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

Invirase/Fortovase (Saquinavir Mesylate, SQV)

Fall 2003/Winter 2004

Invirase and Fortovase (saquinavir mesylate, SQV) are different versions of the same drug. Invirase caused a big splash in December 1995 when it became the first protease inhibitor approved by the FDA -- the first in a whole new class of antiretrovirals. Unfortunately, Invirase isn't absorbed by the body as well as other anti-HIV drugs, so a more readily-absorbed formulation called Fortovase was eventually released in November 1997. The plan was to gradually pull Invirase from the market, but it has made a comeback of sorts in recent years. When used as the only protease inhibitor in a combination, either version required taking many pills a day, and neither had the punch to reduce viral load as well as other protease inhibitors. Because of these factors, most people take Invirase or Fortovase with low-dose Norvir (ritonavir). This "boosting," as it's called, lowers the daily number of pills and increases the amount of saquinavir that's absorbed by the body.


Background

When Invirase was being developed, there were only a handful of nucleoside analogs on the market and a lot of questions about how best to use them. Many people were desperate for new options, especially drugs that worked at a different part of the HIV lifecycle. At the time, some activists complained that this desperation led to cutting corners when it came to what we demanded to know about Invirase before its approval.

What was known was gathered not by comparing the drug to other approved drugs, but by observing the effect of adding Invirase to existing drug combinations. (At the time, we were just learning that using two drugs together was better than using one alone.) The company developing Invirase, Hoffmann-La Roche, was very specific about which drugs it used to test with Invirase and mainly conducted studies with its own approved HIV medication Hivid (ddC). In ACTG 229, 302 people who had been on Retrovir (AZT) alone for at least four months took Retrovir plus Invirase, Retrovir plus Hivid, or Retrovir, Hivid, and Invirase together. After six months, 70% of the people on the triple-drug combination had an increase in their CD4 counts, although by one year, only 51% still had an increase compared to 33% in the Retrovir plus Invirase arm and 34% in the Retrovir plus Hivid arm. The triple-drug combination also seemed to reduce viral load more than the other two arms and didn't seem to increase the number of side effects. Eager to have the first approved protease inhibitor on the market, Roche made the case for the accelerated approval of Invirase. Some activists were concerned about the small size (only 302 patients!) of the study and appealed to the FDA not to approve the drug so quickly but, instead, to ask Roche to design a "large simple trial" that would enroll thousands of people and gather more information. Others were furious at the idea of community members delaying the approval of a drug that many were desperate for.

In response, Roche doubled the size of ACTG 229 with a new trial called NV14256B, in which people took Invirase, Hivid, or both together. Everyone in this study had previously been on Retrovir. Even as the weakest drugs in their respective classes, Hivid and Invirase used together had stronger results than either one used alone. A later study (SV14604) showed that using Invirase with Hivid and Retrovir reduced disease progression by up to 50% (compared to using Retrovir or Hivid alone) based on 17-month follow-up. Once four-month data from ACTG 229 were available, the FDA quickly approved the drug.

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Unfortunately, Invirase had many drawbacks, some of which arguably could have been addressed prior to its speedy approval in 1995. For one, Roche went ahead with its clinical trials using a 600-mg dose three times a day, which was too low to have enough of an antiviral effect. Roche didn't conduct further dosing studies to see if a higher dose might be necessary, even though doses as high as 3,600-5,400 mg/day were found to be safe in HIV-negative individuals. A study done in 1995 showed that a 1,200-mg dose was more potent than and just as tolerable as the 600-mg dose. Regardless, the ACTG 229 and NV4256B studies were pushed ahead using what was known to be a dangerously low dose. There was a real concern that people taking this low dose could develop resistance to Invirase as well as other protease inhibitors to come. Also troubling was how little Invirase was absorbed by the body -- only 4%. However, these concerns didn't deter Roche from establishing an average wholesale price of about $7,000 per year for the drug, a price that set the precedent for other protease inhibitors to come.

Roche also angered community groups with its meager attempt at an early access program for Invirase. In 1995, almost 30,000 people got Epivir (3TC) through an expanded access program. But in that same year, people desperate for Invirase had a difficult if not impossible time trying to get it before FDA approval. Roche argued that their supply of the drug was limited and offered a lottery in July for only 2,200 people. A second lottery was held in November of that same year, even though many lucky winners from the first lottery had never received drug. Surprisingly, Invirase received FDA approval the next month, leaving many "winners" of both lotteries on their own. Roche's lotteries have been cited many times by activists whenever a drug company claims it doesn't have enough drug for an expanded access program. In November 1995, Roche claimed to have only enough drug for a small lottery. One month later, they had enough drug for every pharmacy in the country.

After its approval, important lessons were learned about how to use (or not use) Invirase. The FDA didn't originally recommend Invirase for advanced HIV disease, largely because it was only moderately effective at lowering viral load. This was because drug levels were too low and the drug itself just wasn't that strong to begin with. The suboptimal dose had many activists and physicians concerned that people taking Invirase would develop resistance to future protease inhibitors. While it's uncertain whether or how many people did develop resistance by using this dose, it is known that HIV that develops resistance to Invirase or Fortovase can also be at least partially resistant to other protease inhibitors. As a result, many people did anything they could to increase the levels of Invirase in the body, including drinking grapefruit juice which was known to increase levels of the drug. Out of both necessity and a struggle to make saquinavir a desirable choice, Roche developed a soft-gel formulation (Fortovase), which was approved in 1997. The dose was higher in this new formulation and was four times better absorbed by the body than Invirase. Also, 80% of people taking Fortovase saw a significant drop in their viral load, twice that of Invirase.

