P&T News: May 1997

Central Nervous System Reactions and Hz-Receptor Blocking Agents: Focus on Famotidine

Jane C. Chandramouli, Pharm.D. and Beth Bryles Phillips, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Joseph Truszkowski, M.D., Assistant Professor, Gastroenterology-Hepatology, Department of Internal Medicine.

The mechanism of action for the CNS effects is not completely understood. The clinical spectrum of CNS effects associated with Hz-receptor blockers includes delirium, psychosis, confusion, disorientation, hallucinations, hostility, agitation, irritability, obtundation, somnolence, slurred speech, or headache.1 Such symptoms are, of course, not specific to Hz-receptor blocker toxicity. In fact, much of the confusion regarding the incidence of Hz- receptor blocker reactions is caused by their nonspecific nature, and their resemblance to the symptoms of "ICU Syndrome." Thus, critically ill patients whose mental status deteriorates while receiving an Hz-receptor blocker may or may not be having a reaction to the drug.3

Risk factors that have been suggested to increase susceptibility to CNS effects with Hz-receptor blocker therapy have included decreased capacity to eliminate these agents (e.g., renal or hepatic dysfunction), high doses, elevated plasma and cerebrospinal concentrations, and advanced age. However, available evidence has not consistently correlated the relationship between these risk factors and increased CNS effects.2,3

Anecdotal experiences do not support a relationship between Hz-receptor blocker dose and CNS reactions. In the management of patients with Zollinger-Ellison syndrome, large doses of cimetidine, ranitidine, and famotidine have not resulted in an increased association with CNS reactions. Additionally, patients experiencing cimetidine overdoses have also been generally free of central nervous system toxicity.3-6

It has been shown that the Hz-receptor blocker can enter the cerebrospinal fluid and cross the blood brain barrier; however, the role of histamine in the CNS is unclear, as are the behavioral correlates of central Hz-receptor blockade.2 It is postulated that H2- receptor blockers partially inhibit the neurotransmitter function of histamine.1

Renal insufficiency has been cited as a possible contributing factor for the development of CNS toxicity. Due to the potential for drug accumulation in renally impaired patients, the manufacturers of the currently marketed H2-receptor blockers recommend a dosage adjustment based on creatinine clearance measurements. Isolated hepatic dysfunction has not consistently been shown to increase the incidence of CNS reactions. However, some studies have suggested that patients with both renal and liver disease are at increased risk for developing CNS reactions.2 Increased monitoring is recommended in these patient populations.

Reported Incidence of CNS Effects with ED-Receptor Blockers
Results from a worldwide spontaneous reporting system survey indicated that mental confusion was reported in approximately 1.1 per 100,000 patients on cimetidine.7 Subsequent surveillance studies have shown the incidence of CNS effects ranges from 0.38% to 0.80%.1 Only one surveillance study has been conducted with ranitidine, where an incidence of 1.9% was found in a survey of 9600 patients. Howden and Tytgat tabulated serious adverse events for over 67,000 patients treated with famotidine in post-marketing surveillance trials.8 Serious famotidine- associated adverse psychiatric events or events related to the nervous system were reported in: 1) 14 of 6,938 (0.2%) in clinical developmental studies; 2) 89 of 5458 (1.63%) in local studies; 3) 43 of 49,692 (0.09%) in event- monitoring surveillance studies; and 5 of 4,992 (0.1%) in investigational studies. Additionally, health care professionals have spontaneously reported 243 serious adverse events to famotidine; forty of these adverse reactions were categorized as psychiatric/nervous disturbances.

Cantu and Korek reviewed the English-language reports of CNS effects associated with Hz-receptor blockers and reports submitted to the FDA between 1977 and 1989.2 The reports included confusion, disorientation, agitation, hostility, delirium, hallucinations, somnolence, psychosis, and paranoia. The reactions generally occurred within the first two weeks of treatment and resolved within three days of discontinuation of therapy. The authors stated that no clear evidence exists that one drug is more likely to cause a reaction than another. Juergens and Smith reported that the overall rate of spontaneous reporting to the FDA of CNS reactions related to Hz-receptor blockers was about one report per 100,000 prescriptions.9

Famotidine CNS Effects
While most published case reports of CNS adverse effects are with cimetidine, there have been multiple reports involving ranitidine or famotidine. Cimetidine was the first Hz-receptor blocker marketed and it was widely used for many years before ranitidine or famotidine were marketed and this is probably why there are more published adverse reactions with cimetidine. Table 1 summarizes the published case reports of famotidine-induced CNS changes. Henann et al published two cases of elderly patients who experienced neurological effects (i.e., hallucinations, confusion, disorientation) after receiving famotidine 20 mg every 12 hours.10 Job described a case of an 83-year-old man who developed agitation, insomnia, delusions, and hallucinations while being followed post-operatively in the ICU. Famotidine-induced toxic psychosis was diagnosed and the patient improved following the withdrawal of the famotidine and the initiation of haloperidol therapy." Yoshimoto et al described two cases where neurosurgical patients with renal failure developed mental deterioration and confusion after receiving IV famotidine. The cerebral spinal fluid concentrations of famotidine were much higher than in neurosurgical patients with normal renal function.12 The most recent report of famotidine-induced CNS effects included 6 patients; all patients were over 65 years old, receiving famotidine 20 mg every 12 hours, had no evidence of elevated serum creatinine values, and had a temporal relationship with the use of famotidine and the development of mental status changes.13

Summary
Although adverse CNS reactions have been more commonly reported with cimetidine, famotidine is not devoid of CNS adverse reactions, and it is likely, as famotidine is more widely used, that more cases of famotidine-associated CNS effects will be reported. If H2-receptor antagonist-associated CNS effects develop, an alternative Hz-receptor antagonist or a proton pump inhibitor may be warranted.

