AIDS TREATMENT NEWS #137, October 18, 1991
John S. James

ddI (VIDEX) is or soon will be available from pharmacies in tablet form with a new buffering chemical (the buffer used in the expanded-access distribution program for ddI was widely blamed for causing diarrhea). It is also available in the same packets of powder used in the expanded-access program, and in a separately formulated powder to be mixed by the pharmacist as a liquid form for pediatric use. The tablets will be in four strengths (25, 50, 100, and 150 mg); recommended doses vary according to the patient's weight. The most common dose of 200 mg twice daily should cost about $2,000 per year retail -- less than the the current price of AZT -- but for persons weighing 75 kg (165 lb) or more, the recommended dose will cost about $3,000 annually, while for those under 50 kg (110 lb) the cost will be about $1250 annually. Persons on the current expanded-access program will continue to receive free drug for at least six weeks from the approval date; and Bristol-Myers has set up a telephone assistance service to help patients obtain reimbursement, or, if all else fails, to provide free drug to those who need it and have no other option for obtaining it.

Who should use ddI? The large, controlled clinical trials which showed benefit from AZT have not yet been completed for ddI; therefore most physicians will probably follow the current recommendation and use AZT as their first choice. ddI is important as an alternative, as an antiviral for persons who cannot tolerate AZT or do not seem to be benefiting from it.

What about combination treatment with ddI and AZT? Trials are now testing this combination. Early data from one trial was presented last June in Florence, at the Seventh International Conference on AIDS. The data suggested some benefit, but was much less dramatic than the results of ACTG 106, which tested a different combination -- ddC and AZT. (For results of the ddC+AZT combination, see AIDS TREATMENT NEWS #115, November 23, 1990). Some patients and physicians might want to combine ddI and AZT, and they are legally able to do so, but it is too early to know how useful such treatment might be. [Note: the FDA "labeling" accompanying the current ddI approval recommends the drug for patients who cannot tolerate AZT or have done poorly while using it. This labeling would probably exclude most combination use. Physicians can legally prescribe drugs for "unlabeled" uses (and sometimes it is standard medical practice to do so), but insurers often refuse to pay in these cases.]

ddI can have serious side effects; they are different from those of AZT. ddI does not cause bone-marrow suppression, as AZT sometimes does. The most serious toxicities of ddI are pancreatitis, which can be life-threatening, and peripheral neuropathy. Various precautions are necessary to control these and other potential problems; hopefully physicians will receive adequate warnings, and inform their patients.

Besides providing a therapeutic alternative, the ddI approval is also important in showing the FDA's new willingness to move more rapidly than before to approve critically important new treatments for life-threatening conditions. Under past procedures, approval would probably have been delayed for at least a year and a half while current studies were completed and analyzed -- mainly because of the need to collect data which statistically proved a survival benefit of the new drug, a requirement which imposed long delays for any drug, no matter how good, used to treat a slowly developing disease like AIDS or cancer. With ddI, the FDA showed that it could accept credible evidence of benefit to approve a drug with great public-health importance, while further studies continue -- especially since there was much safety information, because thousands of people had received ddI under the expanded-access program. This example removes hopeless delays which stood in the path of the new generations of AIDS drugs now being developed. It should speed not only the regulatory steps to approval, but the whole development process, as pharmaceutical companies realize that they now have a feasible path to market for potentially life- saving new drugs -- where they did not before.

How to Pay for ddI

The fact that the FDA approves a drug should mean that public and private health insurance programs will pay for it; however, this is not always the case. With AZT, for example, the public does not realize how much work Burroughs-Wellcome did, with little publicity, to assure that the drug would be reimbursed.

With ddI, indications are that companies will pay. The San Francisco Examiner, in a page-one story published October 14, called major health-insurance companies and associations nationally and in Northern California, including the Health Care Association of America, the Blue Cross-Blue Shield Association, Kaiser Permanente, Bay Pacific, and Heals/Qual-Med; all said they intended to pay for ddI as for other approved drugs.

Bristol-Myers, following what is becoming a common practice when companies introduce a costly new pharmaceutical, has set up a program to help patients obtain payment from third parties. According to the company, physicians or patients can call the VIDEX HelpLine to work with trained specialists, who have a database of almost 300 possible reimbursement sources and are familiar with payers' policies and procedures. Reimbursement sources are identified based on information such as state and county of residence, total annual income, monthly expenses, and total liquid financial assets; information from the prescribing physician is also required. Two weeks later, the HelpLine will follow up with the physician to make sure that reimbursement is available, or to plan other courses of action; in some cases its specialists can serve as advocates in appealing denials. If all other options are exhausted, the HelpLine will provide the physician with an application for the VIDEX Temporary Assistance Program, which will provide the drug without charge to patients meeting the company's medical and financial criteria, for up to three months; after three months, a new application will be required.

