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Protease Inhibitors at a Glance ...

Winter 1998/1999

What is the correct dose when used with nRTIs (nucleoside reverse transcriptase inhibitors)?
Invirase: Three 200mg capsules, 3 times a day (9 pills a day, 1800 mg).

Fortovase: Six 200mg capsules 3 times a day (18 pills a day; 3600 mg.)

Two 400mg capsules (total 800 mg) every 8 hours. CAUTION: Taking Crixivan every 12 hours does NOT work well with nRTIs. If taken with ddl (Videx), take 1 hour apart on an empty stomach (wait at least 2 hours after meals. In people with cirrhosis of the liver, the Crixivan dose should be reduced to 600mg every 8 hours. TAKE AS PRESCRIBED.
600mg (6 capsules) twice a day. To reduce side effects in the drug naive, treatment can begin with no less than 300mg twice a day and increase by 100mg twice a day to reach full dose within 2 weeks. Take 1 or 2 hours apart from Diadanosine (ddl, brand name Videx) as ddI affects absorption of Norvir. (See liquid formulation.)
Three 250 mg tablets (750 mg) 3 times a day. A dosing schedule of 5 250 mg tablets (1250 mg) every 12 hours appears to work as well, but the duration of effectiveness is unknown. Until twice-daily dosing is approved, it should probably be used only if people are having severe problems sticking to the 3 times a day schedule. With ddI, take 2 hours before or 1 hour after.
What is the correct dose when used with nnRTIs (non-nucleoside reverse transcriptase inhibitors)?
Invirase: Avoid use with Viramune which decreases Invirase levels by 27%. When used with Rescriptor (delavirdine), it causes a near 3-fold increase in Invirase levels; no dose change is required; however, monitor liver enzymes closely. Invirase levels are reduced by 60% when combined with Sustiva, and this combination is NOT recommended.

Fortovase: Same as above.

If taken with Viramune, Crixivan blood levels are lowered by close to 30%.1 If taken with Rescriptor (delavirdine), Crixivan blood levels are increased. It is recommended that the dose of Crixivan be reduced to 600mg every 8 hours.2 If taken with Sustiva (efavirenz), Crixivan dosing must be increased to 1,000mg (two 400mg capsules plus one 200 mg capsule) every 8 hours. Crixivan should NOT be used twice daily with Sustiva.
Norvir and Viramune are used in standard doses when used together. Rescriptor increases Norvir levels by 70% which may merit a reduction in Norvir dosing to 400mg twice daily, although no studies have been done. Although no dose adjustment is recommended when used with Sustiva, this combination resulted in more liver abnormalities. Monitor liver enzymes closely.
Although some studies show no important drug interaction when used with Viramune, some increase Viracept to 1000mg 3 times daily when used with Viramune. Viracept lowers Rescriptor levels by 50% although no dose recommendation has been made. Standard doses of Viracept and Sustiva can be used together.
What is the correct dose when used with other protease inhibitors?
Much of this is experimental. The greatest experience is with the combination of Norvir plus Invirase where Norvir greatly increases the blood levels of Invirase and viral load reductions are similar to other strong anti-HIV drug combinations. The dose is: Norvir 400mg (four 100mg capsules) + Invirase 400mg (two 200mg capsules) twice daily. Alternatively, the new formulation of saquinavir -- Fortovase -- can be used instead of Invirase: Norvir 400mg (four 100mg capsules) twice daily + Fortovase 400mg (two 200mg capsules) twice daily. Viracept also increases the blood levels of Fortovase. The dose being studied is Viracept 750mg (three, 250mg tablets) three times daily + Fortovase 800mg (four, 200mg capsules) three times daily. Crixivan should not be used with Invirase or Fortovase. Small studies have been reported using Crixivan 400mg (one, 400mg capsule) twice daily + Norvir 400mg (four 100mg capsules) twice daily with good blood levels of both drugs. Other doses of this combination are also being studied. The doses of Crixivan with Viracept are still unknown. In a clinical trial, the doses were just increased to Viracept 1,250mg (five, 250mg tablets) + Crixivan 1,200mg (three, 400mg capsules) twice daily. Viracept levels are also increased by Norvir and various doses are being studied including Norvir 400mg (four, 100mg capsules) twice daily + Viracept 500mg (two, 250mg tablets) or Viracept 750mg (three, 250mg tablets) twice daily.
Should it be taken with or without food?
lnvirase and Fortovase should be taken with food.
For best absorption, it should be taken with water but no food 2 hours after and 1 hour before a meal. It's okay to take Crixivan with a light, NON-FAT snack such as dry toast with jelly, juice, corn flakes, coffee, sugar and skim milk. It is important to drink lots of water (at least 1.5 quarts) to reduce the chances of getting kidney stones. Grapefruit juice reduces Crixivan blood levels by about 25% and should be avoided.
Both formulations (capsule and liquid) can be taken with or without food, but food helps to reduce the nausea side effect of Norvir.
Viracept should be taken with a meal or snack.
How should I store it?
Store both at room temperature in tightly sealed containers.
Store at room temperature in a tightly sealed container.
Capsules: Keep refrigerated.

