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Drugs! Drugs! Drugs!
An Overview of the Approved Anti-HIV Medications

Crixivan (Indinavir Sulfate, IDV)

Fall 2003/Winter 2004

Crixivan (indinavir sulfate, IDV) was approved by the FDA in March 1996, just two weeks after Norvir (ritonavir). Crixivan's ability to lower viral load to undetectable levels in most people who used it in a three-drug combination made it the "gold standard" of the day. As more drugs with less severe food restrictions and fewer doses per day have become available, Crixivan's popularity has waned. Originally, Crixivan needed to be taken every eight hours on an empty stomach. Combined with low doses of Norvir -- an option that has become increasingly common -- the number of daily Crixivan doses is reduced from three to two and the food restrictions are no longer necessary. Although no longer the "gold standard" it was in the late '90s, Crixivan remains a powerful part of many people's regimens.


Background

Several studies made the argument for Crixivan's original FDA approval. The first was ACTG 320, a trial that recruited 1,156 people with CD4 counts less than 200 who had been on Retrovir (AZT) for at least three months. Everyone in the study took Retrovir with Epivir (3TC), and half also took Crixivan. Although designed to follow people for one year, the study was stopped after only 38 weeks because people taking the three-drug combination were 50% less likely to progress to AIDS or die than those taking only the two NRTIs. A second study, Protocol 035, followed 97 people who took Crixivan alone, Retrovir plus Epivir, or all three drugs together. After one year, just as in ACTG 320, people taking Crixivan with the two other drugs did best. Those on the triple combination had an average increase of 215 CD4 cells compared to 160 in those taking only Crixivan and 20 in those on Retrovir and Epivir. A similar difference was seen in viral load -- 86% of those on the triple combination had viral loads less than 500 copies compared to 56% of those on Crixivan alone and none of those on Retrovir and Epivir.

Further studies compared Retrovir to Crixivan and also found the protease inhibitor to be stronger. Protocol 028 was conducted in Brazil, where there would be a greater chance of including participants who hadn't already taken -- and become resistant to -- Retrovir. In this study, 224 people who had never been on antiretroviral therapy took Retrovir, Crixivan, or both together. This study, too, was stopped early (after 58 weeks) because people taking Crixivan alone or with Retrovir were significantly less likely to experience disease progression, and were more likely to have viral loads less than 500 copies and greater CD4 count increases than those on Retrovir alone.

There was no question that when it was released, Crixivan was one of the strongest protease inhibitors out there and would be an appealing option to many. Because adding Crixivan to a drug combination lowered the amount of virus so much, the drug's manufacturer, Merck Laboratories, knew that there would be a high demand for this powerhouse of a drug. To entice people further, they set their average wholesale price for a year's worth of drug at $5,500, significantly lower than Norvir's $8,100 average wholesale price. Many factors made Crixivan a desirable drug, even before its approval in 1996 -- the only problem was getting it.

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While expanded access programs are meant to provide access to people who really need a drug, Merck made no greater effort than either Roche or Abbott to make Crixivan accessible before it was approved. In August 1995, more than 11,000 people applied for the drug through a lottery system, but only 1,100 received Crixivan in the months prior to its approval. The thousands who were turned away -- and many others -- hoped that once the drug was approved, access would be easier. Unfortunately, it became even more complicated. Because Merck claimed not to have enough drug to distribute to pharmacies throughout the country, it made an exclusive agreement with Stadtlanders, a mail order pharmacy, to distribute the drug. Stadtlanders was able to set whatever price it chose, which was especially difficult on people without any insurance. The price for them included a whopping 37% mark-up -- over $1,600 higher than the price the pharmacy charged insurance programs that were covering the drug. This mark-up had many activists in an uproar, and soon after protests, Stadtlanders offered individuals the same discount offered to insurance companies.

Once Crixivan became widely used, many people on the drug raised concerns about the long-term side effects that it might be causing -- fat gain in the belly, what they called "Crix belly" or "protease paunch." According to some studies, as many as 64% of people on any of the protease inhibitors -- not just Crixivan -- experience changes in body fat and/or blood fat levels (lipodystrophy), including the "Crix belly." Later on, this effect was seen in people who were not using protease inhibitors at all, and studies show that it may be related to the use of antiretrovirals in general, rather than one single drug or group of drugs. HIV itself may also contribute to body fat redistribution and changes in blood fats.

One of the challenges of taking Crixivan as it was originally prescribed was the strict every eight hours dosing schedule, made even more difficult by the empty stomach requirement. In 1998, Merck launched a 287-person study to see if Crixivan would be as effective if it were taken every twelve hours. The study was short-lived. After just six months, only 64% of those on the twice-a-day dose had undetectable levels of virus compared to 91% of those taking the drug three times a day. Unfortunately, twice-a-day dosing allowed drug levels in the body to drop too low, and some people in the trial developed resistance to Crixivan. People can now successfully use Crixivan twice a day by adding a small dose of Norvir.

The current Department of Health and Human Services (DHHS) treatment guidelines differ significantly from the original 1997 version, which gave Crixivan a higher recommendation as a starting regimen. Studies at the time showed that 80-90% of people starting treatment with a protease inhibitor achieved undetectable viral loads. This began a push to get everyone, including people with undetectable viral loads who were on other regimens, to switch to Crixivan or other protease inhibitor-containing combinations. The current guidelines recognize that, while Crixivan is a strong drug, it may be saved for later use, and drugs with more convenient dosing may be better to start with.