References

1. Am J Med 1987; 83(suppl A):58-4.

2. Ann Intern Med 1991; 114:1027-34.

3. Drug Intel Clin Pharm 1985; 19: 13-20.

4. Br Med J 1979; 1:4534.

5. Ann Emerg Med 1987; 16:1217-21.

6. Lancet 1979; 2:1367.

7. J Am Med Assoc 1980; 243:19124.

8. Clin Ther 1996; 18:36-54.

9. Post Marketing Surveillance. 1991; 5:13544.

10. Drug Intel Clin Pharm 1988; 22:976-8.

11. J Pharm Pract 1992; 5:vii-viii.

12. Clin Pharmacol Ther 1994; 55:693-700.

13. Psychosomatics 1996; 37:349-55.

14. Psychosomatics 1995; 36:74-77.

15. Am J Health Sys Pharm 1995; 52:1889-94.

Table 1. Published Case Reports of Famotidine-Induced CNS Changes

Reference	Number of Patients	ADR Description Comments
Catalano et al, 13	6	Six hospitalized patients more than 66 y.o. developed delirium after a range of 3 to 29 days of famotidine therapy. All patients showed a clearing of mental status after famotidine withdrawal.
Henann et al, 10	2	First case: 68 y.o. male with upper GI bleed experienced restlessness, irritability, hallucinations after 5 doses of famotidine 20 mg q 12 hours Second case: 73 y.o. woman with upper GI bleeding experienced confusion and disorientation after 3 doses of famotidine.
Job ML, 11	1	83 y.o. male who post-operatively developed agitation, insomnia, delusions, and hallucinations. Patient improved following discontinuation of famotidine and initiation of haloperidol therapy.
Yoshimoto, 12	2	Two hemodialyzed neurosurgical patients developed mental deterioration and convulsions after receiving IV famotidine.
Picotte-Prillmayer et al, 14	1	79 y.o. female with normal renal function who post-surgically developed delirium while on rantidine. Once the rantidine was stopped, the delirium resolved. Patient was changed to famotidine and after 3 doses developed delirium again which resolved upon discontinuation of drug.
Fish, 15	1	Disorientation and confusion were noted in one patient 15 minutes after administration of the sixth dose of famotidine. Changes in mental status resolved within about 2 hours but recurred several times over the next few days.

DRUGS ADDED TO STOCK

ANAGRELIDE Capsules: 0.5 mg Anagrelide (Agrylin[R] - Roberts ) is an inhibitor of platelet production that is indicated for the treatment of essential thrombocythemia. NOTE: The prescribing of anagrelide is restricted to Hematology/Oncology.

GLATIRAMER Injection: 20 mg per vial Glatiramer (Copaxone[R] - Teva) is a copolymer of L-alanine, L-lysine, L-glutamic acid, and L- tyrosine that is indicated for the reduction of the frequency of relapses in patients with relapsing-remitting multiple sclerosis. NOTE: The prescribing of glatiramer is restricted to Neurology.

PREDNISOLONE Oral Liquid: 15 mg per 5 ml Prednisolone (Prelone - Muro) oral liquid is a commercially available oral glucocorticoid. NOTE: The UIHC also stocks an extemporaneously compounded prednisone 20 mg per 5 ml oral liquid To avoid confusion doses should only be prescribed in milligrams and not by volume.

ROPIVACAINE Injection: 0.2%, 0.5%, 0.75%, 1% Ropivacaine (Naropin[R] - Astra) is an amide-type anesthetic agent indicated for local or regional anesthesia, post-operative pain management, and obstetrical procedures. NOTE: The prescribing of ropivacaine is restricted to Anesthesia.

VALPROATE Injection: 500 mg per vial Intravenous valproate (Depacon[R] - Abbott) is indicated as an alternative in patients for whom oral administration of valproate is currency not feasible, including these patients with complex partial seizures, simple and complex absence seizures, and multiple seizure types. .

NEW DOSAGE FORMS ADDED TO STOCK

NICOTINE POLACRILEX 4 mg GUM This product provides an additional strength to accommodate the smoking cessation needs of "heavy" smokers.

PRENATAL MULTIVITAMINS WITH 1 mg FOLIC ACID

DRUGS DELETED FROM STOCK

CYCLANDELATE (CYCLOSPASMOL[R]) TABLETS Discontinued by the manufacturer. Papaverine capsules are available.

DACARBAZINE INJECTION 100 mg VIAL Discontinued by the manufacturer. The 200 mg vial is available.

HYDROCORTISONE 10% IN RICH-MAR LOTION Deleted because of low use. Hydrocortisone 5% in Rich-Mar lotion is available.

PENTOBARBITAL 30 mg SUPPOSITORY Discontinued by the manufacturer. The 60 mg suppository is available.

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