On April 5, a group of community advocates, including myself, met with Abbott to discuss Norvir patient/doctor education, drug interactions, side effects and the upcoming trial of the combination of saquinavir and ritonavir.

Possible ways to reduce side effects
Present were a couple of individuals taking ritonavir (Norvir) and Abbott's pharmacokinetics experts. Emerging from the discussion was that an individual's food intake can affect the magnitude of the side effects experienced. A high calorie, relatively fatty meal (for example, a meal including a steak) in the evening and at breakfast (eggs and bacon) may reduce the side effects experienced. Some individuals find that eating chocolate when taking Norvir may help. Also, eating a salty food, like potato chips may be helpful.

It is recommended by Abbott that dose escalation at the initial start-up of taking Norvir may also reduce the incidence of side effects, such as nausea. The dosing regimen they recommend is: 300 mg., twice daily, for 2 days; 400 mg., twice daily for 2 days; 500 mg. twice daily for 2 days; you can stay at the 500 mg. dose for a maximum of 6 days before moving to the 600 mg., twice daily dose; or, you may want to try the 600 mg., twice daily dose after only 2 days of the 500 mg., twice daily dose. It is recommended that you reach the full dose within 14 days. A slightly different dose escalation regimen is described in Abbott's package insert, based on their clinical trials, which is available at your pharmacy. Abbott said, this process will induce the liver to process the drug better; this dose escalation method provides adequate drug levels, at the initial stages of taking the Norvir, to suppress virus without the initially high drug levels associated with taking the 600 mg. dose. Therefore, Abbott is saying, although you are building up to the full recommended dose, you should not be concerned that you are sub-optimally dosing and creating resistance; the liver has to get used to the drug and the processing of it.

After taking the standard dose of Norvir (600 mg. 2 times per day), an individual's blood level of the drug rise up before starting to settle down. It is the high blood level, that may cause the side effects. It's been reported that some doctors may be experimenting with a different dose regimen that may reduce side effects--the common ones, such as nausea, dizziness, skin snsations, and circumoral paresthesia. The regimen they are using is 400 mg. of Norvir, 3 times per day. This reduces the higher blood levels acheived by the 600 mg. dose, and therefore might explain a possible reduction in side effects; a 400 mg. dose will not raise blood levels as high as a 600 mg. dose.

Drug interactions
Abbott took the time and effort to take us through this difficult subject; and, to explain to us the extensive research they conducted in order to compile the drug interaction information, which they have submitted to the FDA and disseminated to the public. More extensive education for doctors and patients is required to adequately inform the public about drug interaction with Norvir, as well as with saquinavir and indinavir. Abbott agreed to increase their educational effort and to cooperate with NATAP and other community groups to disseminate the proper information.

A certain enzyme in the liver, named CYP450, is responsible for metabolizing or getting rid of foreign substances that may come into the body through drugs or food. Abbott conducted a systematic review of over 200 medications.

This review included 12 general classes of medications, and commonly used AIDS drugs. They reviewed metabolism and pharmacokinetic literature, review articles, test references, package inserts, in vitro data from ritonavir studies, and clinical interaction data from other drugs with similar metabolic pathways as ritonavir. Their conclusions are based on theoretical judgements and drug interaction studies. Abbott said they took a proactive position from the very beginning in their committment to research drug interactions, and they said it was unprecedented for a drug company to conduct such extensive research and put so much information on their package insert.

This review process is ongoing and they said there are limitations to their predictive abilities. When a foreign substance or drug is processed by the CYP 450 enzyme, there are 8 different important isoforms which may be involved in the process. Norvir effects just a few of these isoforms. Sometimes, it is uncertain which isoform processes a drug or foreign substance; if multiple isoforms are involved in the process, it may be uncertain the degree of effect by each one. Abbott explained that the inhibition of this liver enzyme, which is what makes Norvir effective, is reversible upon cessation of Norvir use.

Abbott has compiled a list of 23 drugs NOT to be coadministered (not to be taken) with Norvir. Accompanying this list are potential alternatives, although some may not be therapeutically equivalent. Also, each Norvir gel-cap contains an amount of alcohol that is almost one ounce, so an individual should not take Norvir with antabuse. Antabuse is an alcohol antagonist, used by individuals as an aid in stopping alcohol abuse.

In some cases, it may be more important to stabilize an individual on their HIV-antiviral therapy as a priority to other medications, such as anti-depressants.

Coadministration of Norvir with some of these drugs may result in potentially serious and/or life threatening adverse events. Precautions should be taken when coadministering Norvir with other drugs metabolized by similar pathways. Large dose reductions and increased monitoring of drug blood levels and adverse events is recommended when these drugs are used concomitantly (taken together) with ritonavir (Norvir).

