Drug Induced Elevation of Blood Sugar with the Antipsychotic Drugs Clozapine (CLOZARIL) and Olanzapine (ZYPREXA)

We are becoming increasingly concerned about reports of elevated blood sugar levels (hyperglycemia) and diabetes with the newer “atypical antipsychotic” drugs clozapine (CLOZARIL) and olanzapine (ZYPREXA).

All antipsychotic drugs usually improve symptoms such as agitation, delusions, hallucinations, and suspiciousness. Atypical anti-psychotics additionally tend to improve negative symptoms such as apathy, disorientation, emotional withdrawal, and lack of pleasure, more than the older antipsychotics. However, there is no clear evidence that they are more effective or better tolerated than the conventional antipsychotics.

In the November 28, 2001, issue of the Journal of the American Medical Association medical officers from the Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research and a physician from the Duke University Medical Center reported a possible link between the use of clozapine and olanzapine in adolescents and elevations in blood sugar levels (hyperglycemia) in 20 children.

The authors of the report searched the FDA’s adverse drug reaction database to identify cases of hyperglycemia in patients younger than 19 years of age. Between January 1996 and May 2001, the FDA received nine reports of hyperglycemia associated with the use of olanzapine in four males and five females aged 13 to 18. In seven of these cases, the hyperglycemia was newly diagnosed and in two instances there was worsening of preexisting diabetes. Elevated blood sugar levels appeared within one week after starting olanzapine in two cases and within six months in six other cases. Control of blood sugar levels improved in four patients after the drug was stopped or the dosage decreased. However, in one case, the hyperglycemia recurred after the patient was switched to other drugs. In this group of patients there was one death from inflammation of the pancreas (pancreatitis).

The FDA also received reports of hyperglycemia in seven males and four females, all between 13 and 18, associated with the use of clozapine between January 1993 and March 2001. Hyperglycemia was newly diagnosed in eight of these children and two experienced worsening of existing diabetes. Hyperglycemia occurred within six weeks of starting clozapine in five children and within six months in five others. The drug was discontinued or the dosage lowered in six, and blood sugar control improved in three of the children.

In these 20 children, two also experienced pancreatitis, though one was already taking a drug known to cause this condition. Again, because pancreatitis is uncommon in children, this suggests a causal association with the use of olanzapine and clozapine. In addition, the two cases of pancreatitis were found in the search for hyperglycemia and may not represent all cases of pancreatitis in the FDA’s database.

At almost the same time, other FDA staff members published a report in the December 15, 2001 issue of The American Journal of Medicine linking clozapine to diabetes. Again, the authors used the FDA’s adverse drug reaction database to identify reports of diabetes with clozapine use from January 1990 through February 2001. These results were pooled with case reports published in the medical literature.

The FDA identified 384 reports of diabetes associated with the use of clozapine. In 242 cases diabetes was diagnosed for the first time and 54 patients experienced a worsening of their existing diabetes. The average age of these patients was 40 years and ranged from 13 to 77 years. The majority of cases appeared within six months of starting the drug. One patient developed diabetes after taking a single 500 milligram dose of clozaril. There were 80 cases of changes in blood acid balance (metabolic acidosis) or the more serious, potentially fatal, ketoacidosis. The FDA found that 25 patients died during episodes of hyperglycemia. Improvement in blood sugar control was seen in 46 patients after discontinuation or a reduction in the dose of clozapine.

On April 16, 2002, the Japanese Ministry of Health, Labor and Welfare issued emergency safety information regarding olanzapine and hyperglycemia resulting in diabetic ketoacidosis and coma. Ketoacidosis is fatal in about 50 percent of cases.

The Japanese authorities received nine reports of serious hyperglycemia in association with olanzapine use, including two cases with fatal outcomes. The professional product labeling for the drug was changed to include the following information:

• Olanzapine is contraindicated for use in patients with diabetes or a history of diabetes.

• Olanzapine should be used with caution in patients with risk factors for diabetes, including hyperglycemia, obesity or a family history of diabetes.

• Patients receiving olanzapine should be carefully monitored for symptoms of hyperglycemia and the drug should be discontinued if such symptoms occur. The symptoms of severe hyperglycemia include weakness, excessive eating, excessive thirst, and excessive urination.

• Physicians should educate patients and their family members about the risk of serious hyperglycemia associated with olanzapine and how to identify the symptoms of hyperglycemia.

The British equivalent of the FDA warned about the risk of diabetes with the use of olanzapine in the April 2002 issue of their newsletter Current Problems in Pharmaco-vigilance. They had received 40 reports of hyperglycemia, diabetes or worsening of diabetes in patients taking olanzapine. Ketoacidosis and coma or both, including one death, were reported in four patients.

The British required that the professional product labeling for olanzapine include information about the risk of diabetes and ketoacidosis and that patients on the drug be monitored for hyperglycemia.

So far the FDA has done little to warn physicians or patients about the risk of hyperglycemia, diabetes and ketoacidosis with olanzapine. The professional product labeling for olanzapine, last revised on March 5, 2002, makes brief reference to diabetes and hyperglycemia buried deep in the adverse reactions section of the drug’s labeling.

The warnings in the clozaril professional product labeling are much more complete. The following appears in the February 2002 revision of this drug’s labeling:

What You Can Do

At this time, the best information we can give you is to follow the advice listed above from the Japanese drug regulatory authorities.