Liquid: Store at room temperature; good for 30 days.

Store at room temperature in a tightly sealed container.
What is the effect on disease progression?
Little is known about the effect of Invirase or Fortovase on disease progression. The combination of Invirase and ddC (Hivid) reduced notably disease progression when compared to ddC alone.
In one study of those who never took protease inhibitors or Epivir (3TC), Crixivan reduced the incidence of serious opportunistic infections and increased survival of those with advanced AIDS (50 T-cells or below). The same trend was seen in those with T-cell counts between 51-200 for men and women. Its effect on disease progression when started in earlier HIV infection is unproven.
Norvir is proven to slow disease progression and delay death for people living with advanced AIDS (under 50 T-cells with or without opportunistic infections). There is no hard data on its effect on disease progression for people with less advanced infection.
The long-term effect on disease progression is unknown. All studies of its use have been based upon its effect on T-cells and viral load.
What is the effect on the virus? How long does the anti-viral effect last? What is the effect on T-cells?
Protease inhibitors are used in combination with other anti-HIV drugs when you want to hit the virus hard. This is called highly active antiretroviral therapy ("HAART"). Crixivan, Norvir, Viracept and Fortovase are the protease inhibitors which are strong enough to be used with nRTIs to create a HAART combination. Invirase, however, is weaker and is usually used with other protease inhibitors (Norvir or Viracept; Invirase or Fortovase are not used with Crixivan) to be powerful enough to be considered HAART. Unless the virus is hit hard when a protease inhibitor is used, it is more likely that the protease inhibitor will not work for long because drug resistance can occur. If this happens, it is likely that the HIV is resistant to all protease inhibitors.

How long the strong antiviral effect of protease inhibitor HAART combination lasts depends on a number of things including: previous anti-HIV drug experience; how high your viral load is; how damaged your immune system is; how you are able to take difficult and complicated drug prescriptions as prescribed. In the best case, a small study has shown that in those with moderate viral loads (about 40,000) and T-cell counts of about 150 who had not previously taken most of the anti-HIV drugs given in the study, about 80% of participants had their viral loads drop to very low levels (a decrease of more than 100-fold) and stay there for at least two years. T-cell counts went up about 100 cells at first, then slowly higher with time.

In the real world results have not been quite as good. It has been reported that only 50% of those on HAART with protease inhibitors maintain viral loads at very low levels for one year. Once again, this depends on a number of things including those listed above. In any case, we don't know how early in HIV infection is the best time to start therapy. There has yet to be a study which answers the very important "WHEN" question. We still don't know how long HAART will work if started early.

Does it have an anti-HIV effect in the brain?
Neither Invirase nor Fortovase are active in the brain.
Recent studies show that Crixivan reduces viral loads in the nervous system as well as in the blood. The effect directly on the brain is not known.
Only about 1% of Norvir gets into the brain -- a very low rate. Therefore, no direct anti-HIV effect is expected in the brain.
It is unknown if enough Viracept crosses into the brain to have a protective effect.
How should it be used with other HIV drugs?
Invirase and Fortovase should ONLY be used in combination with other anti-HIV drugs. Invirase and Fortovase should not be used with either Crixivan or Sustiva.
Crixivan MUST be used with other anfi-HIV drugs as prescribed. If resistance to Crixivan occurs, your virus is likely to be resistant to other protease inhibitors currently available. Do not use Crixivan with Invirase or Fortovase. With ddI (Videx), take one hour apart and on an empty stomach.
Norvir must be used with other drugs. With ddI (Videx), take one hour apart.
It should be used only in combination with other anti-HIV drugs. With ddI (Videx), take one hour apart.
Can it be used with other types of drugs?
Don't use with Seldane, Hismanal, Propulsid, Rifampin, Rifabutin.
Don't use with Seldane, Propulsid, Hismanal, Halcion, Versed, rifampin, ergot medications (Wigraine and Cafergot) and antacids. If used with rifabutin, decrease rifabutin dose by 50% and increase Crixivan dose to 1,000 mg/8 hours. If used with ketoconazole, reduce Crixivan dose to 600 mg although some doctors use standard dose for both in hopes of increasing Crixivan blood levels.
There is a list of about 25 medications that should not be taken with Norvir. This list can be obtained from your health care provider, the Office of Special Health Issues at the FDA (310-827-4460) or by calling the PWA Health Group.

Oral Contra-
Norvir reduces ethinyl estradiol by 40%. Use a secondary contraceptive or alternative to oral tablets.

