Selective serotonin reuptake inhibitor-induced rhabdomyolysis associated with irinotecan.

Abstract: A 74-year-old man was admitted with rhabdomyolysis after undergoing initial treatment for gastrointestinal cancer with irinotecan. The syndrome partially resolved after the discontinuation of all of his usual medications, including his chronic selective serotonin reuptake inhibitor (SSRI). The rhabdomyolysis was exacerbated upon reinitiation of the SSRI and disappeared when the SSRI was discontinued. The combination of irinotecan and SSRI resulted in potentially lethal rhabdomyolysis.

Key Words: citalopram, irinotecan, rhabdomyolysis, selective serotonin reuptake inhibitors 

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Selective serotonin reuptake inhibitors (SSRIs) are considered less toxic and have rarely been implicated in the induction of rhabdomyolysis. Rarely, a serotonin syndrome has been reported with confusion, agitation, rigidity, myoclonus, orthostatic hypotension, involuntary movements, and hyperreflexia, but not with creatine kinase elevations. (1) Rhabdomyolysis as part of neuroleptic malignant syndrome has been frequently reported, especially with imipramine and moclobemide. The first case reports with SSRIs were in six patients with citalopram overdoses. These patients developed electrocardiographic changes, seizures, and a rhabdomyolysis syndrome. (2) Two cases of delayed increase in creatine kinase were reported with venlafaxine. The SSRIs are metabolized by the cytochrome system. Polymorphisms in CYP2D6 and CYP2C19 have been associated with cardiovascular toxicity and prolonged half-life of the drug. Each of the individual SSRIs displays a distinct profile of cytochrome P-450 inhibition. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19, paroxetine is a potent inhibitor of CYP2D6, norfluoxetine is a potent inhibitor of CYP3A4, and sertraline is a potent inhibitor of CYP2D6. Citalopram is less inhibitory than other SSRIs. (3)

The racemic antidepressant citalopram is an SSRI, of which mainly the S-enantiomer is pharmacologically active. In human liver microsomes, several P-450 isoforms including CYP2C19, CYP3A4, and CYP2D6 metabolize citalopram to demethylcitalopram, which is then further metabolized to didemethylcitalopram. In a minor pathway, monoamine oxidase mediates the production of citalopram propionate from citalopram, demethylcitalopram and didemethylcitalopram. (4)

Although interactions with other medications have been described, interactions with chemotherapy agents are only rarely related. We report the case of an elderly man treated with chemotherapy who developed rhabdomyolysis likely due to concomitant therapy with the SSRI citalopram.

Discussion

Irinotecan is a camptothecin, which acts primarily as a topoisomerase I inhibitor. It is a water-soluble prodrug for the more potent but water-insoluble SN-38. The hydrolysis is mediated by a carboxylesterase, and perhaps other mechanisms, present in many tissues. It is oxidized by the cytochrome P-450 family. (5) Irinotecan and SN-38 competitively inhibited CYP3A4 and competitively and noncompetitively inhibited CYP2C9. CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and CYP2E1 were not affected. (6)

Citalopram and irinotecan therefore share at least one metabolic pathway, that of CYP3A4. The prolonged half-life of irinotecan (6-12 hours) in humans may have contributed to the effect, allowing levels of citalopram to increase. In addition, CYP3A activity has been reported to be significantly compromised in cancer patients with an acute phase response. (7) Although not reported to date, similar effects might be anticipated with fluoxetine and its metabolite norfluoxetine, which are also metabolized via the CTP3A4 system.

Because many patients with cancer are depressed, a high incidence of SSRI use might be expected in this population. Because many patients with malignancy have complaints of weakness and fatigue, identification of the drug interaction leading to rhabdomyolysis might be delayed unless the practitioner is acutely aware of the possibility.

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Conclusions

An unanticipated drug interaction between an SSRI antidepressant and irinotecan resulted in a rhabdomyolysis syndrome. Because the admitting complaint was weakness, this could have been misdiagnosed and could have led to a potentially fatal complication. The interaction appears to be due to inhibition of the CYP3A4 system, and could be aggravated by polymorphisms in the protein or by the down-regulation of the cytochrome system seen in cancer patients. An awareness of this potential complication may increase the frequency with which it is diagnosed.

You can get a large audience together for a strip-tease act. Now suppose you came to a country where you could fill a theater by simply bringing a covered plate onto a stage and then slowly lifting the cover so as to let every one see, just before the lights went out, that it contained a mutton chop or a bit of bacon, would you not think that in that country something had gone wrong with food?

