Crixivan

Use of indinavir during pregnancy has not been adequately evaluated.

It is not known whether indinavir 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.

If you also take didanosine, take it 1 hour before or after you take indinavir, on an empty stomach.

Taking indinavir will not prevent you from passing HIV to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Many drugs can interact with indinavir. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• midazolam given by injection;
• quetiapine;
• rifabutin;
• antifungal medicine--itraconazole, ketoconazole;
• heart or blood pressure medication--amlodipine, felodipine, quinidine;
• other HIV medicines--efavirenz, delavirdine;
• seizure medicine--carbamazepine, phenobarbital, phenytoin; or
• steroid medicine--dexamethasone, prednisone, and others.

This list is not complete and many other drugs can interact with indinavir. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Crixivan is part of the drug class:

• Protease inhibitors

There are six important things you must do to help you benefit from Crixivan:

1. Take Crixivan capsules every day as prescribed by your doctor. Continue taking Crixivan unless your doctor tells you to stop. Take the exact amount of Crixivan that your doctor tells you to take, right from the very start. To help make sure you will benefit from Crixivan, you must not skip doses or take "drug holidays". If you don't take Crixivan as prescribed, the activity of Crixivan may be reduced (due to resistance).
    
2. Take Crixivan capsules every 8 hours around the clock, every day. It may be easier to remember to take Crixivan if you take it at the same time every day. If you have questions about when to take Crixivan, your doctor or health care provider can help you decide what schedule works for you.
    
3. If you miss a dose by more than 2 hours, wait and then take the next dose at the regularly scheduled time. However, if you miss a dose by less than 2 hours, take your missed dose immediately. Then take your next dose at the regularly scheduled time. Do not take more or less than your prescribed dose of Crixivan at any one time.
    
4. Take Crixivan with water. You can also take Crixivan with other beverages such as skim or non-fat milk, juice, coffee, or tea.
    
5. Ideally, take each dose of Crixivan without food but with water at least one hour before or two hours after a meal. Or you can take Crixivan with a light meal. Examples of light meals includes dry toast with jelly, juice, and coffee (with skim or non-fat milk and sugar if you want) and cornflakes with skim or non-fat milk and sugar.
   Do not take Crixivan at the same time as any meals that are high in calories, fat, and protein (for example — a bacon and egg breakfast). When taken at the same time as Crixivan, these foods can interfere with Crixivan being absorbed into your bloodstream and may lessen its effect.
    
6. It is critical to drink plenty of fluids while taking Crixivan. Adults should drink at least six 8-ounce glasses of liquids (preferably water) throughout the day, every day. Your health care provider will give you further instructions on the amount of fluid that you should drink. Crixivan can cause kidney stones. Having enough fluids in your body should help reduce the chances of forming a kidney stone. Call your doctor or other health care provider if you develop kidney pains (middle to lower stomach or back pain) or blood in the urine.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your liver function

The recommended dose of Crixivan is 800 mg (usually two 400-mg capsules) orally every 8 hours.

Indinavir is a protease (PRO-tee-ayz) inhibitor antiviral medicine that prevents human immunodeficiency virus (HIV) cells from multiplying in your body.

Indinavir is used to treat HIV, which causes the acquired immunodeficiency syndrome (AIDS). Indinavir is not a cure for HIV or AIDS.

Indinavir may also be used for purposes not listed in this medication guide.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Symptoms of an indinavir overdose may include nausea, vomiting, diarrhea, lower back pain, and blood in your urine.

If you also take didanosine, take it 1 hour before or after you take indinavir, on an empty stomach.

Taking indinavir will not prevent you from passing HIV to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Also, do not stop taking this medicine without checking first with your doctor.

Indinavir is used with other medicines to treat HIV infection. Take all other medicines your doctor has prescribed as part of your combination treatment. Your dose of indinavir may depend on the other medicines you are using.

This medicine comes with a patient information insert. Read and follow the instructions in the insert carefully. Ask your doctor if you have any questions.

This medicine should be taken with water on an empty stomach (1 hour before or 2 hours after a meal) or with a light meal. Indinavir may also be taken with other liquids (eg, skim milk, juice, coffee, or tea) or with a light meal (eg, dry toast with jelly, juice, coffee with skim milk and sugar, or corn flakes with skim milk and sugar).

While you are taking indinavir, it is important that you drink extra fluids so that you will pass more urine. This will help prevent possible kidney stones. Follow your doctor's instructions carefully about how much fluid to drink. Usually you will need to drink at least 48 ounces (1.5 liters or 6 full glasses) of fluids every day during your treatment.

Keep taking indinavir for the full time of treatment, even if you begin to feel better.

This medicine works best when there is a constant amount in the blood. To help keep the amount constant, do not miss any doses. Also, it is best to take the doses at evenly spaced times, day and night. For example, if you are to take three doses a day, the doses should be spaced about 8 hours apart. If you need help in planning the best times to take your medicine, check with your doctor.

Only take medicine that your doctor has prescribed specially for you. Do not share your medicine with others.

