Strong Safety Signal Seen for New Varenicline Risks

EXECUTIVE SUMMARY

A strong signal of multiple safety problems with Chantix (varenicline), a drug to help people stop smoking, has been seen in a pilot program to identify new drug risks in adverse drug events reported to the U.S. Food and Drug Administration.

Varenicline is suspected in various adverse drug event reports of causing a wide spectrum of injuries, including serious accidents and falls, potentially lethal cardiac rhythm disturbances, severe skin reactions, acute myocardial infarction, seizures, diabetes, psychosis, aggression and suicide. The cases were analyzed and classified using computerized excerpts of adverse event reports which the FDA publishes for research use.

The FDA approved varenicline in May 2006 after granting it a priority review. Varenicline is a partial agonist of one of the nicotinic acetylcholine receptors in the brain and nervous system,¹ and currently the only marketed and approved drug with this mechanism of action.

In the 4^th quarter of 2007 varenicline accounted for 988 serious injuries in the U.S. reported to the FDA, more than any other individual drug in this time period. By comparison the FDA received a median of 5 reports of serious injury for 769 different drugs in the 4^th quarter. Only 35 drugs accounted for 100 or more reports. This large volume of reports prompted us to conduct an analysis of all adverse events for varenicline since marketing approval in 2006.

The FDA has recently issued a Public Health Advisory about one of the most marked adverse effects of varenicline, psychiatric symptoms that included “changes in behavior, agitation, suicidal ideation, attempted and completed suicide.” ² However, the FDA alert provided no information about the numbers of reported neuropsychiatric events among treated smokers.

From May 2006 through December 2007, the FDA had received 227 domestic reports of suicidal acts, thoughts or behaviors, 397 cases of possible psychosis and 525 reports of hostility or aggression. These totals included 28 cases of suicide and 41 mentions of homicidal ideation, 60 cases of paranoia and 55 cases of hallucination. The categories were not mutually exclusive.

However, the adverse drug event reports for varenicline describe other kinds of serious harm for which no warnings now exist, either from the FDA or from the manufacturer, Pfizer Inc. The cases (including those with psychiatric effects) were classified using standardized medical queries developed by the pharmaceutical industry to identify potential adverse events in clinical studies and postmarket surveillance. Adverse event reports in themselves do not establish a causal link to the drug, only that an observer suspected a relationship. Depending on the features of the specific event, it could be counted in multiple categories, and classifications are not definitive. Among the most prominent were:

· Accidents and injuries. A total of 173 serious events described accidental injury, including 28 road traffic accidents and 77 falls, some leading to fractures of rib, facial bones, hand, ankle, spine, and lower limbs. In these cases a variety of potential causes were identified, including loss of consciousness, mental confusion, dizziness and muscle spasms.

· Vision disturbance. At least 148 reports contained medical terms indicating vision disturbances, including 68 cases described as blurred vision and 26 terms indicating transient or other forms of blindness. This reported effect could also describe a mechanism that could or did contribute to accidents and injuries.

· Heart rhythm disturbances. The FDA received 224 domestic reports classified as potential cardiac rhythm disturbances. This category, however, was dominated by reports of sudden loss of consciousness, an event that could also have non-cardiac causes. However, this category also included smaller numbers of cardiac arrests and identifiable abnormal cardiac rhythms

· Seizures and abnormal muscle spasms or movements. Serious reported events included 86 cases of convulsions (seizures), 372 reports of a wide variety of movement disorders, including tremors, muscle spasms, twitching, tics, drooling, and motor hyperactivity. The extent to which these problems resolved with a reduced dose or by halting treatment could not be determined from these data.

· Moderate and severe skin reactions. Reported serious events included 338 cases of hives or swelling of the tongue, face, eyes, lips or other areas. In addition, 65 cases were classified as severe and included blisters, exfoliation of the skin and lips, and Stevens-Johnson Syndrome.

· Diabetes. The FDA has received 544 reports suggesting varenicline may be related to a loss of glycemic control. This category included many cases of weight loss or gain that could have alternative causes, but also identified numerous cases of symptoms and laboratory tests consistent with new onset diabetes.

Recommendations

We have immediate safety concerns about the use of varenicline among persons operating aircraft, trains, buses and other vehicles, or in other settings where a lapse in alertness or motor control could lead to massive, serious injury. Other examples include persons operating nuclear power reactors, high-rise construction cranes or life-sustaining medical devices. Based on reports of sudden loss of consciousness, seizures, muscle spasms, vision disturbances, hallucinations, paranoia and psychosis, we believe varenicline may not be safe to use in these settings. The extent to which varenicline has already contributed to accidental death and injury has not yet been investigated because these adverse effects had not been previously reported. The Federal Aviation Administration approved varenicline for use by airline pilots³ before most of these reports were available.

