Varenicline is a nicotinic acetylcholine receptor agonist, and is available as an intranasal spray and oral tablet. The intranasal spray is FDA-approved for the treatment of signs and symptoms associated with dry eye disease. The oral tablet is used to aid in smoking cessation. For smoking cessation, varenicline is effective because it provides some nicotine effects to help with nicotine withdrawal symptoms while also blocking the effects of nicotine if the user were to relapse. Most other smoking cessation therapies either try to replace nicotine or mimic the effects of nicotine by inhibiting dopamine reuptake. Varenicline was evaluated in 3,659 chronic smokers (about 21 cigarettes per day for 25 years) in 6 premarketing clinical trials. In 5 of the clinical trials, patients treated with varenicline were more successful than those receiving placebo. In 2 of the 5 studies, varenicline-treated patients were more successful than patients treated with bupropion; nausea was a frequent side effect during treatment. In a large placebo-controlled study evaluating subjects who were not able or willing to quit smoking within 4 weeks, but were willing to gradually reduce their smoking over 12 weeks before quitting, a 50% reduction in the number of cigarettes smoked occurred in varenicline treated patients. After 24 weeks of treatment followed by post-treatment assessments through week 52, subjects in the varenicline group had a significantly higher Continuous Abstinence Rate (CAR) compared with those receiving placebo at weeks 15 through 24 and weeks 15 through 52. In a study evaluating the safety and efficacy of varenicline in 460 patients with mild to moderate chronic obstructive pulmonary disease (COPD), varenicline was more effective than placebo in helping patients quit smoking and remain abstinent for as long as 1 year. Varenicline is essentially unmetabolized and has no clinically significant metabolic drug interactions. However, behavioral changes and neuropsychiatric events may occur in some patients.
NOTE: Globally, as well as in the U.S., all lots of oral varenicline (Chantix) have been recalled from the market because they contain unacceptable levels of a nitrosamine, N-nitroso-varenicline, at or above the FDA interim acceptable intake limit. Long-term ingestion of N-nitroso-varenicline may be associated with a theoretical potential increased cancer risk in humans, but there is no immediate risk to patients taking this medication. The health benefits of stopping smoking outweigh the theoretical potential cancer risk from the nitrosamine impurity in varenicline. Nitrosamines are common in water and foods, including cured and grilled meats, dairy products and vegetables. Everyone is exposed to some level of nitrosamines. These impurities may increase the risk of cancer if people are exposed to them above acceptable levels over long periods of time. Patients currently taking Chantix should consult with their health care provider to discuss if alternative treatment options are available. Patients should contact Stericycle Inc. for information about product returns. Health care providers can contact Pfizer for more information.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Administer tablets after eating with a full glass of water.
Intranasal Inhalation Administration
-Each carton contains 2 glass nasal spray bottles. Each nasal spray bottle provides enough medication to deliver 1 spray in each nostril twice daily for 15 days. DO NOT open the second bottle until the contents of the first bottle have been exhausted.
-DO NOT shake the nasal spray bottles.
-Before the initial use, prime the pump by spraying 7 actuations into the air away from the face. If not used for more than 5 days, the pump must be re-primed with 1 spray into the air. Avoid priming the pump more than needed.
-To administer the spray:
--If needed, blow nose to clear the nostrils.
-Remove the cap and clip. Do not throw away the cap or clip as they will be placed back on the nasal applicator after each use.
-Hold the bottle upright. Place 1 finger on each side of the base of the nasal applicator and place the thumb underneath the bottle.
-Tilt head back slightly without lying down.
-Insert the nasal applicator into 1 of the nostrils. Tilt the nasal applicator to point the tip towards the top of the ear on the same side as the nostril. Leave space between the tip and the inside wall of the nose; DO NOT press the tip against the inside wall of the nose.
-Place the tongue on the roof of the mouth and breathe gently while pressing and releasing the nasal applicator once.
-Repeat this process to deliver the second spray into the other nostril.
-Wipe the nasal applicator with a clean tissue after each use.
-Replace the applicator cap and clip.
-Discard nasal spray bottle 30 days after opening the bottle.
The adverse reaction profile for oral varenicline is based on premarketing studies in over 4,500 people, with over 450 treated for at least 24 weeks and about 100 for a year. Most individuals were treated for 12 weeks or less. The safety of intranasal varenicline is based 3 clinical studies conducted in 349 patients who received at least 1 dose. The majority of patients in the intranasal studies had 31 days of treatment exposure, with a maximum exposure of 105 days.