If you miss a dose or forget to use your medicine less than 2 hours, use it as soon as you can. If your next regular dose is more than 2 hours, wait until then to use the medicine and skip the missed dose.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For treatment of HIV infection:
    • Adults—800 milligrams (mg) every 8 hours. Your doctor may adjust your dose if needed.
    • Children—Use and dose must be determined by your doctor.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Indinavir capsules are very sensitive to moisture. Keep them in their original container and leave the drying packet in the container.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Blood in the urine
• sharp back pain just below the ribs

• Abdominal or stomach pain
• chills
• clay-colored stools
• dark urine
• dizziness
• fever
• headache
• itching
• loss of appetite
• nausea
• rash
• unpleasant breath odor
• unusual tiredness or weakness
• vomiting of blood
• yellow eyes or skin

• Confusion
• dehydration
• dry or itchy skin
• fruity mouth odor
• increased hunger
• increased thirst
• increased urination
• pale skin
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting
• weight loss

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Change in sense of taste
• diarrhea
• difficulty with sleeping
• generalized weakness

• Acid or sour stomach
• acid regurgitation
• belching
• cough
• general feeling of discomfort or illness
• heartburn
• increase in appetite
• indigestion
• sleepiness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• If you have an allergy to indinavir or any other part of Crixivan (indinavir).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you take any drugs (prescription or OTC, natural products, vitamins) that must not be taken with this medicine, like certain drugs that are used for high cholesterol, migraines, or mood problems. There are many drugs that must not be taken with Crixivan.
• If you are taking St. John's wort. Do not take St. John's wort with this medicine. This medicine may not work as well.
• If you are breast-feeding. Do not breast-feed while you take Crixivan.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Crixivan with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Belly pain.
• Feeling tired or weak.
• Upset stomach or throwing up.
• Back pain.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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.

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.

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.

Summary of Use during Lactation

In the United States and other developed countries, HIV-infected mothers should generally not breastfeed their infants. Published experience with In the United States and other developed countries, HIV-infected mothers should generally not breastfeed their infants. Published experience with indinavir during breastfeeding is limited. In countries in which no acceptable, feasible, sustainable and safe replacement feeding is available, World Health Organization guidelines recommend that all women with an HIV infection who are pregnant or breastfeeding should be maintained on antiretroviral therapy for at least the duration of risk for mother-to-child transmission. Mothers should exclusively breastfeed their infants for the first 6 months of life; breastfeeding with complementary feeding should continue through at least 12 months of life up to 24 months of life.[1] The first choice regimen for nursing mothers is tenofovir, efavirenz and either lamivudine or emtricitabine. If these drugs are unavailable, alternative regimens include: 1) zidovudine, lamivudine and efavirenz; 2) zidovudine, lamivudine and nevirapine; or 3) tenofovir, nevirapine and either lamivudine or emtricitabine. Exclusively breastfed infants should also receive 6 weeks of prophylaxis with nevirapine.[2][3]

Drug Levels

Maternal Levels. One woman was receiving indinavir 600 mg twice daily as part of a highly-active antiretroviral combination regimen. During the first 5 days postpartum milk was collected just before and 2 hours after the dose of indinavir. Milk indinavir concentrations ranged between 90 and 540% of the maternal serum concentration. Further details on the timing, or actual breastmilk concentrations were not provided.[4]

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen.[5][6][7] Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients,[8][9] although this has been disputed.[10] The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

References

1. Anon. Guideline: Updates on HIV and infant feeding: The duration of breastfeeding, and support from health services to improve feeding practices among mothers living with HIV. Geneva: World Health Organization. 2016. PMID: 27583316

2. World Health Organization. HIV and infant feeding: update. 2007. http://whqlibdoc.who.int/publications/2007/9789241595964_eng.pdf

3. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization. 2013. http://www.who.int/hiv/pub/guidelines/arv2013/en/

4. Colebunders R, Hodossy B, Burger D et al. The effect of highly active antiretroviral treatment on viral load and antiretroviral drug levels in breast milk. AIDS. 2005;19:1912-5. PMID: 16227801

5. Garcia-Benayas T, Blanco F, Martin-Carbonero L et al. Gynecomastia in HIV-infected patients receiving antiretroviral therapy. AIDS Res Hum Retroviruses. 2003;19:739-41. PMID: 14585204

6. Pantanowitz L, Evans D, Gross PD, Dezube BJ. HIV-related gynecomastia. Breast J. 2003;9:131-2. PMID: 12603389

7. Evans DL, Pantanowitz L, Dezube BJ, Aboulafia DM. Breast enlargement in 13 men who were seropositive for human immunodeficiency virus. Clin Infect Dis. 2002;35:1113-9. PMID: 12384846

8. Hutchinson J, Murphy M, Harries R, Skinner CJ. Galactorrhoea and hyperprolactinaemia associated with protease-inhibitors. Lancet. 2000;356:1003-4. PMID: 11041407

9. Orlando G, Brunetti L, Vacca M. Ritonavir and saquinavir directly stimulate anterior pituitary prolactin secretion, in vitro. Int J Immunopathol Pharmacol. 2002;15:65-8. PMID: 12593790

10. Montero A, Bottasso OA, Luraghi MR et al. Galactorrhoea, hyperprolactinaemia, and protease inhibitors. Lancet. 2001;357:473-4; author reply 475. PMID: 11273087