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

Viracept (Nelfinavir Mesylate, NFV)

Fall 2003/Winter 2004

Viracept (nelfinavir mesylate, NFV) has enjoyed wide use since its FDA approval in March 1997. By 1999, it was the most frequently prescribed protease inhibitor (PI) on the U.S. market and today is second only to Kaletra (lopinavir/ritonavir). Viracept's original approval was for use in both adults and children, which was a first. For other antiretrovirals, pediatric approval -- if it happens at all -- usually occurs years after approval for use in adults.

One plus for Viracept is that if it's used as your first PI and your HIV develops resistance to it, most other PIs are still likely to work. Another plus is that, although Viracept was originally approved to be taken three times a day, it was later shown to be equally effective when taken twice a day at a slightly different dose. For people with HIV who also have chronic hepatitis B or C, Viracept is a useful option because it's easier on the liver than the other PIs. There are some important trade-offs when considering Viracept, though. It doesn't have the strength of many other anti-HIV drugs when it comes to reducing viral load, and it causes diarrhea more often than any other commonly-used antiretroviral. Many people who take Viracept experience this infamous side effect, so it's important to figure out ways to manage the diarrhea when considering this drug.


Background

From the time Viracept was first studied in clinical trials through its FDA approval, there were many questions about which dose to use. In developing the drug, Agouron Pharmaceuticals had looked at 500, 750, and 1,000-mg doses in trials such as AG 503. While the 1,000-mg dose reduced viral load more than the two lower doses, it also caused kidney stones more often. So Agouron ditched the 1,000-mg dose and used the 500 and 750-mg doses in later clinical trials. In the studies submitted to the FDA for the drug's approval, the two lower doses worked equally well.

In AG 511, 297 people who had never been on anti-HIV medications were divided into three groups. They took Viracept at a dose of either 500 mg or 750 mg three times a day with Retrovir (AZT) and Epivir (3TC) or just Retrovir and Epivir. After 48 weeks, people on either dose of Viracept did much better than those on just Retrovir and Epivir -- 57% on 750 mg and 38% on 500 mg had viral loads less than 400 copies. Only 4% on just Retrovir and Epivir had viral loads that low. Another trial, AG 506, enrolled 308 people who had been on antiretroviral therapy but had never taken a PI or Zerit (d4T). The trial participants took Zerit alone or with one of the same two doses of Viracept. After six months, people taking either Viracept dose had a 90% drop in viral load, while those on Zerit had only a 75% drop. People on Viracept also had greater rises in CD4 cells (100 cells compared to 40 in the Zerit arm). Overall, both doses of Viracept provided a benefit when used with at least one nucleoside analog, but it was hard to tell which dose worked best. Furthermore, people on either dose were just as likely to experience diarrhea. Agouron petitioned the FDA to approve the lower, 500-mg dose three times a day, arguing that it might save people from long-term side effects.

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Some activists and doctors were concerned that this dose was too low and would allow resistance to develop. The FDA took a closer look at the AG 511 study data and found that people who entered the study with viral loads over 100,000 and took the 750-mg dose did better than those who took the 500-mg dose. 81% of those on the higher dose had undetectable viral levels after 48 weeks, compared to 65% of those on the lower dose. With no significant difference in the incidence of diarrhea between the two doses, the FDA approved the 750-mg dose.


Side Effects

Viracept's most common side effect is diarrhea, which can be debilitating. As many as 20% of people who took Viracept in clinical trials had diarrhea. Based on anecdotal and community clinic reports, an even higher percentage have diarrhea outside of the trial setting. For most people, the diarrhea is mild to moderate, but it can be hard to control and significantly interfere with quality of life. Other side effects include nausea, vomiting, weakness, gas, and rash.


Drug Interactions

Viracept can affect and be affected by other anti-HIV medications. When combined with Viracept, levels of Agenerase (amprenavir) and Invirase/Fortovase (saquinavir) can increase, while levels of Kaletra and Rescriptor (delavirdine) can decrease. Viracept levels can increase when it's taken with Norvir (ritonavir), Crixivan (indinavir), Kaletra, Rescriptor, or Sustiva (efavirenz). These interactions don't affect the way that Viracept and the other anti-HIV medications are used, and no dose adjustments are recommended.

Viracept interacts with a number of other medications. Drugs to avoid while on Viracept include Zocor (simvastatin), lovastatin (Mevacor or Atocor), rifampin, triazolam (Halcion, Restoril, Dalmane, and others), Versed (midazolam), and ergot derivatives (used for migraines). Some of these interactions can lead to serious events such as irregular heartbeats (cardiac arrhythmia) and can even be fatal.

Some drugs might require dose adjustments when taken with Viracept, while others might require the Viracept dose to be adjusted. For example, Viracept can lower the amount of methadone in the body by up to 47%, and a higher dose of methadone may be necessary to avoid symptoms of opiate withdrawal. Viracept can lower levels of the oral contraceptives norethindrone and ethinyl estradiol, so an alternative or additional method of birth control may be necessary. Blood levels of Viagra (sildenafil) can be eleven times higher when taken with Viracept. Starting with a lower dose of Viagra and increasing it every 48 hours, if necessary, can help reduce the risk of serious side effects. The tuberculosis drug Mycobutin (rifabutin) requires that doses of both drugs be adjusted when the two are taken together.