Nausea is the most frequently reported adverse effect of oral varenicline, and is generally transient and considered mild to moderate in severity. However, it may persist for several months in some patients and a dose reduction may be necessary in some cases. For patients with intolerable nausea, a dose reduction should be considered. During a one-year study, nausea was reported in up to 40% of varenicline-treated patients and at rates exceeding placebo. In a placebo-controlled trial of patients with stable schizophrenia or schizoaffective disorder, nausea (24%) and vomiting (11%) were reported more frequently in patients receiving oral varenicline than placebo. During 12-week placebo-controlled clinical trials comparing varenicline 0.5 to 1 mg PO twice daily to placebo, the following gastrointestinal (GI) effects were reported more frequently in the varenicline groups than with placebo: nausea (16% to 30%), abdominal pain (5% to7%), flatulence (6% to 9%), dyspepsia (5%), vomiting (1% to 5%), constipation (5% to 8%), gastroesophageal reflux (1%), xerostomia (4% to 6%), dysgeusia (5% to 8%), appetite stimulation (3% to 4%), and anorexia or decreased appetite (1% to 2%). Nausea was responsible for treatment discontinuation in 3% of patients. In a clinical trial of adults with stable schizophrenia or schizoaffective disorder, nausea (24%) and vomiting (11%) occurred more frequently in patients treated with varenicline than placebo. In other clinical trials, nausea was observed in 27% of adults with major depressive disorder and 25% of patients with or without a history of a psychiatric disorder treated with varenicline. During other evaluations, diarrhea and weight gain were classified as frequent. Infrequent effects included dysphagia, enterocolitis, eructation, esophagitis, gastritis, GI bleeding (hemorrhage), and oral ulceration. Rare effects included peptic ulcer, intestinal GI obstruction, and acute pancreatitis.
During 12-week placebo-controlled clinical trials comparing varenicline 0.5 mg to 1 mg PO twice daily to placebo, the following centrally-mediated (CNS) effects were reported more frequently in the varenicline groups than the placebo group: headache (15% to 19%), drowsiness (3%), lethargy (1% to 2%), fatigue (4% to 7%), insomnia (18% to 19%), abnormal dreams (9% to 13%), sleep disorder (2% to 5%), and nightmares (1% to 2%). In a placebo-controlled trial of patients with stable schizophrenia or schizoaffective disorder, CNS events occurring in 5% or more of patients and more frequently than placebo were insomnia (10%) and headache (11%). In adults with major depressive disorder, the following adverse CNS effects occurred more frequently in patients treated with varenicline than placebo: headache (17%), abnormal dreams (11%), and insomnia (11%). In a separate clinical trial, the following CNS effects were reported more frequently in adults receiving oral varenicline than placebo in cohorts with or without a history of a psychiatric disorder, respectively: headache (12% each varenicline group), sleep disorder (3% each varenicline group), insomnia (9% vs. 10%), and abnormal dreams (12% vs. 8%). During other clinical trial evaluations, disturbance in attention, dizziness, and sensory disturbance were classified as frequent. Infrequent effects included amnesia, migraine, parosmia, psychomotor hyperactivity or restlessness, restless legs syndrome (RLS), and tremor. Rare effects included balance disorder, dysarthria, facial palsy, mental impairment (unspecified), multiple sclerosis, and psychomotor impairment. There have been postmarketing reports of accidental injuries including motor vehicle accidents, near-miss traffic incidents, and other accidental injuries during the use of oral varenicline. In some cases, patients experienced drowsiness, dizziness, loss of consciousness, or difficulty concentrating that resulted in cognitive impairment, or concern about potential impairment, in driving or operating machinery. Patients should be advised to use caution when driving or operating machinery or performing other tasks that require mental alertness until they know how varenicline will affect them. In addition, complex sleep-related behaviors, including somnambulism (sleep-walking) have been reported in patients taking varenicline, with some cases describing harmful behavior to self, others, or property. Seizures have also been reported in patients with and without a seizure disorder treated with varenicline during clinical trials and postmarketing experience. In most cases, the seizure occurred within the first month of therapy. Patients should be advised to discontinue varenicline and contact a healthcare provider immediately if they experience a seizure, complex sleep-related behaviors (e.g., somnambulism), or other serious effects while on treatment.