--C.S. Lewis

From the Winship Cancer Center and the Department of Medicine, Emory University School of Medicine, Atlanta, GA.

We have no commercial or proprietary interest in any drug, device, or equipment mentioned or any financial interest in any item in the article.

Reprint requests to Jay N. Umbreit, MD, PhD. Winship Cancer Institute. Emory University School of Medicine, 1365-B Clifton Road, N.E., Suite B4100, Atlanta, GA 30322. Email:[e-mail]

Accepted April 25, 2003.

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9610-1031

References

1. Bodner RA. Lynch T, Lewis L, et al. Serotonin syndrome. Neurology 1995;45:219-223.

2. Grundemar L, Wohlfart B, Lagerstedt C, et al. Symptoms and signs of severe citalopram overdose. Lancet 1997;349:1602(letter).

3. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: An update. Curr Drug Metab 2002;3:13-37.

4. Kosel M, Gnerre C, Voirol P, et al. In vitro biotransformation of the selective serotonin reuptake inhibitor citalopram, its enantiomers and demethylated metabolites by monoamine oxidase in rat and human brain preparations. Mol Psychiatry 2002;7:181-188.

5. Rivory LP. Metabolism of CPT-11: Impact on activity. Ann N Y Acad Sci 2000;922:205-215.

6. Hanioka N, Ozawa S, Jinno H. et al. Interaction of irinotecan (CPT-11) and its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) with human cytochrome P450 enzymes. Drug Metab Dispos 2002;30:391-396.

7. Rivory LP, Slaviero KA, Clarke SJ. Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response. Br J Cancer 2002;87:277-280.

RELATED ARTICLE: Case Report

A 74-year-old white man presented with a 2-month history of fatigue, weight loss, and decreased appetite. A computed tomographic scan showed multiple pulmonary nodules and supraclavicular adenopathy. A positron emission tomographic scan showed bilateral lung lesions and uptake in the mediastinal nodes of the right neck. There were extensive osseous metastatic lesions. Fine-needle aspiration performed 1 month before the current illness of a right rib showed a moderately differentiated mucin-producing adenocarcinoma. Immunohistochemistry was cytokeratin 20-negative, strongly cytokeratin 7-positive, and CA 19.9- and carcinoembryonic antigen-positive. He was diagnosed as having adenocarcinoma of unknown primary, histologically most consistent with an upper gastrointestinal tract origin.

Three days before admission, he was treated with irinotecan in the outpatient clinic. On the day of admission, he presented to the emergency department complaining of weakness and pain. He had gotten up to go to the bathroom and was unable to get up from the toilet. He rolled himself to the floor and crawled out of the bathroom. His family brought him to the hospital.

His medical history was significant for coronary artery disease, dyslipidemia, and chronic obstructive lung disease. He denied alcohol use. His chronic medications included enalapril (Vasotec: Merck & Co., Inc., Whitehouse Station, NJ), alprazolam (Xanax; Pharmacia & Upjohn, Kalamazoo, MI), simvastatin (Zocor; Merck & Co., Inc.), nitroglycerin (Nitrostat; Parke-Davis, Inc., Morris Plains, NJ), and aspirin. Approximately 2 months before admission, he had been started on citalopram for depression. He denied flushing episodes.

Admission physical examination was remarkable for generalized weakness but the absence of focal neurologic signs. He also had diffuse muscle tenderness. The electrocardiogram was unchanged from prior examinations with a bifascicular block, but no QT prolongation. The chest radiograph was unchanged from previous radiographs. His sodium level was 131 mmol/L, his potassium was 6.1 mmol/L, and his serum creatinine was 1.3 mg/dl (with a baseline of 0.8 mg/dl). At admission, the creatine kinase (CK) level was 7,400 U/L (reference range, 49-397 U/L). With a presumptive diagnosis of rhabdomyolysis, all medications were discontinued, and the CK decreased to 5,542 U/L. However, the patient became tearful and depressed and citalopram was reinitiated on the evening of April 12. Subsequently, the CK increased to 13,529 U/L, and myoglobin was 27,579 ng/ml (Fig. 1). The citalopram was discontinued and the CK, and myoglobin again decreased during the next 5 days. The patient's strength returned with discontinuation of medications, and he was increasingly able to ambulate without pain.

RELATED ARTICLE: Key Point

* Selective serotonin reuptake inhibitors can interact with irinotecan to produce rhabdomyolysis.

Sarah Richards, MD, Jay N. Umbreit, MD, PHD, Michael P. Fanucchi, MD, Joan Giblin, MS, APN, and Fadlo Khuri, MD