Summary Safety Review - Serotonin blocking drugs (serotonin antagonists) ALOXI ® (palonosetron), ANZEMET ® (dolasetron), KYTRIL ® (granisetron) and generics, and ZOFRAN ® (ondansetron) and generics - Serotonin Syndrome

Review decision

A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.


Issued: 2014-05-14

issue

Health Canada has completed a safety review of the serotonin blocking drugs (serotonin antagonists) dolasetron (was sold under the brand name ANZEMET® and was recently withdrawn from the market by the manufacturer), granisetron (KYTRIL®1 and generics), ondansetron (ZOFRAN®2 and generics) and palonosetron (ALOXI®3). These drugs are used for treating nausea and vomiting due to cancer therapy. This review identified a potential risk of serotonin syndrome.4 Serotonin syndrome occurs when serotonin accumulates to high levels in the body.

A 2012 article in the World Health Organization (WHO) Pharmaceuticals Newsletter prompted the review. The publication indicated that ondansetron used together with other drugs that affect serotonin levels (serotonergic drugs) may contribute to the development of serotonin syndrome in susceptible patients.5

Background

Approved use of serotonin blocking drugs (5-HT3 receptor antagonists) in Canada

These drugs are indicated for the treatment of nausea and vomiting associated with cancer therapy in adults. However, individual drugs in this class have specific indications (please refer to the drug specific Canadian Product Monograph1, 2, 3 for details).

How do serotonin blocking drugs work to treat nausea and vomiting?

Cells which are part of the intestine store about 90% of the body's serotonin.6 Cancer therapy can damage the intestine and trigger the release of serotonin.7 The released serotonin can cause nausea and vomiting. Serotonin blocking drugs (5-HT3 receptor antagonists) help prevent nausea and vomiting by blocking the effect of serotonin.

Serotonin syndrome

Serotonin syndrome occurs when serotonin, a chemical normally found in the body, accumulates to high levels. This usually happens with combinations of certain drugs that affect serotonin levels, but may also occur with a single drug.

It is very important to diagnose serotonin syndrome early as it can be fatal if not treated. Symptoms of serotonin syndrome may include any combination of confusion, agitation, restlessness, muscle twitching or stiffness, fever, increased sweating and heart rate, blood pressure fluctuations, pupil dilatation, nausea and/or vomiting, loss of consciousness and coma.8, 9 Neuroleptic malignant syndrome is a life-threatening condition with changes in the nervous, muscular and cardiovascular system.  Neuroleptic malignant syndrome is associated with the use of antipsychotics and dopamine enhancing drugs10, 11 and it presents with clinical features similar to serotonin syndrome. Dopamine is another chemical normally found in the body. The way neuroleptic malignant syndrome occurs in the body is different to how serotonin syndrome occurs in the body. However, these two syndromes raise a diagnostic problem to the treating healthcare professional. As the treating healthcare professional could misdiagnose serotonin syndrome, it is important that patients who experience any of these symptoms talk to a healthcare professional immediately.

Objective

To assess the available evidence concerning the risk of developing serotonin syndrome associated with serotonin blocking drugs used to treat nausea and vomiting. The evidence considered Canadian patient reports, scientific and medical literature, and other publically available information about the use of these drugs both in Canada and internationally. The review evaluated the risk and suggested ways to minimize it.

Key findings

Usage of serotonin blocking drugs used to treat nausea and vomiting in Canadai

  • Health Canada estimates the number of prescriptions for serotonin blocking drugs used to treat nausea and vomiting increased from about 165,000 in 2007 to about 260,000 in 2012.

Canadian and foreign reports of serotonin syndrome associated with the use of serotonin blocking drugs to treat nausea and vomiting

  • As of September 30, 2012, Health Canada received two Canadian reports of serotonin syndrome with serotonin blocking drugs used to treat nausea and vomiting. One report described an incident of serotonin syndrome in a 30-year-old man taking ondansetron and other medications. The other report described an incident of serotonin syndrome and neuroleptic malignant syndrome in a 12-year-old boy taking granisetron and olanzapine. Both patients recovered.
  • International reports of serotonin syndrome with serotonin blocking drugs used to treat nausea and vomiting have also been identified.

Scientific reports

  • In the Health Canada review, there were 14 reports of serotonin syndrome related cases in the literature. In many cases, the suspect drug was the serotonin blocking drug used to treat nausea and vomiting. Some authors proposed that the use of these drugs with other drugs that affect serotonin levels could lead to increased stimulation of serotonin receptors involved in the development of serotonin syndrome.
  • In the Health Canada review, many articles, including review articles on serotonin, list serotonin blocking drugs used to treat nausea and vomiting among other drugs that can cause serotonin syndrome. It is important to highlight that serotonin syndrome occurs only due to the use of medicines and cannot occur without their use.
  • The literature evidence points to a risk of serotonin syndrome with serotonin blocking drugs used to treat nausea and vomiting.  This is especially true when these drugs are used together with other drugs that affect serotonin levels.

Conclusions and actions

  • The Health Canada review noted that when used as indicated, serotonin blocking drugs used to treat nausea and vomiting alone are unlikely to cause serotonin syndrome. However, when these drugs are used in combination with other drugs that affect serotonin levels, the way they work together in the body could explain how serotonin syndrome can occur.

    Health Canada has requested that manufacturers incorporate the risk of serotonin syndrome into the Warnings and Precautions section and the Consumer Information section of the Canadian Product Monograph for these drugs. The Canadian Product Monographs for ALOXI®, KYTRIL®, and ZOFRAN® now contain this new safety information. ANZEMET® has recently been discontinued by the manufacturer in Canada. Manufacturers of generic versions of these drugs will also update their Product Monographs. On May 14, 2014 Health Canada also issued an Information Update to the public communicating the risk of serotonin syndrome with serotonin blocking drugs used to treat nausea and vomiting.

References

  1. Hoffman-La Roche Ltd. Canadian Product Monograph for KYTRIL® (dated December 13, 2013).
  2. GlaxoSmithKline Inc. Canadian Product Monograph for ZOFRAN® and ZOFRAN® ODT (dated September 13, 2013).
  3. Eisai Ltd. Canadian Product Monograph for ALOXI® (dated November 25, 2013).
  4. Boyer EW, Shannon M. Current concepts: The serotonin syndrome. N Engl J Med. 2005; 352(11):1112-1120.
  5. WHO Pharmaceuticals Newsletter. Ondansetron and serotonin syndrome. 2012; 3:16-21.
  6. Kovac AL. Prophylaxis of postoperative nausea and vomiting: Controversies in the use of serotonin 5-hydroxytryptamine subtype 3 receptor antagonists. J Clin Anesth. 2006; 18(4):304-318.
  7. Feyer P, Jordan K. Update and new trends in antiemetic therapy: The continuing need for novel therapies. Ann Oncol. 2011; 22(1):30-38.
  8. Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004; 42(3):277-285.
  9. Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: Review. J Clin Psychopharmacol. 1997;17(3):208-221.
  10. Moscovich M, Nóvak FTM, Fernandes AF, Bruch T, Tomelin T, Nóvak EM, et al. Neuroleptic malignant syndrome. Arq Neuropsiquiatr. 2011; 69(5):751-755.
  11. Perry PJ, Wilborn CA. Serotonin syndrome vs neuroleptic malignant syndrome: A contrast of causes, diagnoses, and management. Ann Clin Psychiat. 2012; 24(2):155-162.

Footnotes

  1. IMS utilization data provided by: IMS Health Canada Inc. An external party cannot refer to nor use IMS data, which have been generated by Health Canada, without a Third Party Agreement in place.

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