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

Norvir (Ritonavir, RTV)

Fall 2003/Winter 2004

Norvir (ritonavir, RTV) is one of the strongest but least prescribed protease inhibitors on the market today. In several studies, Norvir has shown a strong reduction in viral load and an increase in CD4 cells, especially when taken with one or two other anti-HIV medications. After its approval in March 1996, the hope that Norvir would be the Superman of its class faded as people struggled with the foul taste, nausea, diarrhea, vomiting, and other intense side effects of the drug, as well as its many drug interactions. These days, Norvir is most often used at much lower doses to increase the levels of other anti-HIV medications in the body, resulting in simpler dosing of the "boosted" drug as well as effective suppression of HIV.


Many people hoped that Norvir would be the protease inhibitor that Invirase (saquinavir) wasn't. Several studies that led to the drug's approval made the case for Norvir in what was then just the beginning of combination therapy. In study M94-247, 1,090 people who had been on treatment for at least nine months and had less than 100 CD4 cells took either Norvir or a placebo in addition to the nucleoside analogs they were already taking. After seven months, 13% of the people taking Norvir experienced disease progression or died compared to 27% of those taking the placebo. Norvir had reduced the risk of disease progression or death by half. These results were quite compelling, as Norvir was the first drug that seemed to extend survival.

In study M94-245, 356 people who had never been on antiretroviral treatment with CD4 cells above 200 and viral loads greater than 15,000 were assigned to take Retrovir (AZT), Norvir, or both together. After 16 weeks, people who took Norvir alone or with Retrovir did better than those who took Retrovir alone. On average, their viral loads dropped more than 90%, and those taking Norvir alone seemed to have the greatest reduction in viral load. On average, CD4 counts increased by 62 in people who took Norvir alone, compared to 35 in those who took Retrovir with Norvir, and 11 in those who took Retrovir alone. It was surprising that participants taking both drugs didn't do better than those who took Norvir alone. One reason may have been that people taking both drugs were far more likely to experience nausea and vomiting than those taking one drug.

In a smaller study done in France, 32 people who had never been on antiretrovirals before took Norvir for two weeks, and then added Retrovir and Hivid (ddC). At the beginning of the trial, participants had an average CD4 count of 170 and an average viral load of 50,000. After 72 weeks, 17 of the 32 trial participants had viral loads below 200 copies. The average CD4 increase was 160 cells. So it was no surprise when Norvir was approved faster than any anti-HIV medication before -- just one day after the FDA's advisory panel recommended approval!

Inspired by Roche's tiny early access program for Invirase, Abbott Laboratories, Norvir's manufacturer, provided very limited access to people who needed their drug before FDA approval. Beginning in December 1995, a mere 1,480 people worldwide with CD4 counts of 50 or below received Norvir by lottery, leaving thousands with no access until the drug was approved. Once again, a manufacturer had "extremely limited supplies" of its drug. Yet when Norvir was approved two months later, there was no supply problem whatsoever. Access to the drug was again limited in September 1998, when manufacturing problems led to a worldwide shortage of the commonly used capsule form. People had to tolerate the bitter taste and aftertaste of the substitute liquid formulation for months.

In recent years, Norvir has re-entered the scene in a modified role. All of the protease inhibitors (PIs) are broken down (metabolized) by the same family of enzymes in the liver. In order for the PIs to be metabolized by these liver enzymes, they must first either slow down or speed up the enzymes' activity. All of the currently approved PIs slow down the activity of these liver enzymes. Norvir is the most powerful of all of the PIs in this regard, even when low doses of the drug are used. In turn, Norvir can prevent other PIs from getting to the enzyme, causing levels of these other PIs to increase -- to become "boosted" -- in the bloodstream. This can make the other PIs more effective against HIV. It also means that lower doses -- or less frequent doses -- of these other PIs can be taken. With Agenerase (amprenavir), for example, adding that small amount of Norvir increases the levels of Agenerase in the body up to ten times, reducing the number of Agenerase capsules required each day from sixteen to ten. For this reason, when Kaletra (lopinavir/ritonavir) was developed, it was packaged to already include a small dose of Norvir in the pill so that less lopinavir would be needed.

Boosting with Norvir is useful with many drugs and holds promise for once-a-day dosing options. Crixivan (indinavir), Viracept (nelfinavir), Agenerase, and Invirase are already being boosted, and other drugs, including the recently approved Reyataz (atazanavir), are being studied with low-dose Norvir in clinical trials. Agenerase has been approved for once-a-day dosing when boosted with Norvir, and several other PIs are in line for review.

Side Effects

Norvir's most common side effects are gastrointestinal -- nausea, vomiting, diarrhea, and abdominal pain. Other side effects include taste perversion, tingling or numbness in the hands, feet and around the mouth, loss of appetite, and tiredness. People taking Norvir may also experience hepatitis (liver inflammation), or pancreatitis (inflammation of the pancreas). Women may be at greater risk for anemia (low red blood cells) because of excessive menstrual bleeding that's sometimes caused by Norvir. Women also seem to experience Norvir side effects more commonly than men, especially nausea and vomiting.

