Health Canada warning about Lamictal (lamotrigine)

[David Baxter PhD]

Health Canada Endorsed Important Safety Information on LAMICTAL (lamotrigine)
September 27, 2004

This document is also available in PDF format as lamictal_hpc_e.pdf
Pages: 03, Size: 26 K, Date: 2004-09-27

The Health Products and Food Branch (HPFB) posts on the Health Canada web site safety alerts, public health advisories, press releases and other notices as a service to health professionals, consumers, and other interested parties. These advisories may be prepared with Directorates in the HPFB which includes pre-market and post-market areas as well as market authorization holders and other stakeholders. Although the HPFB grants market authorizations or licenses for therapeutic products, we do not endorse either the product or the company. Any questions regarding product information should be discussed with your health professional.

This is duplicated text of a letter from GlaxoSmithKline Inc..
Contact the company for a copy of any references, attachments or enclosures.

Health Canada Endorsed Important Safety Information on
LAMICTAL (lamotrigine)
September 2004

Subject: Important new safety information concerning the antiepileptic, LAMICTAL (lamotrigine).

Dear Healthcare Professional,

GlaxoSmithKline Inc. (GSK), following discussions with Health Canada, would like to inform you of important new safety information concerning the antiepileptic, LAMICTAL® (lamotrigine).

• A recently completed clinical pharmacology study has demonstrated that concomitant use of hormonal contraceptives with Lamictal may significantly decrease serum lamotrigine levels. There have also been a limited number of post-marketing reports of break-through seizures occurring with the concomitant use of Lamictal and hormonal preparations. Significant adjustments in the maintenance dose of Lamictal may be required in some patients
• Patients should be advised not to start or stop their oral contraceptives without consulting their physician.
• In the same study, Lamictal had a modest effect on levonorgestrel plasma concentrations and a minimal effect on ethinylestradiol concentrations. However, a limited number of reports have been received of unexpected pregnancies and of menstrual bleeding disorders (e.g. breakthrough bleeding) occurring with the concomitant use of Lamictal and hormonal preparations. Women should be advised to promptly notify their physician if they experience changes in menstrual pattern (e.g., break-through bleeding) while receiving Lamictal in combination with these medications.
• The effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been evaluated, although the effect may be similar to oral contraceptive preparations, and as such, dosage adjustments may be necessary. [/list:u]A recently completed clinical pharmacology study, in healthy human volunteers, investigating the interaction between lamotrigine 300 mg once daily and an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel has documented that:
  • An oral contraceptive preparation administered in combination with lamotrigine significantly decreased serum levels of lamotrigine (on average, 52% decrease in AUC and 39% decrease in Cmax)
  • During the “pill-free” week of the oral contraceptive there was a gradual increase in trough lamotrigine serum concentrations, by approximately two fold by the end of the “pill-free” week.
  • Lamotrigine had a modest effect on levonorgestrel plasma concentrations (on average, 19% decrease in AUC and 12% decrease in Cmax). The effect on ethinylestradiol concentrations was minimal.
  • An increase in serum FSH and LH concentrations and a marginal increase in serum estradiol concentrations were observed during the period of co-administration of the oral contraceptive and lamotrigine
  • There was no hormonal evidence of ovulation as evidenced by progesterone serum concentrations.
  • GlaxoSmithKline has received a limited number of reports of break-through seizures, unexpected pregnancies and of menstrual bleeding disorders (e.g. breakthrough bleeding) occurring with the concomitant use of Lamictal and hormonal preparations. [/list:u]The CLINICAL PHARMACOLOGY, PRECAUTIONS, DOSAGE AND ADMINSTRATION, and the INFORMATION FOR CONSUMER sections of the Product Monograph will be revised to reflect the results of this study. A summary of the major changes are outlined below.
    • The Clinical Pharmacology and Precaution sections will be revised to include the drug interactions noted above.
    • The DOSAGE AND ADMINISTRATION section will be revised to reflect the following recommendations for the use of Lamictal in women taking oral contraceptives:
      • Starting Lamictal in Women Taking Oral Contraceptives. No change to the recommended titration guidelines for Lamictal should be necessary based solely on the use of oral contraceptives. Please refer to the Lamictal Product Monograph for recommended guidelines for initiating therapy with Lamictal.
      • Adjustments to the Maintenance Dose of Lamictal
        • Taking or Starting Oral Contraceptives: The maintenance dose of Lamictal may need to be increased by as much as two-fold in women starting or currently taking oral contraceptives and who are not also taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.
        • Stopping Oral Contraceptives: The maintenance dose of Lamictal may need to be decreased by as much as 50% below the maintenance dose if oral contraceptives are stopped in patients who are not also taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.
        • Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: Although not formally evaluated, similar adjustments may be needed for women receiving Lamictal in combination with other hormonal contraceptive preparations or hormone replacement therapy.[/list:u][/list:u]
        • The CONSUMER INFORMATION section will be revised to include the following:
          • Women should be advised to notify their physician if they plan to start or stop use of oral contraceptives or other hormonal preparations. They should also be advised to promptly notify their physician if they experience changes in menstrual pattern (e.g., break-through bleeding) while receiving Lamictal in combination with these medications. [/list:u][/list:u]GSK continues to work closely with Health Canada to monitor adverse event reporting and to ensure that up-to-date information regarding the use of lamotrigine is available.
            
            Sincerely,
            
            original signed by
            
            Ravinder Kumar, Ph.D.
            Vice-President, Regulatory Affairs & Pharmaceutical Development
            GlaxoSmithKline Inc.