenz decrease the blood levels of Crixivan and thus can reduce the effect of Crixivan.
• Crixivan increases blood levels of sildenafil and the risk of side effects such as low blood pressure, prolonged erection, and fainting. 

Use of Crixivan during pregnancy has not been adequately evaluated. It is unknown if Crixivan is excreted in breast milk. Nevertheless, HIV-infected mothers should not breastfeed because of the potential risk of transmitting HIV to an infant that is not infected.

The most common side effects of indinavir are:

• abdominal pain,
• weakness,
• nausea,
• diarrhea,
• vomiting,
• headache,
• insomnia and
• abnormal taste sensation.

Other important side effects include:

• anemia (break-down of red blood cells),
• liver failure and
• kidney stones.

Like other protease inhibitors, use of indinavir may be associated with:

• redistribution or accumulation of body fat,
• increased blood cholesterol, and
• worsening of diabetes.

Kidney stones may be prevented by adequate fluid intake. Adequate fluid intake can be achieved by consuming at least 48 ounces of fluid daily. Immune reconstitution syndrome which is an inflammatory response to infection may occur in patients treated with combination antiretroviral therapy.

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

• 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

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, 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; 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.

Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4. Coadministration of Crixivan and drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects.

Indinavir is metabolized by CYP3A4. Drugs that induce CYP3A4 activity would be expected to increase the clearance of indinavir, resulting in lowered plasma concentrations of indinavir. Coadministration of Crixivan and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir.

Table 8: Drugs That Should Not Be Coadministered with Crixivan

Table 9: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction