Pancreatitis Associated With Atypical Antipsychotics: From the Food and Drug Administration's MedWatch Surveillance System and Published Reports

Elizabeth A. Koller, M.D., James T. Cross, M.S., P. Murali Doraiswamy, M.D., Saul N. Malozowski, M.D., Ph.D., M.B.A.

Disclosures

Pharmacotherapy. 2003;23(9) 

In This Article

Results

We identified 192 cases of pancreatitis; 18 of these were reported in 17 publications. Of these reports, 131 originated in the United States and 61 were from foreign sources ( Table 1 ).

Seventy-two cases of pancreatitis occurred in patients receiving clozapine monotherapy ( Table 1 ). An additional 10 cases occurred in patients receiving clozapine plus olanzapine, risperidone, and/or haloperidol. Sixty-two cases occurred in patients receiving only olanzapine, with an additional seven cases in patients receiving olanzapine plus clozapine, risperidone, and/or haloperidol. Thirty-one cases occurred in patients receiving only risperidone, with an additional two cases in patients receiving risperidone plus haloperidol. Twelve cases occurred in patients receiving haloperidol monotherapy. Another 12 occurred in patients receiving haloperidol plus one or more of the three atypical antipsychotics. Only two of the reported haloperidol cases (one U.S., one foreign) occurred before 1991. An additional three monotherapy cases (all foreign) and three combination therapy cases (all U.S.) occurred before 1996.

Documentation for the diagnosis of pancreatitis was provided in most cases: clozapine 72% (59 of 82 cases), olanzapine 67% (46 of 69), risperidone 54% (18 of 33), and haloperidol 58% (14 of 24). Only three cases were documented in which concomitant acidosis or ketosis could confound diagnoses based on hyperamylasemia alone. The antipsychotic drug (one or more with combination therapy) was discontinued in 60% of patients (clozapine 67% [55 of 82 patients], olanzapine 64% [44 of 69], risperidone 56% [19 of 33], and haloperidol 21% [5 of 24]), although the period of discontinuation was often brief.

Mean ± SD ages of patients with pancreatitis who were receiving clozapine, olanzapine, risperidone, and haloperidol, alone or in combi-nation, were 38.9 ± 13.4, 39.7 ± 14.0, 43.0 ± 19.2, and 43.8 ± 23.4 years, respectively ( Table 1 ). Although the patients treated with haloperidol alone were older than those treated with haloperidol in conjunction with an atypical antipsychotic agent, the differences did not reach statistical significance (p=0.37). Similarly, the mean age differences between patients receiving haloperidol versus an atypical antipsychotic did not reach statistical significance. Ten pediatric patients were affected: four (aged 15, 16, and 18 yrs, and an unspecified adolescent) were treated with olanzapine, three (aged 10, 13, and 16 yrs) with risperidone, one (aged 15 yrs) with clozapine, one (aged 17 yrs) with haloperidol, and one (aged 17 yrs) with a combination of clozapine and haloperidol.

A slight male predominance was noted in those treated with clozapine, olanzapine, and haloperidol in combination with an atypical antipsychotic agent ( Table 1 ). These sex differences were absent with risperidone. These findings contrast with the female predominance observed with haloperidol monotherapy.

Time-to-diagnosis information was available for 82% of patients; sometimes, however, information was available for only one of the antipsychotic agents (10 patients). The time to diagnosis of pancreatitis in patients for whom such data were available was 6 months or less for most patients in all treatment groups: clozapine 63% (46 of 73 patients), olanzapine 63% (32 of 51), risperidone 79% (22 of 28), and haloperidol 90% (9 of 10).

Some dosing information was available for 81% of patients. For six patients, information was available on only one of the antipsychotic agents. The mean ± SD daily doses were clozapine 306.7 ± 202.9 mg (range 12.5-1000 mg, 73 patients), olanzapine 15.0 ± 6.3 mg (range 2.5-30 mg, 53 patients), risperidone 4.0 ± 3.7 mg (range 0.5-20.0 mg, 27 patients), and haloperidol 8.2 ± 7.7 mg, (range 0.5-20 mg, nine patients). There was no significant correlation between daily dose and the time to diagnosis. Drug levels, which may be more predictive of clinical effects, were not available.

Although completeness of the information is uncertain, concomitant drug information was provided for 82% (157 of 192) of patients. Reporting rates were similar for all drugs administered: clozapine 78% (64 of 82 patients), olanzapine 90% (62 of 69), risperidone 76% (25 of 33), and haloperidol 92% (22 of 24). The most commonly administered concomitant drugs were clonazepam, lorazepam, lithium, paroxetine, sertraline, thyroid hormone, and valproate, as well as various agents given to treat hypertension, diabetes, constipation, and peptic disease. Valproate was administered as a concomitant drug in a minority of patients: clozapine 34% (22 of 64), olanzapine 34% (21 of 62), risperidone 16% (4 of 25), and haloperidol 14% (3 of 22). Valproate reportedly also had been administered for extended periods in some patients whose pancreatitis did not develop until after the start of antipsychotic therapy. Pancreatitis also occurred in the documented absence of concomitant drugs for eight patients receiving clozapine; seven, olanzapine; two, risperidone; and one, haloperidol.

Reporting of alcohol abuse was incomplete, but 11 patients were reported as current abusers. Perhaps more significant are the 39 reports in which patients had no recent history or any history of alcohol abuse: those receiving clozapine (6 patients), olanzapine (25), risperidone (6), haloperidol (1), and combined clozapine-olanzapine-haloperidol (1).

Hyperglycemia. Pancreatitis sometimes occurred in patients with hyperglycemia. For clozapine, there were 16 reports of newly diagnosed hyperglycemia, such as one that occurred with a second episode of pancreatitis. There were two reports of an exacerbation of preexisting diabetes. For one patient, we could not determine whether the onset of hyperglycemia was new or an exacerbation of preexisting disease. For another patient, data were conflicting regarding potential new-onset diabetes. Follow-up with the psychiatric institution did not resolve the discrepancy in serial reports. Eight patients had preexisting diabetes that did not worsen with the pancreatitis; in two of these patients, hyperglycemia occurred after the start of clozapine therapy but before the onset of pancreatitis.

For olanzapine, there were 21 reports of newly diagnosed hyperglycemia. For another two patients, we could not determine whether the onset of hyperglycemia was new or an exacerbation of preexisting disease. An additional patient experienced diabetic ketoacidosis and unconfirmed pancreatitis with her first exposure to olanzapine followed by hyperamylasemia (amylase level 933 IU/L) and recurrence of ketoacidosis with reexposure. Five patients had preexisting diabetes that did not worsen with the pancreatitis; in one of these patients, hyperglycemia occurred subsequent to the start of olanzapine therapy but before the onset of pancreatitis.

For risperidone, four patients were reported with newly diagnosed hyperglycemia and one with an exacerbation of preexisting disease. Three patients had preexisting diabetes that did not worsen.

For haloperidol, no patients were reported with newly diagnosed hyperglycemia or an exacer-bation of preexisting diabetes. Two had preexisting diabetes that did not worsen.

Acidosis. Sometimes pancreatitis occurred with acidosis that generally was associated with glucose abnormalities. Metabolic abnormalities ranged from mild ketosis to frank diabetic ketoacidosis. For clozapine, there were 11 reports of ketosis. For olanzapine, there were 13 reports of ketosis and one report of an unspecified type of metabolic acidosis. There was one report of ketosis in a patient receiving combined olanzapine-clozapine therapy. For risperidone, there were three reports of ketosis. For haloperidol monotherapy, there were no reports of acidosis. There was a single report of an unspecified type of metabolic acidosis in a patient receiving both haloperidol and clozapine.

Fatalities. Twenty-two patients died; one was a 15-year-old boy. In some patients, such as the 15-year-old boy, death was directly related to the pancreatitis. In other patients, the pancreatitis was a comorbidity. Frequently, the reported data were insufficient or the clinical picture was unclear, so that comorbidity and direct cause of death could not be distinguished. Of the 22 patients who died, seven received clozapine, nine olanzapine, two risperidone, and three halo-peridol; one patient received both clozapine and haloperidol.

The demographics and clinical presentation of the patients who died did not differ substantially from those who survived. Of the patients with fatal outcomes who received atypical antipsychotics, mean ± SD age was 45.8 ± 17.0 years (range 15-74 yrs, 16 patients with data). Mean ± SD age of those with fatal outcomes who received haloperidol was 55.0 ± 46.7 years (range 22-88 yrs, two patients, both monotherapy cases, with data). Of the patients with fatal outcomes who received atypical antipsychotics, nine were women and nine were men. Of the remaining three with fatal outcomes who received haloperidol (monotherapy), two were women, and the sex of the third patient was unknown. A man who was receiving both clozapine and haloperidol also died. Eight patients who received atypical antipsychotics and died were reported to have received valproate concomitantly. None of the deceased patients who received haloperidol, including the patient who received both clozapine and haloperidol, received valproate concomitantly. One of patients who received haloperidol reportedly received no other drug.

For the deceased patients who received atypical antipsychotics, including the patient who received both clozapine and haloperidol, time to onset of pancreatitis was 6 months or less for 72% (13 of 18 patients for whom time-to-onset data were available). Four cases occurred within 8 days of the start of drug therapy. For two patients who received haloperidol, time to onset was less than 11 days. Information regarding time to onset was not provided for two patients receiving haloperidol; one was the patient who received combination therapy. Seven of the deceased patients who received atypical antipsychotics had experienced new-onset diabetes or an exacerbation of preexisting diabetes. No deceased patients who received haloperidol had such deterioration in glycemic control. Five patients who received atypical antipsychotics had ketosis or frank ketoacidosis. In addition, one patient who received the combination clozapine-haloperidol therapy had an unspecified type of metabolic acidosis. None of the patients who received haloperidol monotherapy was reported to be acidotic.

Estimates of exposure to antipsychotic agents were lowest for patients receiving clozapine and highest for those receiving haloperidol ( Table 2 ). Moreover, the calculated exposure to haloperidol is an underestimate because it does not incorporate data from the first decade of marketing the drug. The reporting rates for pancreatitis were comparatively higher for the atypical antipsychotic agents than for the conventional neuroleptic agent, haloperidol. The reporting rate ratios for clozapine were the highest. This was evident whether the calculations were based on all-use or mono-therapy data. The reporting rate ratios increased approximately 3-fold when only those patients treated with a single antipsychotic were included in the analyses. The same interdrug differences in reporting rate ratios were observed whether the haloperidol-exposure data were limited to 1991 and beyond or were more inclusive, with data from 1981-2002.

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