The Bay Area Reporter - May 7, 1996
Rob Sabados, ACT UP/Golden Gate Writers Pool

This very significant issue has been largely concealed by many drug companies and ignored by mainstream AIDS organizations whose mission it is to inform people with AIDS. Pharmaceutical firms hide behind the complexity of the issue and many people's unfamiliarity with government regulations. Only by increasing community awareness and understanding can physicians and patients have the tools necessary to address these important issues.

The problem

People with HIV disease frequently experience opportunistic infections, depression, or other conditions that require multiple medications. When the drugs that patients take for long periods, such as antivirals, interfere with the treatment of other health problems, physicians and patients are left with difficult choices. For example, the New York-based National AIDS Treatment Advocacy Project (NATAP) publication Protease Inhibitors states, "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."

This raises a difficult question: is it better for a patient to take anti-viral drugs in the hope of living a few months longer, even if it means spending much of that time struggling with depression? This is a question that people with AIDS must answer for themselves.

According to Abbott, which manufactures the protease inhibitor ritonavir (Norvir), ritonavir has 23 known "significant" and many more "moderate" or "potential" drug interactions. In some cases, these interactions impair the ability of physicians to appropriately treat patients. For example, Flagyl (metronidazole) is the drug of choice for some bacterial and parasitic infections. However, according to NATAP, "Ritonavir contains alcohol, which can produce reactions when co-administered with ... metronidazole." Ritonavir also interferes with the metabolism of other anti-parasitic drugs that might serve as "second line" treatments. This leaves patients with a choice: continue taking ritonavir and hope the infection goes away on its own, take them both and "hope for the best" or temporarily discontinue the ritonavir knowing that this may lead to the emergence of viral strains resistant to both ritonavir and Crixivan (indinavir, the Merck protease) and possibly saquinavir (Invirase(r), the Hoffman-LaRoche protease).

Why do interactions happen?

Drug interactions occur when one drug interferes with the absorption, distribution, metabolism or excretion of another. When two drugs are metabolized by the same enzyme, interactions such as inhibition or induction can occur. Probably the most important pathway for drug metabolism is the family of enzymes known as cytochrome P-450. Initially thought to be one enzyme, scientists have found approximately 70 different closely related enzymes, called isoenzymes or isozymes. Each isozyme is known by a designation such as "CYP 3A4" or "CYP 2E1." CYP 3A4 is responsible for the metabolism of, or is directly affected by, many anti-depressants, some antibiotics such as rifampin, rifabutin, and erythromycin, all three protease inhibitors, and the NNRTIs nevirapine and delavirdine, as well as grapefruit juice.

Inhibition occurs when one drug prevents another from being metabolized by an enzyme. This can occur when two (or more) drugs compete for the same site on the enzyme or when one drug affects the enzyme so as to make it unable to bind to the other drugs. As a result, the affected drug is metabolized more slowly, leading to increased, and possibly unsafe, amounts of drug in the body.

Induction, the opposite of inhibition, occurs when a substance causes the body to increase the production of an enzyme. With more enzyme present, drugs metabolized by that enzyme will be metabolized faster, leading to lower drug levels. Because metabolites (what's left over after a drug is initially metabolized) can behave very differently than the parent drug, induction can also lead to toxicity when metabolites accumulate faster than the body is able to remove them.

How to find out about drug interactions

When prescribing a drug known to cause enzyme inhibition or induction, physicians must carefully monitor for possible interactions with other drugs. The Food and Drug Administration (FDA) mandates that known or suspected drug interactions be included in a drug's labeling, which can be found in the package insert (which most pharmacies give out upon request) and the Physician's Drug Reference (PDR).

Even so, pharmacists and physicians are often unaware of these interactions. For example, the FDA-approved labeling for the anti-depressant Serzone (nefazodone) states, "Caution is indicated in the combined use of nefazodone with any drugs known to be metabolized by the 3A4 isozyme."

According to Merck's labeling for Crixivan, "In vitro studies indicate that cytochrome P-450 3A4 (CYP 3A4) is the major enzyme responsible for [six of seven] metabolites." Clearly, the potential for problems and need for caution exists when mixing Crixivan and Serzone - but Stadtlanders, the pharmacy with the monopoly on Crixivan, stated that they were "not aware" any problems with taking Serzone with any other drugs, even though Serzone's labeling warns of potentially fatal interactions with two popular antihistamines, Seldane (terfenadine) and Hismanal (astemizole).

Drug companies, the truth, and the FDA

While the FDA mandates that drug interaction information be provided for approved drugs, expanded access programs are another matter. Until a drug's labeling is approved, drug companies are not required to release interactions to the public. Unfortunately, most drug companies choose to interpret "not required" as "we don't have to, so we'll find reasons why we can't."

With the notable exception of Abbott, most drug companies have tried to withhold drug interaction data during expanded access, stating that unspecified "FDA regulations" prevent them from making patients and activist groups aware of known drug interactions. For example, the manufacturers of the NNRTIs delavirdine (Pharmacia & Upjohn) and nevirapine (Boehringer Ingelheim) have used this excuse in their dealings with ACT UP/Golden Gate. While it is true that FDA restricts the advertising of unapproved drugs under (21 CFR 312.7(a)), the regulation also states, "This provision is not intended to restrict the full exchange of information concerning the drug, including dissemination of scientific findings in scientific or lay media." In other words, their excuses are little more than a smokescreen.

In order to protect patients, drug companies should be required to conduct in vitro and animal studies of drug interactions as well as provide patients and providers with detailed and up-to-date information regarding the results. At the present time, ACT UP/Golden Gate is working to ensure that this information will be made available to patients and providers interested in receiving nevirapine or delavirdine.

Only by telling drug companies and community organizations that this issue is important can you get them to provide information necessary to make informed decisions. Talk to your health care provider and pharmacist (try to have only one pharmacy) about drug interactions and how to avoid them. t

For more information, contact NATAP at (718)624-8541 or at http://www.aidsnyc.org/natap or read "Interactions and drug metabolizing enzymes" in the September 1995 issue of American Pharmacy.
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