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Nutritional Considerations Affect Bioavailability of New P.I.

July 1999

On April 15, Agenerase® (amprenavir) was the first brand new protease inhibitor to be approved by the FDA in over two years.

Agenerase® belongs to the same family of antiretroviral drugs such as Crixivan® (indinavir), Invirase® (saquinavir mesylate), Fortovase® (saquinavir), Viracept® (nelfinavir mesylate), and Norvir® (ritonavir). Unlike other drugs in its class, Agenerase® can be taken without food or water restrictions, except not with meals high in fat.

Agenerase® must be taken in combination with other antiretroviral drugs, yet how Agenerase® will work with other protease inhibitors in either first-line or salvage regimens has not been determined.


Dosages and storage

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Agenerase® should be taken twice daily. Reportedly, Agenerase® capsules have a metallic taste. They are also rather large, and may be difficult to swallow.

Soft gel capsules come in either 50mg or 150mg formulations. Its oral solution dosage is 15mg and has a grape bubble gum flavored solution. It is important to note, however, that the capsules and the oral solution are not interchangeable on a milligram per milligram basis.

In adults, the recommended dosage is eight 150mg capsules of Agenerase® twice a day, with or without food that is not high in fat.

Children between the ages of 4 and 12 or for teen-agers between 13 and 16 who weigh less than 110 pounds will take Agenerase® oral solution. Unlike adults, prescribing Agenerase® for children and adolescents depend on body weight.

For children who weigh less than 110 pounds, the dose is 10.23mg/lb (1.5mL/kg) twice daily, or 7.72mg/lb (1.1mL/kg) three times a day. The maximum daily dosage must not exceed 2800mg.

Certain precautions must be taken to store Agenerase® and increase its shelf life. Agenerase® should be stored in a tightly closed bottle at room temperature (77 degrees Farenheit), and should not be refrigerated. It should not be left in direct sunlight or in extreme heat, such as in the car during a hot day.

Since Agenerase® comes in the form of a soft gel capsule, discard cracked or broken capsules. There have been reports that capsules may also leak and clump together easily.


Vitamin E and bioavailability

Although the absolute bioavailability of Agenerase® in humans has not been established, vitamin E has been added to aid in its absorption.

Because the amount of vitamin E is so high, it is advised not to take additional vitamin E supplements. Ingesting vitamin E through a basic multimineral vitamin, however, can be continued.

Each 150mg of Agenerase® contains 109 IU (IU=international unit) of vitamin E, thus totaling to 1744 IU per day in an adult dose. The maximum pediatric oral solution contains 8587 IU of vitamin E per day. These amounts of vitamin E are extremely high, and have raised concern amongst pediatric HIV clinicians, registered dieticians, and researchers.

The Reference Dietary Intake (RDI) for vitamin E, recommend that adults should take 30 IU and children 10 IU per day.

So what does this all mean? The manufacturers (Vertex Pharmaceuticals and Glaxo-Wellcome) state that "the effects of long term, high dose vitamin E administration in humans is not well characterized and has not been specifically studied in HIV infected individuals. High vitamin E doses may exacerbate the blood coagulation defect of vitamin K deficiency caused by anticoagulant therapy or malabsorption."

Dosage recommendations of vitamin E are relatively inconsistent and its effects in high doses are inconclusive, but it is safer to avoid taking additional supplements.

Shirley A. Heiman from Glaxo Wellcome says that Glaxo Wellcome has "committed to evaluate the safety of chronic, high-dose vitamin E administration in adults and children receiving Agenerase long-term."

As part of their Phase IV committments to the FDA, a 48 week study will evaluate changes in patients' vitamin E levels over time. A group of patients receiving Agenerase® will also be studied for the next two years to detect any effects of high vitamin E concentrations.


Avoid high fat meals

Agenerase® can be taken with or without food, but in one feeding vs. fasting study, results showed that meals that are high in fat decrease the bioavailability of the drug. The high fat meal consisted of 67 or more grams of fat. Without other studies, however, it is difficult to qualify this information.

Since Agenerase® can be taken without food, its timing is flexible. Treatment advocates encourage clients to take Agenerase® every 12 hours to maximize blood levels. For instance, Agenerase® can be taken in the morning with breakfast at 6 a.m. and then again in the evening at 6 p.m., 10 a.m. and 10 p.m., 1 a.m. and 1 p.m. There is room to adjust your medication schedule.

Special considerations are made when Agenerase® is taken with other drugs such as Mycobutin® (rifabutin) and Videx® (didanosine ddl). Your doctor should lower the Mycobutin® dose, and Videx® and Agenerase® should be taken at least one hour apart. Be sure to check with your treatment advocate as well.

Although there is no specific recommendation for increase fluid intake with Agenerase®, it is always beneficial to drink more water. Intake goals of safe drinking water are 10-12 cups (8 oz. cup) for men, and 9-11 cups for women. Safe water is water that has either been brought to a rapid boil for one minute, distilled, or has gone through a filter meeting NSF standard 53 for cyst reduction. Unless bottled water meets these requirements, it is not guaranteed to be safe.

