Published: 7 June 2019

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Phenytoin (Dilantin) capsules formulation change – How did it affect patients?

Prescriber Update 40(2): 29-30
June 2019

Introduction

Changes to the brand of phenytoin taken by patients should be avoided. Even when different brands demonstrate bioequivalence, there are reports of clinically relevant differences¹.

In July 2018, Pfizer, the manufacturer of Dilantin, announced a formulation change for the 30 mg and 100 mg capsules². Here we review reports made to the Centre for Adverse Reactions Monitoring (CARM) concerning adverse events associated with the formulation change.

Dilantin formulation changes

The manufacturer announced minor formulation changes to the Dilantin capsules³:

• addition of lactose to the 30 mg capsules
• in both the 30 mg and 100 mg capsules, pre-mixed sucrose and maize starch was used instead of individual excipients.

The new formulation demonstrated bioequivalence to the old formulation.

The manufacturer recommended close monitoring of patients during the change. This included measuring phenytoin levels 7 to 10 days after starting the new formulation and, if needed, adjusting the dose to achieve the clinically effective serum total concentration of phenytoin of 10 to 20 mcg/mL.

In 2018⁴:

• 1,096 patients were taking phenytoin 30 mg capsules
• 3,855 patients were taking phenytoin 100 mg capsules.

Reports to CARM

As of April 2019, CARM had received 4 reports of patients experiencing problems following the phenytoin formulation change (CARM ID numbers: 131358, 131605, 131438, 131917).

Three patients experienced seizures, and one patient experienced suicidal ideation. Of the three patients who had seizures, phenytoin levels were measured and found to be low.

• 131358: the seizure occurred before the patient could attend for a phenytoin level measurement.
• 131605: levels were measured 4 days after the change and were low. The phenytoin dose was increased, but the patient still experienced a life-threatening prolonged seizure.
• 131438: the patient declined phenytoin level testing. Levels were tested after the seizure and found to be low.

All three patients had previously experienced long periods of being seizure free.

The low number of cases illustrates that close monitoring of patients and obtaining timely phenytoin levels can ensure a smooth transition. However, even with appropriate monitoring, some patients still experienced problems, including life-threatening seizures and loss of driving licence.

Medsafe has approved a similar formulation change for Dilantin Infatabs (50 mg phenytoin, paediatric chewable tablets). Closely monitor patients when changing to the new formulation – this can include blood monitoring within the first 7 days after changing formulation.

References

1. Medicines and Healthcare products Regulatory Agency. 2017. Antiepileptic drugs: Updated advice on switching between different manufacturers’ products. Drug Safety Update 11(4): 5. URL: www.gov.uk/drug-safety-update/antiepileptic-drugs-updated-advice-on-switching-between-different-manufacturers-products (accessed 8 April 2019).
2. Pfizer NZ Ltd. 2018. Dissolution profile of Dilantin 30 mg and 100 mg capsules (New Formulation). URL: https://medsafe.govt.nz/safety/DHCPLetters/DilantinFormulationChangeJuly2018.pdf (accessed 8 April 2019).
3. Pfizer NZ Ltd. 2018. Clarification regarding Dilantin Dear Healthcare Professional Letter dated 19 July 2018. URL: https://medsafe.govt.nz/safety/DHCPLetters/Dilantin14.08.2018.pdf (accessed 8 April 2019).
4. Ministry of Health. 2019. DataPharm version 13 May 2019 (data extracted from Pharmaceutical Collection on 26 March 2019). URL: https://minhealthnz.shinyapps.io/datapharm/ (accessed 14 May 2019).