To lower the risk of side effects, some people who took full-dose Norvir early on started with a smaller dose (no lower than 300 mg) and gradually increased it until reaching the full dose of 600 mg twice a day. Today, dose escalation is not as much of an issue, as people usually take smaller amounts of Norvir to boost another drug. Although Norvir can be taken with or without food, it may be easier on the stomach if it's taken with food. Some people say that taking it with yogurt can be particularly helpful in reducing some of the side effects.

Using Norvir to boost PIs can ease food restrictions and allow less frequent dosing, but it can also increase the risk of side effects. For example, there's no need to worry about Agenerase's food restrictions when boosting with Norvir, but the risk of a rash is greater than when taking Agenerase without Norvir. When boosting Fortovase, there is a higher risk of Fortovase's gastrointestinal side effects, which is why many people boost Invirase, the hard-gel version of saquinavir, instead. When used to boost Crixivan, Norvir eliminates Crixivan's food restriction, but the trade-off is that there may be a higher risk of kidney stones. Therefore, people taking boosted Crixivan should be particularly sure to drink lots of water.

Drug Interactions

Norvir has the longest list of drug interactions of any antiretroviral by far. This list includes some antihistamines, tranquilizers, sleeping pills, antiarrhythmics (used to regulate an erratic heartbeat), and ergot alkaloids (used to treat migraines). Combining Norvir with any of these drugs may cause serious or even life-threatening interactions. Norvir capsules and liquid contain small amounts of alcohol, which can cause severe reactions, even death, when taken with Antabuse (disulfiram). Because of Norvir's alcohol content, Flagyl (metronidazole) should also be avoided.

Other drugs that shouldn't be used with Norvir include Vascor (bepridil), Zocor (simvastatin), lovastatin (Mevacor or Atocor), Priftin (rifapentine), Mycobutin (rifabutin), and St. John's wort (hypericum). Viagra (sildenafil) levels can be twice as high when taken with Norvir, 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. Norvir can increase or decrease levels of warfarin, a blood thinner, depending on which type of warfarin is used. A dose adjustment of warfarin may be necessary. Sporanox (itraconazole) and Flonase (fluticasone) may require lower doses when either is combined with Norvir and should be used with caution. Because the list of interactions is so long, it's best to check the package insert that comes with the drug and talk with your healthcare provider about the other medications you're taking.

Norvir can also raise levels of certain street drugs, such as Ecstasy (MDMA). At least one person died when taking the two together. Norvir may also lower methadone levels by 37%, so the methadone dose may need to be increased to compensate.

When to Consider It

The current Department of Health and Human Services (DHHS) treatment guidelines don't recommend full-dose Norvir as part of any combination. For someone just beginning treatment, the PI-based regimen most highly recommended by the guidelines includes Kaletra (which already has some Norvir in it). Some PI-based regimens recommended as alternatives include PIs boosted with Norvir. The number of pills in these combinations is still anywhere from 8 to 16 a day, which is one reason why Norvir-boosted combinations haven't made first picks as starting regimens.

Norvir has significant cross-resistance with Crixivan, meaning that if someone has resistance to one drug, they will most likely be resistant to the other. Resistance to Norvir is also likely to eliminate Viracept as an option, although the reverse isn't necessarily true -- resistance to Viracept doesn't seem to eliminate Norvir as an option. Cross-resistance with other protease inhibitors is also possible, but depends on the number and types of mutations acquired. However, if someone has become partially or even fully resistant to Norvir, it can still be useful as a boosting agent.

Good to Know

  • Taking Norvir with a light, low-fat meal may help the drug to be better absorbed in the body.

  • Norvir levels may be up to 40% lower in people with moderate liver damage who take the drug. No dose adjustment is recommended, but response to treatment should be monitored particularly carefully in such cases.

  • Many people don't like to use the liquid form of Norvir because of the bitter taste. Adults who have a difficult time swallowing pills sometimes use the liquid version and for young children it's the only choice. Some tips to help get the liquid version down include:

    • Drinking the liquid through a straw so that it goes straight down.

    • Mixing the liquid with chocolate milk or a nutritional supplement.

    • Coating your tongue with peanut butter.

    • Sucking a popsicle beforehand to numb the taste buds.


Norvir is classified as an FDA pregnancy category B drug. Animal studies fail to demonstrate a risk to the mother and fetus, but some long-term animal studies have shown the development of liver tumors in rats as well as developmental problems in unborn rodents. This doesn't necessarily mean that the same would be true in humans. Well-controlled studies of pregnant women have not been conducted.


Norvir comes in two forms: soft gelatin capsules of 100 mg each and a liquid formulation (80 mg/mL). If taken alone, the standard dose is 1,200 mg a day, (600 mg taken twice a day) with or without food. If being used to boost another drug, the dose is usually 100 to 200 mg twice a day. Refrigeration used to be recommended for both the liquid and capsule forms, but that has changed. The capsules no longer need to be refrigerated if they'll be used within a month and are kept in a cool place (below 77°F). The recommended dose for children ages 2-14 is 400 mg twice a day.

FDA Approval: 1996

Manufacturer: Abbott Laboratories

Patient Assistance Program: 800-222-6885

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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.