For avid coffee drinkers, it is best to be aware that caffeine in both foods and beverages can speed up the gastrointestinal tract, causing looser stools with potential fluid loss from excretion and urination. Avoid skipping meals since caffeine can also suppress your appetite.


Dangerous combinations

At no time should Agenerase® be mixed with Amiodarone®, Lidocaine® (systemic), tricyclic antidepressants and quinidine because serious or life-threatening drug interactions may occur.

Rifampin® should also not be used in combination with Agenerase® because it decreases the plasma concentration by 90 percent. The drug Sustiva® has been shown to decrease blood levels of Agenerase® as well.

Doctors should now be recommending that patients who are already on blood thinners should stop taking additional vitamin E since 1744 IU/day is a blood thinning dose. If blood thinners are prescribed, they must be monitored carefully.

Agenerase® may reduce the effectiveness of Viagra® or birth control pills, but it is best to talk to your doctor and your treatment advocate about possible side effects.

Agenerase is a sulfonamide, so patients with a known sulfa condition should be treated cautiously.

Adverse reactions should be reported to MedWatch at (800) FDA-1088, or by through the FDA website at www.fda.gov/medwatch/how.htm


Side effects

As with all drugs, there are side effects that will vary from person to person, or may not occur at all.

Common side effects of Agenerase® are nausea, vomiting, diarrhea, gas or flatulence, rash and a numbing sensation around the mouth. More severe side effects include a life-threatening rash called Stevens-Johnson syndrome. This rash has appeared in 1 percent of people treated with Agenerase® so far.

Body composition is also always a legitimate concern when taking antitretrovirals. Abnormal lipid profiles or lipidystrophy are common side effects with other antiretrovirals. How Agenerase® affects the body composition and fat distribution is still difficult to determine.

Agenerase® may adversely affect triglycerides, cholesterol and blood sugar levels as well. Blood levels may increase, and should be monitored through blood work at least every three months. The reason for high levels, its effect on the body, and its management continue to be researched. Symptoms of high blood sugar levels should be observed, too. Symptoms include extreme thirst, frequent urination, and unexplained weight loss.

Agenerase® places additional stress on the liver, which metabolizes all drugs. For those who have liver problems, it is best to avoid consuming alcohol when taking any drugs.


Investigation continues

Data is rarely complete when a new drug hits the market. Unknown side effects, both beneficial and harmful, may surface as more doctors prescribe it. Since all drugs affect the body, specific nutritional considerations and warnings about drug interactions have been made.

The FDA took a positive step in approving another protease inhibitor, but the steps that patients must take should be anticipatory and cautious.


High fat meals that you should not eat when using Agenerase
(and how to modify them so you can)

BreakfastLunchDinner
1 cup whole milk
3 egg omelet
1 ounce cheese
1 tablespoon vegetable oil
2 sausage links
2 slices toast
2 teaspoons butter
1 tablespoon jam
1 orange
1 1/2 cups whole milk
1 cup cooked pasta
1 cup marinara sauce
3 tablespoons parmesan cheese, grated
3 soft bread sticks
4 teaspoons butter
1 cup snap beans
1 cup assorted green salad
3 tablespoons Italian salad dressing
1 cup whole milk
4 ounces baked sole
1 tablespoon olive oil
1 cup squash
1 teaspoon butter
1 cup brown rice
1 teaspoon butter
1 whole wheat roll
1 teaspoon butter
1 cup green salad
2 tablespoons Italian dressing
2 scoops vanilla ice cream
TOTALS TOTALS TOTALS
1,131 calories 1,185 calories 1,137 calories
47.1 g protein 32.3 g protein 49 g protein
75.5 g fat 70.9 g fat 73 g fat
67 g carbohydrate 112 g carbohydrate 130 g carbohydrate

Reduce fat grams by substituting nonfat or lowfat milk for the whole milk, no sausage, use only 1/2 the pat of butter, use a lower fat cheese. Reduce fat grams by deleting or using less parmesan cheese, delete or use only 1 pat of butter on bread stick, substitute the Italian dressing with a light or nonfat Italian dressing. Reduce fat grams by substituting nonfat or lowfat milk for whole milk, no butter on the rice or roll, substitute a light or nonfat dressing for the Italian dressing,use light ice cream or ice milk instead of regular ice cream.


AIDS Project Los Angeles' fact sheet on Agenerase and its nutritional considerations is available by calling (323) 993-1612.

Candice Tong is an intern in AIDS Project Los Angeles' Publications Program. Marcy Fenton, M.S., R.D. is a nutrition advocate in APLA's Client Health Education and Advocacy Unit. Monica Hall is a dietetic intern in the nutrition program.


This article has been reprinted at The Body with the permission of AIDS Project Los Angeles (APLA).



  
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This article was provided by AIDS Project Los Angeles. It is a part of the publication Positive Living.
 

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