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New warnings regarding ALERTEC (modafinil) and serious rash, allergic reactions, and mental problems - For Health Professionals

Starting date:
December 18, 2007
Posting date:
December 21, 2007
Type of communication:
Dear Healthcare Professional Letter
Subcategory:
Drugs
Source of recall:
Health Canada
Audience:
Healthcare Professionals
Identification number:
RA-170001520

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

Notice about Health Canada advisories

Health Canada Endorsed Important Safety Information on ALERTEC (modafinil)

December 18, 2007

Dear Health Care Professional:

Subject: New warnings regarding ALERTEC®Footnote * (modafinil) and severe cutaneous adverse reactions, serious hypersensitivity reactions and psychiatric symptoms

Shire Canada Inc., in consultation with Health Canada, would like to inform you of new warnings concerning modafinil (Alertec®). The Product Monograph has been updated to include the following new warnings and important safety information:

  • Modafinil can cause life-threatening skin and other serious hypersensitivity reactions:
    • Severe cutaneous adverse reactions (SCARs), including Toxic Epidermal Necrolysis (TEN), Stevens-Johnson Syndrome (SJS), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), have occurred in adults and children using modafinil.
    • Angioedema, anaphylactic reaction, and multi-organ hypersensitivity reactions, including at least one fatality, have also been reported with the use of modafinil.
  • Modafinil is not approved for use in pediatric patients for any indication.
  • Modafinil can cause psychiatric symptoms.

Also:

  • It is recommended that modafinil not be used in patients with a history of left ventricular hypertrophy or in patients with clinically significant manifestations of mitral valve prolapse in association with central nervous system stimulant use.

Serious Rash, including Stevens Johnson Syndrome, and hypersensitivity reactions
Rare cases of TEN or SJS have been reported in adults and children who received modafinil treatment, including one non-fatal case in Canada. For modafinil, the post-market reporting rate of TEN and SJS exceeds the background incidence rate (1-2 cases per million person-years) in the general population. Reporting rates are generally accepted to be an underestimate due to under-reporting.

Although benign rashes also occur with modafinil, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, modafinil should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug-related.

Physicians should instruct their patients to immediately discontinue the use of modafinil and contact them if a rash or any signs or symptoms suggesting angioedema or anaphylaxis occurs.

Psychiatric Symptoms
Psychiatric adverse experiences have been reported in adult and pediatric patients treated with modafinil. Caution should be exercised when modafinil is given to patients with a history of psychosis, depression or mania. Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in patients treated with modafinil. If psychiatric symptoms develop, consider discontinuing modafinil.

Please refer to the attached Product Monograph Safety Revisions for complete revisions and updates.

Patients are being advised to stop taking modafinil and to seek medical attention without delay if they have any of the following: skin rash, hives, sores in the mouth, blisters and peeling skin; swelling of the face, eyes, lips, tongue or throat; trouble swallowing or breathing; hoarse voice, or if they experience mental problems. (See the Public Communication associated with this Letter).

Modafinil (Alertec®) is indicated for the symptomatic treatment of excessive sleepiness in patients with narcolepsy, obstructive sleep apnea/hypopnea syndrome and shift work sleep disorder.

Managing marketed health product-related adverse reactions depends on health care professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post-marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any case of serious rash, anaphylactic reaction, hypersensitivity reaction, psychiatric symptom or other serious or unexpected adverse reactions in patients receiving modafinil should be reported to Shire Canada Inc. or Health Canada at the following addresses:

Shire Canada Inc.
2250 Alfred-Nobel Blvd, Suite 500
Saint-Laurent, Quebec H4S 2C9
Tel: 1-800-268-2772
Fax: 514-787-2425

Any suspected adverse reaction can also be reported to:
Canada Vigilance Program
Marketed Health Products Directorate
HEALTH CANADA
Address Locator: 0701C
Ottawa, Ontario, K1A 0K9
Tel: 613-957-0337 or Fax: 613-957-0335
To report an Adverse Reaction, consumers and health professionals may call toll free: Tel: 866-234-2345 Fax: 866-678-6789
CanadaVigilance@hc-sc.gc.ca

The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.

For other inquiries related to this communication, please contact Health Canada at:
Marketed Health Products Directorate
E-mail: mhpd_dpsc@hc-sc.gc.ca
Tel: 613-954-6522
Fax: 613-952-7738

Should you have any questions regarding Alertec® or require a copy of the revised Alertec® Product Monograph, please contact Shire Canada's medical information department at 1-800-268-2772.

Sincerely,

original signed by

Louis Turcotte, B.Pharm., M.Sc.
Manager, Medical Communications
Shire Canada Inc.

*ALERTEC® (Trade-mark of Cephalon, Inc.)

[Text of letter ends]

ALERTEC®Footnote *
Product Monograph Safety Revisions - November 2007

INDICATIONS AND CLINICAL USE:
Pediatrics: Serious skin rashes, including erythema multiforme major (EMM) and Stevens-Johnson Syndrome (SJS) have been associated with modafinil use in pediatric patients.

CONTRAINDICATIONS:
Addition of patients who are hypersensitive to armodafinil (the R enantiomer of modafinil; not marketed in Canada).