While Fortovase was indeed a new and improved version of its predecessor, several factors have kept it from becoming a treatment favorite. More people experience gastrointestinal problems on Fortovase and no one is thrilled about taking the daily dose of eighteen (!) huge pills. But don't count Invirase out -- it has re-entered the scene in a potent twice-a-day combination with low-dose Norvir.


Side Effects

Overall, both formulations of saquinavir are well tolerated. The most common side effects are gastrointestinal (diarrhea, nausea, abdominal pain), which are more common with Fortovase. About 10-20% of people on Fortovase have diarrhea or nausea, and this rate is higher when it is taken with Norvir. Headaches are also relatively common. Saquinavir can also cause liver enzymes (ALT/AST) to increase, but this isn't necessarily a cause for concern or a signal to stop the drug; overall, saquinavir doesn't interfere with liver function as much as most other protease inhibitors do.


Drug Interactions

Invirase and Fortovase have several interactions with other antiretrovirals. Viracept (nelfinavir), Kaletra (lopinavir/ritonavir), and Rescriptor (delavirdine) can raise levels of either formulation of saquinavir in the body and may increase the risk of side effects, so it may be best to lower the dose of saquinavir. On the other hand, Viramune (nevirapine), Agenerase (amprenavir), and Sustiva (efavirenz) can lower levels of saquinavir in the body. These interactions, however, are dealt with differently -- lower doses of Invirase or Fortovase together with a small dose of Norvir are recommended when using Viramune or Sustiva. There isn't enough information about whether the dose needs to be adjusted if you're on Agenerase, and no recommendations to change the dose exist.

Other drugs should be used with caution and, in some cases, avoided, when using either Invirase or Fortovase. Both formulations can cause large increases in levels of the lipid-lowering drugs Zocor (simvastatin) and lovastatin (Mevacor or Atocor); other drugs, like Pravachol (pravastatin) and Lescol (fluvastatin) are recommended. Lipitor (atorvastatin) should not be used with boosted Invirase because it can increase the amount of Invirase to dangerously high levels (450% higher). Nizoral (ketoconazole) can triple levels of either formulation and may need to be lowered in dose if gastrointestinal side effects result. Furthermore, Fortovase can increase levels of Viagra (sildenafil) by up to 210%, so caution should be used if the two are taken together.

Some natural products, specifically garlic supplements and St. John's wort (hypericum), can reduce levels of saquinavir to dangerously low levels and should be avoided. Drinking grapefruit juice while taking either formulation can raise drug levels in the body and increase the risk of side effects, so that morning glass of juice may not be the best idea.

In addition, the anti-tuberculosis medications rifampin and Mycobutin (rifabutin) can lower Invirase/Fortovase levels significantly.


When to Consider It

Because both formulations mean swallowing a large number of pills and, at full dose, lower viral load only moderately, neither Invirase nor Fortovase are popular HIV medications. Neither formulation has been a top seller since its approval. For someone choosing a first treatment combination, the Department of Health and Human Services treatment guidelines currently require boosting Invirase or recommend boosting Fortovase with Norvir as part of an alternative, rather than preferred, regimen. Most people do not use either formulation at full dose unless they have few other options. When boosting, the newly-approved 1,000-mg twice-a-day dose of Invirase may provide more punch, as more drug seems to get into the body than with Fortovase, but either can be used. Boosting of both formulations with Norvir has become relatively common and by reducing the number of pills may make the drug more bearable to those who have to take it.


Good to Know

  • A new 500-mg Invirase tablet is being developed by Roche and may be available early in 2004. These new tablets will be smaller than the current Invirase and Fortovase capsules and will only require taking two pills twice a day (compared to five) when used with low-dose Norvir.


Pregnancy

Saquinavir is classified as an FDA pregnancy category B drug. Animal studies fail to demonstrate a risk to the mother and fetus, but well-controlled studies of pregnant women have not been conducted.


Dose

Both Fortovase and Invirase come in 200-mg capsules.

  • The FDA-approved dose of the soft-gel Fortovase is 3,600 mg a day taken as six 200-mg capsules every 8 hours. Many healthcare providers also prescribe Fortovase using a twice-daily dosing schedule based on data from clinical trials, even though it isn't officially approved by the FDA. Twice-daily dosing calls for eight 200-mg capsules every 12 hours. Fortovase is better absorbed when taken with a large meal or within two hours after a large meal.

  • Hard-gel Invirase is not recommended unless it's taken together with low-dose Norvir. Invirase can be taken with or without food when taken with Norvir.

  • When used with low-dose Norvir, five 200-mg capsules of either formulation are taken twice a day.

  • The 1,200-mg dose of Fortovase every 8 hours may not be sufficient for pregnant women. Instead, these women may choose to consider a higher dose of Invirase taken with a small dose of Norvir. One study found that this combination was well tolerated and maintained adequate levels of the drug in women.

  • Neither formulation has been approved for use by children, but both appear to be effective in small studies.

FDA Approval: Invirase 1995; Fortovase 1997

Manufacturer: Hoffmann-La Roche

Patient Assistance Program: 800-282-7780





  
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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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