GMHC Treatment Issues; Volume 4 no. 2 April 6, 1990
Gabriel Torres, M. D.

Toxicity to Date

ddI (dideoxyinosine) was made available in September 1989 by Bristol-Myers Squibb Company as part of an expanded access program to persons with AIDS and ARC who are intolerant of AZT (Treatment-IND protocol) and to persons with AIDS who are clinically deteriorating on AZT (open safety protocol). The latter includes patients with neurological deterioration, weight loss, three opportunistic infections within the previous six months, low performance scores (totally disabled and bedridden), or T4 cell count of 50 or less on two measurements. The patients are monitored on a monthly basis by their personal physicians for signs of toxicity with physical examinations and laboratory tests. In the Phase I trials, the most common toxicities seen were peripheral neuropathy and pancreatitis, which occurred more frequently at the higher doses. For example, at doses of 1400- 3500 mg/day, peripheral neuropathy occurred in 58% of patients and pancreatitis in 12.5% of patients. At doses of 800-1400 mg/day, neuropathy occurred in 18% and pancreatitis in 14%. At the lower doses of 500-800 mg/day, no patients developed neuropathy, and only two (6.4%) developed pancreatitis. The highest dose used in the expanded access program is 750 mg/day, and is based on body weight and adjusted for any conditions predisposing patients to either pancreatitis or peripheral neuropathy.

Neuropathy

ddI neuropathy manifests itself as numbness, burning or pain in the feet, which can last for hours, yet is reversible if the drug is discontinued. If patients develop symptoms suggestive of neuropathy, they are instructed to discontinue the drug and are followed closely until all the symptoms disappear. ddI has been restarted successfully at a lower dose, without recurrence of neuropathy in several patients. When symptoms of neuropathy occur, various other possible causes must be ruled out. These include vitamin deficiencies (especially vitamin B12), toxic neuropathies due to other drugs frequently used by HIV-infected persons or direct damage by HIV.

Pancreatitis

Seven deaths related to pancreatitis were also reported in The New York Times article of March 12. Five deaths occurred in the expanded access protocols and two patients in the clinical trials died. Unfortunately no details were given about the circumstances surrounding these deaths, including other opportunistic infections or malignancies, concomitant medications or temporal relationship between intake of ddI and death.

Pancreatitis refers to inflammation of the pancreas, which is an organ whose enzymes metabolize fats, carbohydrates and proteins. The condition is characterized by nausea, vomiting and constant abdominal pain, which is worsened by eating. In addition, the pancreas regulates the production and release of insulin in response to the blood sugar level. Toxins such as alcohol can produce severe pancreatic inflammation. Drinking alcoholic beverages should be avoided while taking ddI since the combination may result in cumulative toxicity. Other commonly used drugs which can cause pancreatitis include steroids, pentamidine, sulfa drugs (Bactrim, Septra, sulfadiazine), cimetidine (Tagamet), tetracycline, opiates, metronidazole (Flagyl), Lomotil, acetaminophen (Tylenol, Anacin, etc.) and diuretics. Since the contributuion of these drugs to the effect of ddI on the pancreas is unknown, persons on both should be monitored closely for this toxicity.

Drugs which decrease stomach acidity, such as those used for gastritis and peptic ulcers (antacids, Tagamet, Zantac and Pepcid), substantially increase ddI absorption.

Physicians participating in the expanded access program are kept informed of new adverse effects which are reported to the pharmaceutical company. Three letters have been sent to physicians reporting new side effects which seem related to use of ddI. The side effects reported so far include:

-Diarrhea reported in less than 1% of patients according to Bristol-Myers, seems to be related to the citrate-phosphate buffer and can be usually controlled with antidiarrheal medications such as Immodium.

-Changes in mental status, ranging from confusion to disorientation, were reported in three patients one to two weeks after starting ddI. Normal mental status was restored between one and 36 hours after discontinuation of the drug. In one case, the change in mental status recurred after ddI was restarted at a lower dose.

-Low levels of potassium, calcium and magnesium have been associated with five seizures and three cases of cardiac arrest.

A summary of adverse drug experiences reported to Bristol- Myers from January 1, 1989 to January 5, 1990 was made available in mid-March to community physicians. It describes the side effects reported from 208 of the 5890 patients who had received ddI in both the expanded access program and the AIDS Clinical Trials Group (ACTG) clinical trials up to that point. The 208 patients reported 267 serious adverse effects, including 111 deaths which occurred predominantly in patients in the expanded access program. Most deaths seemed to be related to progression of HIV disease. Neurologic complaints including both the central and peripheral nervous system occurred in 50 patients. Conversely agitation-hyperactivity-anxiety also occurred in five patients. None of the patients reporting symptoms of peripheral neuropathy was receiving less than 750 mg/day of ddI, the highest dose in the expanded access program. The report also describes reports of elevation in amylase levels, which occurs vbefore pancreatitis without accompanying symptoms. There were also nine reports of seizures (convulsions). Two of the patients had HIV- demential, and two had toxoplasmosis. In the others the cause could not be determined. Anemia was reported by three patients; low white blood cell counts, by eight patients; and low platelet counts, by five patients. Yet some of these patients had a history of decreasing cell counts with AZT, and others received other drugs which could have caused the low cell counts. Rashes and allergic reactions were reported by 11 patients, which could represent allergic reactions to ddI. However two cases may have been food allergies. Miscellaneous adverse effects, which occurred in very few patients, include elevation in liver function tests, uric acid and triglyceride levels.

The most recent report from Bristol-Myers, on March 28, 1990, described a total of 78 cases of pancreatitis. Seven of these cases progressed rapidly to death. With approximately 8300 patients currently under treatment with ddI in the U. S., this constitutes an apparent incidence rate of 0.9% of pancreatitis. There is no current evidence, however, that the proportion of patients with pancreatitis is increasing with expanded access. Careful screening of patients for a history of pancreatitis or recent alcohol abuse is strongly encouraged. Avoidance of other drugs which may also cause pancreatitis is strongly recommended, especially sulfa drugs or intravenous pentamidine, which require discontinuation of ddI therapy. Early symptoms of pancreatitis require immediate attention. Blood levels of amylase and triglycerides should be monitored closely, since they may be early signs of pancreatitis. Despite the new information on ddI toxicity, patients who cannot take AZT or are deteriorating despite AZT have few options, and the benefit of ddI for many may outweigh the possible risk. Access to the drug through early release programs should continue for those eligible, with emphasis on closer supervision and awareness of early symptoms associated with toxicity.

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