Update on varenicline (Champix®) and neuropsychiatric events

HSA would like to update healthcare professionals on the local adverse drug reaction (ADR) reports and recent international developments related to varenicline (Champix®) that have taken place since our last report¹ on this issue in July 2008.

Varenicline (Champix®, Pfizer), a partial nicotinic acetylcholine receptor agonist, is licensed as an aid to smoking cessation treatment and was registered in Singapore in August 2007.

Regulatory updates from international agencies

(A) US Food and Drug Administration (FDA)

The US FDA had in July 2009, approved safety labeling revisions submitted by Pfizer Inc. which included a black-box warning regarding the risk for serious neuropsychiatric (NP) events.² This was following post-marketing reports of NP events such as psychosis, hallucinations, paranoia, delusions, hostility, agitation, suicidal ideation, suicide attempt and completed suicide in patients with and without pre-existing psychiatric disease.

While some NP symptoms may have occurred in association with nicotine withdrawal, it was also noted that there were cases reported in patients who had not yet discontinued smoking. The majority of cases occurred during treatment, but some were also reported after withdrawal of varenicline therapy.

FDA recommended that healthcare professionals advise patients to stop taking varenicline and contact a healthcare provider immediately if they experience agitation, depressed mood, and any changes in behavior that are not typical of nicotine withdrawal, or if they experience suicidal thoughts or behavior. Patients and their families/caregivers should also be alerted to the potential for changes in mood or behaviour during varenicline treatment and report any observed changes to their healthcare provider.

The FDA had also included label warnings on motor vehicle crashes, near-miss accidents and other unintentional injuries occurring in patients taking varenicline. Some of these cases reported somnolence, dizziness and loss of consciousness, or difficulty concentrating. On this basis, patients were advised to be cautious when driving and engaging in potentially hazardous activities until they know how varenicline will affect them.³

(B) Australia Therapeutic Goods Administration (TGA)

As of May 2010, the TGA had received 1,025 reports of suspected adverse reactions to varenicline of which 691 (67%) reported psychiatric symptoms such as depression, agitation, anxiety, altered mood and aggression. 206 cases of suicide-related events and 15 completed suicides in people taking varenicline were also reported to the TGA. The TGA has also urged healthcare professionals to discuss the possibility of these events with their patients and their families.⁴

(C) Health Canada (HC)

Health Canada informed healthcare professionals on 31 May 2010 that it had received serious NP reports such as depressed mood, agitation, aggression, hostility, changes in behaviour, suicide related events and worsening of pre-existing psychiatric disorder in patients treated with varenicline. These events were reported in patients with and without pre-existing psychiatric disorder. Some reported cases were confounded by symptoms of nicotine withdrawal. Alcohol intake was also observed to increase the risk of patients experiencing psychiatric adverse events during treatment with varenicline. HC advised patients taking varenicline to stop treatment and contact their healthcare provider immediately if such NP symptoms were observed.⁵

Reports from literature

1) Cohort study on varenicline and suicidal behaviour

In 2009, Gunnell et al. published their findings from a cohort study nested within the General Practice Research Database of UK in the British Medical Journal.6 The objective of the study was to determine whether varenicline was associated with an increased risk of suicide and suicidal behaviour compared to bupropion and nicotine replacement therapy (NRT).

A total of 80,660 men and women aged 18-95 years were prescribed a smoking cessation product between 1 September 2006 and 31 May 2008 and were followed up for primary outcomes such as fatal and non-fatal harm, as well as secondary outcomes such as suicidal thoughts and depression.

The results showed that there was no clear evidence that varenicline was associated with an increased risk of fatal or non-fatal self-harm. Compared with NRT, the hazard ratio for self harm among patients prescribed varenicline was 1.12 (95% CI: 0.67 - 1.88).

2) Case series of reports of thoughts and acts of aggression or violence toward others

Moore et al. published in the September 2010 issue of The Annals of Pharmacotherapy a case series of reports of thoughts and acts of aggression or violence towards others related to use of varenicline.7 The authors obtained 78 adverse event reports from the FDA MedWatch database, four reports from clinical trials and three others from published literature which contained medical terms describing possible acts or thoughts of aggression or violence.

The most frequent and common characteristics of the cases reviewed were: 1) an inexplicable and unprovoked event; 2) the victim of the aggression was anyone nearby; 3) there was no indication of a prior history of similar behaviour in the patient; 4) early onset of psychiatric adverse effects often before stopping smoking. In the 14 cases with dechallenge/rechallenge information, the psychiatric adverse effects resolved in 13 cases (93%) after discontinuation of varenicline.

On studying the characteristics of the reported events, the authors concluded that clear temporal relationship, lack of prior history to aggressive and violent behaviour, and unusual nature of these events strengthen the evidence that varenicline is associated with thoughts and acts of aggression or violence.

Local ADR reports

Since November 2008, the Vigilance Branch of HSA has received 13 ADR reports related to varenicline which have been assessed to be of probable or possible causality. Among these, there were two reports describing psychiatric effects such as mood swings, disconnected thoughts, abnormal dreams and depression. No reports of thoughts or acts of aggression or violence towards others were received. It is unknown if the patients were still smoking at the time the adverse reaction occurred.

Of note were three cases which described impaired judgement, impaired mental capability to drive or work and an inability to concentrate. One of these cases resulted in a non-fatal motor vehicle accident.

Other ADRs reported with varenicline included nausea, flu-like symptoms, somnolence, drowsiness, insomnia, loss of appetite, weakness, breathlessness, increased creatine phosphokinase and aggravation of skin allergy.

HSA's advisory

The local package insert of Champix® has been updated with warnings of NP reactions and suicidality. Healthcare professionals are reminded to inform their patients on the potential of occurrence of these NP symptoms, including violent and aggressive thoughts and to ask them to contact their doctor immediately should such symptoms occur. Additionally, in view of the cases of impaired judgement and impaired mental capability reported locally, patients prescribed varenicline should also be cautioned on driving, operating heavy machinery and engaging in potentially hazardous activities until they know how varenicline will affect them.

Healthcare professionals are encouraged to report adverse reactions suspected to be associated with varenicline to the Vigilance Branch. To aid in our assessment of the reports, healthcare professionals are urged to include relevant patient information such as concomitant psychotropic medicines, reactions to smoking cessation, history of mental illness, smoking, alcohol and substance use, suicidal ideation or suicide attempts or recent psychosocial stresses. These information will be useful in the causality assessment of these reports as the association of varenicline as NP symptoms may be confounded by factors such as the effects of nicotine withdrawal, the association of smoking and psychiatric conditions and the effects of smoking on the blood levels of some antipsychotics.

References

1. HSA ADR News bulletin July 2008; 10, No. 2

2. Information for Healthcare Professionals: Varencline (marketed as Chantix) and Bupropion ( marketed as Zyban, Wellbutrin and generics)
   http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm169986.htm ↗ (opens in new tab)

3. US Package Insert for Chantix® approved on 22 April 2010.
   http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021928s014s017lbl.pdf ↗ (opens in new tab)

4. TGA Medicines Safety Update No. 4; 2010

5. Health Canada Dear Healthcare Professional Letter on Champix®.
   http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2010/14595a-eng.php ↗ (opens in new tab)

6. BMJ 2009; 339:b3805

7. Ann Pharmacother 2010; 44:1389-1394