Patients or physicians can call the HelpLine, 800/788-0123, from 8:00 a.m. to 8:00 p.m. Eastern Time on business days. Spanish-speaking specialists are available.

Package-Insert Information

The "package insert" for ddI, four pages of very fine print written for physicians, provides certain basic information about proper use the drug. But it does not address all of the issues which physicians have encountered during the expanded-access program. Besides reading and understanding the package insert, physicians need to have good communication with each other, so that those who are prescribing the drug for the first time will hear from those who are experienced with it.

Here is some basic information which patients should know.

Of the three different formulations of ddI which will now be available (tablets, buffered powder for oral solution, and pediatric powder for oral solution), most adults will use the tablets; the buffered powder used in the expanded-access program remains available as a backup. The recommended dose depends on body weight. For adults weighing 35 to 49 kg (77-108 lb), the starting dose is 125 mg twice daily; 50 to 74 kg (110-163 lb), 200 mg twice daily; and 75 kg (165 lb) or more, 300 mg twice daily. These starting doses may be adjusted by the physician because of side effects, or for other reasons.

A chemical buffer is necessary to reduce stomach acidity; without it, the ddI would be destroyed by the acid environment of the stomach. To get the correct buffering, two tablets always need to be taken together (except for infants from six months to one year of age, for whom one tablet is enough). Therefore, if the dose needs to be reduced, different tablets need to be used; it would not work to just take part of the two-tablet dose, since the buffering would not be sufficient.

The two tablets "should be thoroughly chewed, manually crushed, or dispersed in at least 1 ounce of water prior to consumption. To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform dispersion forms, and drink the entire dispersion immediately."

Doses should be taken every 12 hours, on an empty stomach, since food can reduce the absorption by as much as half.

Because the ddI formulations affect stomach acidity, drugs which require an acid stomach, such as ketoconazole or dapsone, should be taken at least two hours before ddI.

Because of the buffering used, the tablets and the pediatric power -- "should not be administered with a prescription antibiotic containing any form of tetracycline." Also, quinolone antibiotics (e.g. ciprofloxacin) "should not be taken within 2 hours of taking VIDEX tablets or pediatric powder, since the buffering used with those formulations can decrease the absorption of some quinolones."

Because of the danger of pancreatitis, it can be dangerous to combine ddI with other drugs which can cause toxicity to the pancreas, such as intravenous pentamidine.

Alcohol use can also increase the risk of pancreatitis. We do not know whether moderate drinking could be a problem, or only alcohol abuse.

The package insert notes that ddI doses may need to be adjusted for patients with kidney or liver impairment.

Perhaps the most important single warning is to watch for signs of pancreatitis and peripheral neuropathy, so that medical attention can be sought quickly and the drug stopped or reduced, at least temporarily, if either occurs. "Patients should be informed that the major toxicities of VIDEX are pancreatitis, which has been fatal in some patients, and peripheral neuropathy. Symptoms of pancreatitis include abdominal pain, and nausea and vomiting. Symptoms of peripheral neuropathy include tingling, burning, pain or numbness in the hands or feet. Patients should be advised that these symptoms should be reported to their physicians. They should be counseled that these toxicities occur with greatest frequency in patients with a history of these events, and that dose modification and/or discontinuation of VIDEX may be required if toxicity develops. They should be cautioned about the use of other medications that may exacerbate the VIDEX toxicity, including alcohol."

According to the package insert, pancreatitis occurred in nine percent of patients in phase I trials who received the currently recommended dose or less, and five percent of those in the expanded-access program; and it was fatal in 0.35 percent of patients treated with the drug, 27 cases out of 7,806 who received ddI. Many physicians use an amylase test -- a test for certain enzymes in the blood -- as an early warning of possible pancreas toxicity. The ddI package insert does not include a recommendation to use the amylase test. For this and other reasons, we believe it is important that physicians closely follow the evolving medical consensus among those most experienced with the drug, and not rely only on the package insert.

This article is not complete, but can only only point to some of the most important information about using ddI. The package insert, for example, mentions a number of other, less frequent, side effects which may be caused by the drug. We believe it would be helpful if patients received, along with their prescription for this and other drugs, written explanations and practical instructions prepared by medical organizations and reflecting the prevailing expert consensus.

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