In addition, we recommend that patients and doctors exercise caution in the use of varenicline and consider the use of alternative approaches to smoking cessation.

Finally, we urge the FDA and the manufacturer to provide warnings to doctors and patients for those adverse effects that can be adequately documented through existing data, and to undertake on a priority basis epidemiological studies or other research to assess other potential risks. We promptly notified the FDA of our findings.

This report was written by:

Thomas J. Moore, Senior Scientist, Drug Safety and Policy, ISMP

Michael R. Cohen RPh, MS, ScD, President, ISMP

Curt D. Furberg, MD, PhD, Professor of Public Health Sciences, Wake Forest University School of Medicine.

Institute for Safe Medication Practices

200 Lakeside Drive, Suite 200

Horsham, PA 19044

215-947-7797

www.ismp.org

Corresponding Author

Thomas J. Moore

tmoore@ismp.org

Full Report

BACKGROUND

Varenicline was approved as an aid to smoking cessation treatment, joining nicotine replacement products and the antidepressant drug buproprion, marketed as Zyban, for this medical use. Varenicline, however, was reported to achieve its effect through a novel mechanism of action, through partially blocking and partially stimulating a type of nicotinic acetylcholine receptor. It was derived from cytisine, an antismoking drug used in Europe for many years.⁴^{, 5} Acetylcholine receptors play numerous roles in the brain and body and are central to muscle contractions—both voluntary movement and the heart muscle contractions as well as the tone of the smooth muscles that line the blood vessels.

Pfizer research scientists who developed the drug focused on a particular role played by one of the subtypes of receptor, the α₄β₂. Varenicline was most active against this subtype and specifically these receptors increase the release of dopamine in the brain.⁵ Dopamine, in turn, plays a major role in addiction, mood, and muscle movement. Many antipsychotic drugs block dopamine receptors, but they also cause movement disorders. The loss of muscle control seen in Parkinson’s disease is the result of the destruction of dopamine-producing cells in the brain. Pfizer scientists theorized that the mixture of blocking and stimulating nicotinic acetylcholine receptors would replace some of the pleasure of smoking through stimulating dopamine release, and block or reduce the effects of nicotine when present.

In clinical studies, varenicline produced 52-week quit rates of approximately 22 percent. ^6-9 Similar quit rates have been observed in nicotine gum, ¹⁰^{, 11} although Pfizer has claimed an advantage over the nicotine patch in a comparative study it conducted.⁶ However, the varenicline results may not be achieved in clinical practice because the initial 12-week treatment program included weekly clinic visits with counseling. More importantly, both the benefits and the safety profile of varenicline were likely influenced by the type and number of patients excluded from the Phase 3 trials. For example, the longest varenicline safety and efficacy trial excluded patients with the following:¹²

· Recently treated for depression, bipolar disorder, psychosis or panic disorder.

· Experienced clinically significant allergic reactions to any drug.

· Had any abnormal laboratory findings.

· Cardiovascular disease within six months

· Were using over-the-counter or prescribed stimulants or diet pills

· Had a history of drug or alcohol abuse or dependence

The trials also prohibited concomitant use of other psychologically active drugs, including stimulants, antidepressants, tranquilizers, antipsychotics, mood stabilizers, naltrexone and anticonvulsants.

Varenicline was approved first in the United States in May of 2006, and then later in the year in Europe. The manufacturer reported that 5 million persons worldwide had taken varenicline; we estimate this includes approximately 3.5 million persons in the United States.¹³

Why this study was conducted

The signal for varenicline was observed in an Institute for Safe Medication Practices (ISMP) pilot program to identify emerging drug risks and new medication errors through monitoring FDA adverse event reports on a quarterly basis. The agency publishes computer excerpts of adverse events from which all identifiable personal information has been removed. The report narrative is replaced by a series of medical terms that describe the event that has occurred.

Adverse event reporting is voluntary for consumers and health professionals. However, manufacturers are required to investigate and report all adverse events of which they happen to learn. The reporting rate is unknown, variable and poorly studied. Crude published estimates suggest that from 1% to 10% of serious adverse events are reported. We maintain a copy of all adverse events reported to the FDA--which is thought to be one of the largest drug safety databases in the world.

