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New FDA labelling for Xyrem warns of depression

Posted by jrbecker on February 23, 2006, at 11:11:44

FDA Safety Changes: Xyrem and NovoSeven CME/CE

News Author: Yael Waknine

Release Date: February 22, 2006;

Feb. 22, 2006 The U.S. Food and Drug Administration (FDA) has approved safety labeling revisions to advise of the risks for depression, confusion, and other neuropsychiatric adverse events in patients treated with sodium oxybate oral solution; and postmarketing adverse events and the potential risk for thrombotic events in patients receiving coagulation factor VIIa injection.

Sodium Oxybate (Xyrem) Linked to Risks for Depression and Confusion
On November 18, 2005, the FDA approved safety labeling revisions for sodium oxybate (Xyrem oral solution, made by Orphan Medical, Inc) to warn of the risk for depression, confusion, and other neuropsychiatric adverse events associated with its use.

In clinical trials, 3.2% of patients receiving sodium oxybate reported depressive symptoms. Although most cases required no changes in treatment, 4 patients (<1%) discontinued therapy as a result of these symptoms.

In the placebo-controlled clinical trial of sodium oxybate at fixed nightly doses of 3, 6, and 9 g, one case of depression was reported at the 3-mg dose. In another trial of the drug uptitrated from a 4.5-g nightly dose, the incidence of depression was 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2 (3.6%) for the placebo and 4.5-, 6-, and 9-mg doses, respectively.

During clinical trials, 2 suicides and 1 attempted suicide were reported in patients with a previous history of depressive disorder. In one suicide, sodium oxybate was used in conjunction with other drugs; the other suicide occurred in a patient not receiving the medication. Sodium oxybate was the only drug involved in the attempted suicide.

The FDA notes that the emergence of depression in patients treated with sodium oxybate requires careful and immediate evaluation. Patients with a prior history of depressive illness and/or suicide attempt should be monitored carefully for the emergence of depressive symptoms during treatment.

The overall rate of confusion was 2.6% in patients treated with sodium oxybate at doses from 6 to 9 g per night during clinical trials. Data from the fixed-dose study revealed a dose-response relationship for confusion, with 17% of patients at 9 g per night reporting the condition. In this trial, all cases resolved soon after termination of therapy.

In the majority of cases across all clinical trials, confusion resolved soon after discontinuation of treatment or with continued therapy. The FDA advises that all patients who become confused during treatment be evaluated fully to determine the need for intervention.

Other reported neuropsychiatric events in sodium oxybate-treated patients included psychosis, paranoia, hallucinations, and agitation. The FDA recommends careful and immediate evaluation of emerging thought disorders and/or behavioral abnormalities in patients receiving sodium oxybate.

Sodium oxybate is indicated for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy.

It is available only through the Xyrem Success Program, which requires enrollment of prescribers and patients in a registry and confirmation that both have been educated regarding the risks and proper use of the medication. All prescribing forms and documents verifying education must be sent to a centralized pharmacy prior to shipping of sodium oxybate to the patient.

Prescribing forms and educational materials may be obtained by contacting the pharmacy at 1-866-XYREM88 (1-866-997-3688). Follow-up visits at 3-month intervals are recommended and healthcare professionals are expected to report all serious adverse events to the manufacturer.

Coagulation Factor VIIa Injection (NovoSeven) May Be Linked to Thrombotic Adverse Events
The FDA approved in November 2005 revisions to the safety labeling for recombinant coagulation factor VIIa intravenous injection (NovoSeven, made by Novo Nordisk) to advise of postmarketing adverse events and to warn of the potential risk for thrombotic adverse events associated with its use.

Postmarketing adverse events related to use of factor VIIa for labeled and nonlabeled indications have included high D-dimer levels and consumptive coagulopathy and isolated cases of anaphylactic and other hypersensitivity reactions. Thromboembolic events, such as myocardial infarction, myocardial ischemia, cerebral infarction and/or ischemia, thrombophlebitis, arterial thrombosis, and deep vein thrombosis and related pulmonary embolism, have also been reported.

The FDA notes that evaluation and interpretation of these events is confounded by underlying diagnoses, concomitant medications, preexisting conditions, and the limitations inherent in passive surveillance. Because postmarketing reports are derived from a population of uncertain size on a voluntary basis, their frequency and the causal role of factor VIIa remain unclear.