When to Consider It

Viracept is undoubtedly the weakest protease inhibitor on the market. It has been removed from the preferred list of recommended starting regimens and is now listed by both the U.S. Department of Health and Human Services and the British HIV Association treatment guidelines as part of an alternative regimen for adults who are beginning treatment with a protease inhibitor.

In the EuroSIDA study, 9,800 people from twenty-six European countries recruited between 1994 and 2001 were followed to see when they started and/or stopped their drug regimens. When data from 1,500 people in the study were analyzed, those on Viracept or Invirase were much less likely to have viral loads below 500 copies and were more likely to later see their viral loads bounce back up than people taking other PIs. Compared to Crixivan and Norvir, Viracept was no match.

Because Viracept is considered to be the weakest PI, it has been used (some would say unfairly) as the control arm in many studies testing new drugs. In ACTG 364, for example, 189 people who had been on treatment took Viracept, Sustiva, or both with two NRTIs. In comparing how well Viracept stood up to Sustiva, the answer was not well at all. After 48 weeks, 60% of those on Sustiva had viral loads below 500 copies, compared to only 35% of those on Viracept. The COMBINE study compared Viracept to Viramune, both taken with Combivir (Retrovir plus Epivir), in 142 people who hadn't been on antiretrovirals before. Again, Viracept was clearly the weaker drug, at least at first. After six months, only 33% of people on Viracept had viral loads below 200 compared to 58% of those on Viramune -- a statistically significant difference. But after 48 weeks, both drugs worked almost as well: 62% versus 75%, respectively. Although there was still a difference, it was no longer statistically significant. Study M98-863 compared Viracept to Kaletra (along with two NRTIs) in 653 people who hadn't been on antiretrovirals before. Those who took Kaletra were significantly more likely to have lower viral loads after 60 weeks. With such generally inferior results, Viracept probably wouldn't be used as often as it is if it weren't for its unique resistance profile.

Many people who use Viracept as a first PI still have all of their PI options intact, even if the drug stops working because their HIV develops resistance to Viracept. The reverse, however, is not true. If someone takes other PIs, develops resistance, and later wants to switch to Viracept, Viracept doesn't usually work. For example, people whose HIV has developed resistance to Invirase, Norvir, or Crixivan have also been found to be resistant to Viracept. So if you decide to start treatment with a PI, Viracept might be a good choice since it leaves other PI options open even if you develop resistance.


Managing Diarrhea

Combining several of the following tips and strategies have helped many people manage diarrhea, including Viracept-related diarrhea:

  • Over-the-counter remedies:

    • Imodium A-D, Kaopectate, Maalox Anti-Diarrheal, and other products that contain loperamide

    • Metamucil

    • SB-Normal Stool Formula

  • Medications that require a prescription:

    • Lomotil (diphenoxylate)

    • Ultrase (a pancreatic enzyme)

    • Tincture of opium

  • Dietary options:

    • BRATT diet -- Bananas, Rice (white), Apple juice or sauce, Toast, and Tea (herbal)

    • Foods high in starch (white rice, white bread, oatmeal, tofu)

    • Juices with less acid, such as apple, pear, and peach

    • 10-13 glasses of water per day

    • Sports drinks like Gatorade that replenish electrolytes

  • Avoid:

    • Coffee, tea, and other caffeinated beverages like soda

    • Chocolate

    • Alcohol

    • Fried and fatty foods

    • Spicy foods

    • Foods high in insoluble fiber (raw vegetables, potato peels, beans, brown rice)

    • Cookies, cakes, donuts, etc.

    • Dairy products, although those with less lactose are okay (yogurt, buttermilk, aged cheeses)

  • Nutritional supplements and vitamins:

    • Calcium or calcium carbonate supplements

    • Probiotic tablets (acidophilus, lactobacillus)

    • Glutamine

    • Zinc


Pregnancy

Viracept is classified as an FDA pregnancy category B drug. A review of over 700 births in which the fetus had been exposed to Viracept in utero found no increased risk of birth defects. According to the Antiretroviral Pregnancy Registry, when Viracept has been used during the first trimester, the prevalence of birth defects was 2.9%, compared to an overall prevalence of 3.1% in the U.S. population. In other words, using Viracept during the first three months of pregnancy -- the time when a fetus is most susceptible to birth defects caused by toxic chemicals and medications -- doesn't seem to have any serious negative effects.


Dose

Viracept is currently available as 250-mg tablets. The FDA approved a 625-mg tablet in April 2003, but it won't be available in pharmacies until sometime early in 2004 due to manufacturing problems. Once the 625-mg tablets are available, twice-daily dosing will require fewer pills and be much simpler. The total twice-a-day dose is 2,500 mg (five 250-mg tablets twice a day or two 625-mg tablets twice a day). The total three-times-a-day dose is 2,250 mg (three 250-mg tablets three times a day).

Viracept is also available as a powder (50 mg/gram). It comes in fruit flavors and can be mixed with water, milk, or pudding to make an oral solution, which can help soften its bitter taste. This can be a useful option for adults who have trouble swallowing pills and for children. The pediatric dose (ages 2-13) is based on weight: 20-30 mg/kg (9-14 mg/pound) three times a day. Adolescents age 14 and older take the adult dose.

Viracept should be taken with food. Meals that are high in calories (500-1,000) and include 15-20% fat increase blood levels of Viracept and may make the drug more effective without causing more diarrhea.

FDA Approval: 1997

Manufacturer: Agouron Pharmaceuticals (a subsidiary of Pfizer)

Patient Assistance Program: 888-777-6637





  
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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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