WARNINGS AND PRECAUTIONS:
Serious Rash, including Stevens-Johnson Syndrome
Serious rash requiring hospitalization and discontinuation of treatment has been reported in adults and children in association with the use of modafinil.
Modafinil is not approved for use in pediatric patients for any indication.

In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil.

Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide post-marketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years.

There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil. Nearly all cases of serious rash associated with modafinil occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash.

Although benign rashes also occur with modafinil, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, modafinil should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.

Angioedema and Anaphylactoid Reactions
One serious case of angioedema and one case of hypersensitivity (with rash, dysphagia, and bronchospasm), were observed among 1,595 patients treated in clinical trials with armodafinil (not marketed in Canada), the R enantiomer of modafinil (which is the racemic mixture). No such cases were observed in modafinil clinical trials.

Angioedema and anaphylactic reaction have been reported in postmarketing experience with modafinil.

Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness).

Multi-organ Hypersensitivity Reactions
Multi-organ hypersensitivity reactions, including at least one fatality in post-marketing experience, have occurred in close temporal association (median time to detection 13 days: range 4-33) to the initiation of modafinil.

Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions associated with modafinil. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur.

If a multi-organ hypersensitivity reaction is suspected, Alertec® should be discontinued.

Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.

Psychiatric Symptoms
Psychiatric adverse experiences have been reported in patients treated with Alertec®. There have been reports of psychotic episodes associated with Alertec® use. Postmarketing adverse events associated with the use of modafinil have included mania, delusions, hallucinations, and suicidal ideation, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history.

In the adult modafinil controlled trials database, psychiatric symptoms resulting in treatment discontinuation (at a frequency >0.3%) and reported more often in patients treated with modafinil compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (<1%), confusion (<1%), agitation (<1%) and depression (<1%). Caution should be exercised when Alertec® is given to patients with a history of psychosis, depression, or mania.

Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in patients treated with Alertec®. If psychiatric symptoms develop in association with Alertec®administration, consider discontinuing Alertec®.

In controlled clinical trials of pediatric patients with ADHD, adverse events categorized as signs and symptoms of psychosis or mania and/or suicidal ideation were reported in <1% of patients treated with modafinil and no patients treated with placebo. Aggression and violent behavior were reported in 1% of modafinil-treated patients and no placebo-treated patients in controlled clinical trials of pediatric patients with narcolepsy or OSAHS. There were no reports of psychosis or mania and/or suicidal ideation in clinical trials with this pediatric population.

Normal Fatigue States
Alertec® should not be used for the treatment of normal fatigue states. One preliminary study in sleep-deprived subjects, employing a between-subject design (n=42) and a single dose (300mg), suggests that Alertec® causes an increased self-estimate of performance which is not commensurate with actual changes in performance (i.e., overconfidence). A subsequent study in sleep-deprived subjects, employing a within-subject design (n=6), using 100 mg administered three times over a period of 24 hours failed to demonstrate an adverse effect on the ability to judge one's own cognitive capabilities.

Additions to Cardiovascular
It is recommended that Alertec® not be used in patients with a history of left ventricular hypertrophy or in patients with ischemic ECG changes, chest pain, arrhythmia, or other clinically significant manifestations of mitral valve prolapse in association with CNS stimulant use. Such signs may include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these symptoms occurs, consider cardiac evaluation.

Blood pressure monitoring in short-term (<3 months) controlled trials showed no clinically significant changes in mean systolic and diastolic blood pressure in patients receiving Alertec® compared to placebo. However, a retrospective analysis of the use of antihypertensive medication in these studies showed that a greater proportion of patients on Alertec® required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential was slightly larger when only studies on OSAHS were included, with 3.4% of patients on Alertec® and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication. Increased monitoring of blood pressure may be appropriate in patients on Alertec®.

Patients Using Cyclosporine (moved from DRUG INTERACTIONS)
The blood levels of cyclosporine may be reduced when used with Alertec®. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when these drugs are used concomitantly.

Additions to Renal
There is inadequate information to determine the safety and efficacy of dosing in patients with severe renal impairment.

ADVERSE REACTIONS
Additions to Post-Market Adverse Drug Reactions
Anaphylactic reactions, erythema multiforme, Stevens-Johnson syndrome, Drug Rash with Eosinophilia and Systemic Symptoms and toxic epidermal necrolysis.

DOSAGE AND ADMINISTRATION
Dosing Considerations (moved from other Sections)
The safety and efficacy of modafinil in children under the age of 18 has not been established. Therefore, modafinil is not indicated for use in pediatric patients (see INDICATIONS AND CLINICAL USE - Pediatrics;
WARNINGS AND PRECAUTIONS - Serious Rash).

Dosage adjustment should be considered for concomitant medications that are substrates for CYP3A4, such as triazolam and cyclosporine.

Drugs that are largely eliminated by CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with Alertec® and may require dosage reduction and monitoring for toxicity.

AND RELATED CHANGES TO THE CONSUMER INFORMATION SECTION.

Footnotes

Footnote *

ALERTEC® (Trade-mark of Cephalon, Inc.)

Return to footnote * referrer