While the risk for arterial and venous thromboembolic adverse events after treatment with the product in patients with hemophilia and inhibitors is unknown, it is considered to be low.

Patients with disseminated intravascular coagulation, advanced atherosclerotic disease, crush injury, septicemia, or those receiving concomitant treatment with activated-nonactivated prothrombin complex concentrates may be at increased risk of developing thrombotic events due to circulating tissue factor or predisposing coagulopathy.

Although the extent of the risk for thrombotic adverse events associated with use of the product in patients without hemophilia is also unknown, data from a clinical study has indicated a potential increased risk for arterial thromboembolic events, including myocardial ischemia, myocardial infarction, cerebral ischemia, and/or infarction.

Coagulation factor VIIa [recombinant] intravenous injection is indicated for the prevention and treatment of bleeding episodes during surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to factor VIII or factor IX. It is also indicated for the treatment of bleeding episodes in patients with congenital factor VII deficiency.


Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
Evaluate the risk for neuropsychiatric adverse events in patients receiving therapy with sodium oxybate.
Describe the risk management program for sodium oxybate.
Identify the risk for thrombotic events associated with use of factor VIIa in patients with and without hemophilia.
Pearls for Practice
Sodium oxybate is linked to risks for depression, confusion, and other neuropsychiatric events. Depression was reported in 3.2% of sodium oxybate-treated patients, and patients with a prior history of depression and/or suicide attempt should be monitored carefully. Confusion was dose-related and occurred in 2.6% of patients overall; most cases resolved with continuation or termination of therapy.
Sodium oxybate is only available through the Xyrem Success Program, which requires clinician and patient registration and education regarding risks and proper use of the drug. Prescriptions are filled and shipped to the patient from a centralized pharmacy. Follow-ups are recommended at 3-month intervals, and all serious adverse events should be reported to the manufacturer.
The risk for thrombotic events after use of factor VIIa in patients with hemophilia and inhibitors is unknown but considered to be low. Data from a clinical study indicate a potential increased risk for arterial thrombotic events in patients without hemophilia receiving the product.
Instructions for Participation and Credit
There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page.

Read the target audience, learning objectives, and author disclosures.
Study the educational content online or printed out.
Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. Medscape encourages you to complete the Activity Evaluation to provide feedback for future programming.
You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 5 years; at any point within this time period you can print out the tally as well as the certificates by accessing "Edit Your Profile" at the top of your Medscape homepage.

*The credit that you receive is based on your user profile.
Target Audience
This article is intended for primary care clinicians, surgeons, cardiologists, psychiatrists, and other specialists who care for narcoleptic patients with excessive daytime sleepiness and cataplexy, patients with hemophilia A or B undergoing surgical interventions or invasive procedures, and patients with congenital factor VII deficiency.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Accreditation Statements

For Physicians

Medscape is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Medscape designates this educational activity for 0.25 Category 1 credit(s) toward the AMA Physician's Recognition Award. Each physician should claim only those credits that reflect the time he/she actually spent in the activity.

Medscape Medical News (MMN) has been reviewed and is acceptable for up to 150 Prescribed credits by the American Academy of Family Physicians. AAFP accreditation begins 09/01/05. Term of approval is for 1 year from this date. This component is approved for 0.25 Prescribed credit. Credit may be claimed for 1 year from the date of this issue.

Contact This Provider

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity: For technical assistance, contact

For Nurses

This Activity is sponsored by Medscape Continuing Education Provider Unit, which has been approved as a provider of continuing education by the New York State Nurses Association, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation.

Approved for 0.3 contact hour(s) of continuing education for RNs, LPNs, LVNs and NPs; 0.3 credits are in the area of pharmacology.

Provider Number: 6FDKKC-PRV-05


Authors and Disclosures

As an organization accredited by the ACCME, Medscape requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

News Author
Yael Waknine
is a freelance writer for Medscape.

Disclosure: Yael Waknine has disclosed no relevant financial relationships.

Clinical Reviewer
Gary Vogin, MD
Senior Medical Editor, Medscape

Disclosure: Gary Vogin, MD, has disclosed no relevant financial relationships.

CME Author
Yael Waknine
is a freelance writer for Medscape.

Disclosure: Yael Waknine has disclosed no relevant financial relationships.




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