Side Effects

Kidney stones, the main concern when using Crixivan, occur in 2-3% of people who take the drug. They're more common in women than in men. If someone on Crixivan experiences pain in their side or back, they should tell their healthcare provider. Left unchecked, kidney stones can lead to kidney damage, which can lead to kidney failure. Crixivan can also cause levels of bilirubin (a substance produced when red blood cells are broken down) to go up, but levels usually return to normal after a few months on the drug.

Other side effects include rash, dry skin, altered sense of taste, mild to moderate hair loss, ingrown toenails, nausea, headache, blurred vision, dizziness, and anemia. The anemia is important to watch for, as it can get dangerous very quickly. Symptoms may include tiredness, feeling lightheaded, and shortness of breath.


Drug Interactions

Crixivan interacts with many other HIV drugs. Drug levels increase when taken with some antiretrovirals, including Norvir, Viracept (nelfinavir), Kaletra (lopinavir/ritonavir), and Rescriptor (delavirdine). Others drugs, such as Sustiva (efavirenz) and Viramune (nevirapine), decrease levels of Crixivan. If any of these drugs are used with Crixivan, the Crixivan dose may need to be adjusted. Crixivan also seems to increase levels of Agenerase (amprenavir), but no change in dose of either drug is recommended.

Other drugs should be used with caution and, in some cases, avoided when using Crixivan. Nizoral (ketoconazole), for example, raises Crixivan levels by 68% and the dose of Crixivan may need to be lowered. The tuberculosis drug Mycobutin (rifabutin) doubles Crixivan levels and doses of both drugs may need to be adjusted. Rifampin has severe interactions with Crixivan and should be avoided. Crixivan can increase levels of the lipid-lowering drugs Zocor (simvastatin), lovastatin (Mevacor or Atocor), and Lipitor (atorvastatin), and they should be avoided if possible. Ergot alkaloids (used for migraines) should also be avoided. Viagra (sildenafil) levels can triple when taken with Crixivan, so starting with a lower dose of Viagra and increasing it every 48 hours, if necessary, can help reduce the risk of serious side effects.

Strong interactions have also been seen with both grapefruit juice and St. John's wort (hypericum). Grapefruit juice and St. John's wort lower levels of Crixivan by 26% and 57% respectively when taken with Crixivan and should be avoided.


When to Consider It

The 2003 DHHS treatment guidelines recommend Crixivan as a component of two protease inhibitor-containing alternative regimens for people choosing their first combination. Both the regular, three-times-a-day dose and the twice-a-day dose boosted with Norvir are included. "Boosting" -- taking the drug with low-dose Norvir -- allows people to take Crixivan twice a day. This seems to be as effective at reducing viral load as when the drug is taken three times a day without Norvir -- one study showed the two dosing strategies to work equally well for over two years. The twice-a-day dosing is much easier, but can increase side effects, including nausea, vomiting, dry mouth, rash, kidney stones, and elevations in cholesterol and triglyceride levels.

If your virus becomes resistant to Crixivan, it may also be resistant to other protease inhibitors (cross-resistant). The strongest cross-resistance is seen with Norvir. If Norvir no longer works, then Crixivan is unlikely to work, and vice versa, even if the other drug has never been used before. Similar cross-resistance can also occur with Viracept, Agenerase, and Kaletra.


Good to Know

  • HIV reproduces in many parts of the body, including the brain. Crixivan is the only protease inhibitor that we know reaches the brain and can help lower levels of HIV there.

  • Crixivan and the buffered versions of Videx (ddI) need to be taken at least one hour apart and both on an empty stomach.

  • The dosage of Crixivan should be lowered in people with serious liver damage (cirrhosis).


Pregnancy

Crixivan is classified as an FDA pregnancy category C drug. Its safety in human pregnancy hasn't been determined. Animal studies looking at dangerous effects to the newborn have been negative, but some studies did show the growth of extra ribs in rodents. Crixivan shouldn't be used during pregnancy unless the potential benefit outweighs the potential risk to the mother and fetus.


Dose

Crixivan comes in 100, 200, 333, and 400-mg capsules. The standard dosage is 800 mg (usually two 400-mg capsules) every 8 hours on an empty stomach, one hour before or two hours after you eat. Boosting Crixivan with Norvir allows for twice-a-day dosing (usually two 400-mg Crixivan capsules with either one or two 100-mg Norvir capsules), but the side effects are often greater with the twice-a-day dosing. Crixivan is not approved for pediatric use.

Although Crixivan was originally approved to be taken on an empty stomach, guidelines were developed by the HIV/AIDS Dietetic Practice Group of The American Dietetic Association and approved by the FDA in August 1997 that listed certain foods that could be eaten with Crixivan without affecting the drug's absorption. An ideal snack, for example, would be low-fat and might include dry toast with jelly or cornflakes with skim milk.

It's important to drink at least eight glasses of water a day while taking Crixivan to reduce the risk of kidney stones. Taking the capsules with other beverages such as skim milk, most juices, coffee or tea should be fine, but be careful not to drink grapefruit juice while on Crixivan since it significantly lowers levels of drug in the body. 1%, 2% or whole milk should be avoided.

FDA Approval: 1996

Manufacturer: Merck & Co.

Patient Assistance Program: 800-850-3430





  
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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
 

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