We are now entering the hay-fever season. Two popular cold and allergy medications, Hismanal and Seldane, are on this list; these two medications are NOT to be given or coadministered with ritonavir (Norvir).

The Norvir package insert includes a drug-drug interaction chart (Table 2) which summarizes the effects of coadministration of ritonavir with a variety of drugs. It shows the effects on AUC and C-max with 95% confidence intervals.

Table 3 in the package insert lists 28 classes of drugs and many individual drugs and the potential effects on these drugs when co-administered with Ritonavir.

Patient education
The meeting was amicable as both Abbott representatives and our community advocates were agreeable on the appropriate concerns and potential solutions. Abbott is undertaking additional efforts to educate doctors and patients regarding the proper use of Norvir. Issues that need attention for educational purposes include effectively comunicating the importance of compliance for individuals taking a protease inhibitor; without proper compliance with recommended dosing guidelines, resistance is a sure bet. For example, missing a dose or taking less than the full dose can lead to resistance.

NATAP's "Protease Inhibitor Report, 2nd edition" is now available. It is a 43-page bound booklet compiling all the latest data available on 5 protease inhibitors. It includes charts, graphs and an extensive chart compiling what we know to-date about resistance mutations. Individuals can order it for themselves or organizations can order it to use use as an educational tool for case managers, treatment educators and clients; when ordering please give us your mailing address for delivery:

by phone: (718) 624-8541
fax: (718) 624-8399
E-mail: JuLev@aol.com
mail: Jules Levin
National AIDS Treatment Advocacy Project
72 Orange Street #3C Brooklyn, N.Y. 11201

In Los Angeles, on Saturday April 13, NATAP held a free 4-hour community treatment forum at Paramount Pictures Studio (5555 Melrose Ave--enter at Bronson Street gate). The forum was devoted to PROTEASE INHIBITORS and VIRAL LOAD. Scientists from each of the protease inhibitor manufacturers participated --Roche, Merck, Abbott, Glaxo Wellcome, and Agouron-- to present data and discuss their protease inhibitor. Also, Dr. Robert Coombs of the University of Washington, an expert on viral load, discussed what we know about the use and application of this test, including how an individual can interpret test results and apply it to their personal situation. Much of the discussion was devoted to compliance issues, side effects and drug interactions for each of the 3 approved protease inhibitors. If you didn't attend, we videotaped the entire event. To order the videotape, you can contact NATAP. The video can be used by individuals for their personal use or as an educational tool by doctors' offices, hospitals and AIDS community service organizations for their case managers, treatment educators and clients.

Ritonavir/saquinavir combination study
Abbott has issued the following statement: "There is a great deal of interest in combination therapy with ritonavir and saquinavir based on pharmacokinetic interactions that result in substantial elevation in plasma saquinavir levels. Although this interaction holds therapeutic promise, the safe use of this combination has not been established. Because of the magnitude of this interaction, a reduction in dose of either or both drugs may be necessary.

The optimal doses of each drug in this combination are being determined in clinical trials underway, with early data expected to be available by mid-summer 1996. In the absence of adequate clinical data, ritonavir and saquinavir doses that are safe and effective in combination are unknown. Until these data are available, this combination should not be used.

"The potential disadvantages of premature ritonavir-saquinavir combination therapy are: (1) safety concern--incorrect dose combinations may result in dangerous drug levels not previously tested in man; (2) efficacy concern-- incorrect dose combinations may result in sub-optimal antiviral efficacy and decrease future response to protease inhibitor therapy."

These cautions make sense to me--especially, the efficacy concern; if you use a dose combination that is too low, you could create resistance to the combination.

THE STUDY
Abbott and Roche are collaborating in a multicenter (7 sites), open-label, randomized study --120 HIV-Infected individuals -- both, drug experienced and naive are included -- CD4 100-500. The study is expected to start in mid-April.

As always, it is advisable to consult with your physician before making any treatment decisions, and to bring to your doctor the Norvir package insert and discuss all these concerns with him. Saquinavir and indinavir also inhibit the CYP 450 liver emzyme, although not as strongly. These two drugs also have drug interaction concerns. If you are taking or plan to take saquinavir or indinavir, you should have the same discussion with your doctor.

See also, Letter from Abbott sent to doctors.

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About the author: Jules Levin is the Executive Director of NATAP, based in New York City.

The National AIDS Treatment Advocacy Project (NATAP) is a New York State non-profit corporation dedicated to facilitating the effort for development of effective treatment for HIV.

Last modified 7/3/96 by Jules Levin
Copyright © 1996 natap