Do not use with Seldane, Hismanal, Propulsid, Halcion, Versed, Cordarone, ergot derivatives, quinidine or rifampin. When taken along with rifabutin, its dose will need to be adjusted by half. Viracept also decreases the blood levels of hormonal contraception so it may decrease the effectiveness of some oral contraceptives or DepoProvera.
What are the side effects?
The most common side effects are nausea, diarrhea, stomach discomfort, liver toxicity, diabetes, and an increase in cholesterol.
Kidney stones. Drink at least 1.5 quarts of water daily to reduce the chances of kidney stones. Some folks also experience nausea, abdominal discomfort, and bloating. Increased bilirubin occurs but only infrequently as a result of decreased liver function. Rarely, rapid breakdown of red blood cells can occur and some with hemophilia have increased bleeding.
Nausea, diarrhea and vomiting. Reduce these by working up to the full dosage over time (see correct dose). Also numbness, tingling and burning sensations in the mouth and extremities, taste perversions and allergic reactions (rash and skin eruptions). Monitor liver enzymes. Risk of liver problems increases with preexisting liver disease.
The major side effects are nausea and mild to severe diarrhea. Diarrhea can be managed by eliminating fried foods, eating "binding" foods such as bananas or matzoh or by taking over-the-counter antidiarrheal drugs like Imodium. Some people have tried to manage the diarrhea using pancreatic enzymes or glutamine.
What about getting fatty deposits ("Crix Belly," "Protease Paunch")?
With all protease inhibitors, a redistribution of fat may occur. This consists of a loss of fat from the face and limbs, and an increase in abdominal fat. Sometimes the upper back can be affected resulting in what has been characterized as a "buffalo hump" on the back of the neck. No one knows why this happens, and some believe it is not even related to the protease inhibitors. It is possible that the human growth hormone may be helpful.
What about increased fats and sugar in the blood?
As with all protease inhibitors, diabetes may occur. This is associated with increases in blood sugar levels. Also, abnormally high blood cholesterol and triglyceride levels may occur. These abnormalities have been associated with an increased risk of heart disease and may need to be treated with diet, exercise, and cholesterol-lowering drugs.
Is there any information on using the drug in children?
There are ongoing studies of children taking Fortovase in combination with other anti-HIV drugs and more information will become available in the future.

The dosage of Fortovase suggested for children is 33 mg/kg three times a day.

For children who can swallow capsules, the dose being studied in pediatrics is 500 mg/m2 every 8 hours (m2=body surface area which is based on height and weight of child). Dosages for each individual child must be determined by the pediatrician. In one small study this dose did not sustain high enough blood levels in many children and the dose frequency was increased to every six hours. But even with the 500mg/m2 every 8 hours dose, kidney problems seemed to occur more often (40%) than in adults.
There is a liquid formulation. The dose for children 2 to 14 years old is 400mg/m2 twice a day to a maximum dose of 600mg twice a day. In young children it should be administered using a syringe calibrated for dosing. A recent study in children showed reductions in viral load to undetectable levels (less than 400 copies/ml) at week 48 in 42% of children when used in combination with one (d4T) or two (AZT, 3TC) nucleosides.
Viracept is approved for use in children ages 2-13 years and its effectiveness appears to be comparable to that seen in adults. The dosage for this age group is 20-30mg/kg every 8 hours. Although many doctors already prescribe it in children and infants younger than 2 years, its use in this age group has not been fully evaluated yet.
Is there a liquid formulation?
There is no liquid formulation.
There is no liquid formulation.
Now only available in liquid form due to manufacture problems. Store at room temperature. Good for 30 days. 600mg in capsule dose=7.50 ml (1 1/2 teaspoons) of liquid.
Viracept comes in an oral powder form (50mg/scooper) and can be mixed with water, milk, or formula.
What about using the drug during pregnancy?
Clinical trials using protease inhibitors during pregnancy have been put on hold because of reports of birth defects and premature labor. The data are currently being analyzed.
Where is the drug available?
Drugstores all over the U.S.

Patient Assistance: 800-282-7780

Drugstores all over the U.S.

Patient Assistance: 800-282-7780

Drugstores all over the U.S.

Patient Assistance: 800-659-9050

Available at most pharmacies.

Patient Assistance: 888-777-6637
Drug Information: 888-847-2237

How much does it cost? (Average Wholesale Price)
Invirase and Fortovase are both about $6,964 annually.
About $5,475 annually. About $8,103 annually. About $6,013 annually. (Reflects October 1, 1998 price increase.)

1. Many increase the Crixivan dose to 1000mg three times daily when taken with Viramune.

2. Some take the standard 800mg every 8 hours w/ Rescriptor in hopes of increasing Crixivan blood levels. Watch for kidney stones! Studies are underway with twice daily Crixivan + Rescriptor but IT IS TOO SOON TO TELL.

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This article was provided by PWA Health Group. It is a part of the publication Notes From the Underground.