Two analytical approaches have traditionally dominated the use of these adverse event data. One technique, called a case series, is to analyze a group of carefully selected, uncomplicated reports. The FDA itself analyzes its adverse event data on a case-by-case basis. A second approach, called data mining, searches for signals through unexpected connections between drugs and event characteristics.

The signal for varenicline, however, was identified using a third approach, which was to monitor the flow of quarterly reports in order to detect changes in the numbers of serious events and other trends.

Varenicline crossed a first signal threshold in the 4^th quarter of 2006 when it appeared for the first time among a small group of drugs that accounted for 100 or more reports of serious injury in a calendar quarter. By the 2d quarter of 2007 it ranked 3d among all drugs in the United States.

By the 3rd quarter of 2007 varenicline produced a signal not previously seen for any other drug. It produced more serious reports than any other drug for multiple types of events: more potential cases of angioedema, cardiac arrhythmia, diabetes and severe cutaneous injury. By the 4^th quarter of 2007 varenicline accounted for more reports of serious drug adverse events in the United States than any other drug. (Table 1)

Table1. Leading Suspect Drugs 2007/Q4*
Drug	Cases
Varenicline	988
Interferon Beta	640
Etanercept	555
Infliximab	554
Fentanyl	404
Oxycodone	372
*Principal suspect drug/US only/serious

The cases selected for this analysis are shown in Table 2 and consist of all U.S. reports of serious injury since the drug was approved. These are the same criteria used in the quarterly monitoring program except that whenever updated or revised reports were found, the latest version was used. These criteria omit two important groups of reports that could contribute substantially to understanding the safety profile of the drug. We excluded 1608 foreign reports because monitoring focuses on risks to patients in the United States . We excluded 473 direct reports to the FDA which had ambiguous coding for the severity of the reaction. “Other serious” could not be distinguished in these data from “other than serious.”

Table 2. Case Selection
	Number	Pct
All Reports	6363	100%
Exclusions*
Prior reports	1509	23.7%
Foreign	1608	25.3%
Not serious	473	7.4%
Not principal suspect	415	6.5%

Cases selected	3063	48.1%
*Report could be excluded for more than 1 reason

RESULTS

Table 3 describes the 3063 reports included in this analysis. The FDA defines a serious adverse event as one that results in death, disability, a birth defect, hospitalization (initial or prolonged), is life threatening or requires intervention to prevent harm. The agency also allows an “other serious” category that might include events such as skin cancer or cardiac rhythm disturbances that did not result in hospitalization.

The patients characteristics show those experiencing serious injury were predominantly female (69%) and median age was 50. Compared to our previously published assessment of all reports to the agency over an 8-year period, the varenicline reports have a greater share of reports from females (69% vs 55%), from consumers (57.3% vs 25.9%), and a substantially lower proportion of reported deaths (2.5% vs 17% ).Varenicline also had a smaller proportion of reports submitted directly to the FDA (8% vs 19%) probably because of problems with the classification of “other serious” adverse events.

Table 3. Reports Overview
n = 3063
Report Type	Number	Pct
Direct to FDA	246	8.0%
Mfr-Expedited	2817	92.0%
Mfr-Periodic	0	0.0%

Report Source
Consumer	1755	57.3%
Health Professional	1045	34.1%
Lawyer	2	0.1%
None Stated	261	8.5%

Outcome Group
Death	78	2.5%
Disability	64	2.1%
Serious	2921	95.4%

Patient Population
Median age	50
Percent female	69%

To evaluate types of reactions we used Standardized Medical Queries (SMQ) developed by the pharmaceutical industry to identify types of adverse reactions in clinical trials and postmarketing adverse event reports. ¹⁵ The SMQs were developed with explicit medical criteria and subject to validation testing. However, these selection criteria do not provide definitive assessments but rather are intended to identify potential cases for additional review. To identify vision disturbances, we used a similar but slightly different kind of category called a High Level Group Term (HLGT) which is used to group similar medical terms in various body systems. ¹⁶

In Table 4 we provide event counts for selected SMQs that were chosen for biological plausibility, association with other drug therapy, appropriately specific criteria, and substantial numbers of cases. Because the individual SMQs varied in specificity and suitability we evaluate the strengths and weaknesses of individual SMQs shown in the discussion section.

Table 4. Selected Adverse Event Types*	Cases
Accidents and injuries	173
Angioedema	338
Cardiac arrhythmias	224
Convulsions	86
Embolic and thrombotic events	139
Extrapyramidal syndrome	372
Hyperglycemia/new onset diabetes mellitus	544
Hostility/aggression	525
Psychosis and psychotic disorders