Orally administered varenicline has been studied for the frequency of psychiatric events occurring in patients with or without specific psychiatric history. In a clinical trial of adults with stable schizophrenia or schizoaffective disorder, there were no commonly reported adverse psychiatric events with varenicline treatment. In a clinical trial of adults with major depressive disorder, the following adverse psychiatric events were reported more frequently in patients receiving varenicline than placebo: irritability (11%), depression (depressed mood disorders or disturbances 11%), agitation (7%), tension (4%), and hostility (2%). In a separate clinical trial, the following psychiatric events were reported more frequently in adults receiving varenicline in cohorts with or without a history of a psychiatric disorder, respectively: agitation (5% vs. 3%), depressed mood (5% vs. 3%), and irritability (5% vs. 3%). Anxiety (8%) occurred more frequently in the active treatment group vs. placebo only in the cohort of patients with a history of psychiatric disorder (8%). The manufacturer categorizes some treatment-emergent adverse reactions occurring during varenicline clinical trials as frequent, infrequent, or rare; however, a precise incidence rate for these events has not been reported. Psychiatric effects classified as infrequent include disorientation, dissociation, libido decrease, mood swings (emotional lability), and abnormal thinking. Bradyphrenia and euphoria are classified as rare. Mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, agitation, hostility, anxiety, panic, and depression have been reported during postmarketing use of oral varenicline. These adverse effects have developed within days to weeks of starting therapy, and may occur in patients with or without an underlying psychiatric disorder. Additionally, some reported neuropsychiatric events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by concomitant use of alcohol. There have been postmarketing reports of patients experiencing increased ethanol intoxication while taking varenicline. Some cases described unusual and sometimes aggressive behavior, and were often accompanied by amnesia for the events. Patients should be advised to reduce alcohol ingestion while taking varenicline until they know whether the drug affects their alcohol tolerance.
Serious skin reactions, including Stevens-Johnson syndrome and erythema multiforme, have occurred during postmarketing use of oral varenicline, and can be life-threatening. Other dermatological adverse reactions have been reported with varenicline use. During 12-week placebo-controlled clinical trials comparing oral varenicline 0.5 to 1 mg twice daily to placebo, the following dermatologic effects were reported in the varenicline groups versus the placebo group: rash (1% to 3% vs 2%) and pruritus (up to 1% vs 1%). During other clinical trial evaluations, hyperhidrosis and hot flashes (hot flush) were classified as frequent; however, the exact incidences are unknown. Infrequent effects included acne vulgaris, xerosis, atopic dermatitis, erythema, psoriasis, and urticaria. Photosensitivity was classified as rare. Patients should be instructed to discontinue the drug if they develop any rash with mucosal lesions or other skin reaction and to seek immediate medical attention.
There have been postmarketing reports of hypersensitivity reactions, including angioedema, in patients treated with oral varenicline. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx, laryngeal edema). There were infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise. Patients should be instructed to discontinue the drug and to immediately seek medical attention if they experience these symptoms.
A meta-analysis of data from 7,002 patients found that major adverse cardiovascular events (MACE) including cardiovascular-related death, nonfatal myocardial infarction (MI), and nonfatal stroke occurred at a higher numerical rate in patients using oral varenicline compared to placebo. However, the overall incidence was low in both groups and was not statistically significant (0.31% vs. 0.21% placebo). This is similar to an estimated increase of 6.3 MACE per 1,000 patient-years of exposure. In addition, although not statistically significant, the incidence of cardiovascular mortality and all-cause mortality was lower in patients receiving varenicline than placebo. These results are consistent with those from a trial of patients with stable cardiovascular disease (n = 700), in which more types and a greater number of cardiovascular events were reported compared to premarketing studies. In the trial of patients with stable cardiovascular disease, the following cardiovascular effects occurred in more than 1% of patients in the active treatment group and more frequently than placebo during the 12-week treatment phase or within 30 days after treatment: angina (3.7%), chest pain (unspecified) (2.5%), peripheral edema (2%), and nonfatal MI (1.1%). During the 40-week non-treatment follow-up phase, the following events occurred more frequently in patients treated with oral varenicline than placebo: need for coronary revascularization (2%), hospitalization for angina (1.7%), and new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (1.1%). Cardiac death occurred in 0.3% of varenicline-treated patients versus 0.6% of placebo-treated patients. Infrequent treatment-emergent adverse events (TEAEs) occurring during varenicline clinical trials include syncope, arrhythmia (unspecified), bradycardia, palpitations, sinus tachycardia, ventricular extrasystoles, abnormal electrocardiogram, and thrombosis, and rare TEAEs include atrial fibrillation, atrial flutter, coronary artery disease, cor pulmonale, and pulmonary embolism. Ischemic and hemorrhagic stroke and MI have been reported during postmarketing use. Most patients experiencing these events had pre-existing cardiovascular disease or other risk factors. Although smoking is a risk factor for MI and stroke, these events have occurred temporally to varenicline administration; therefore, an association to the drug cannot be ruled out.
The manufacturer categorizes some treatment-emergent adverse reactions occurring during oral varenicline clinical trials as frequent, infrequent, and rare. The incidence of these adverse reactions has not been reported by the manufacturer. Musculoskeletal and connective tissue disorders classified as frequent included arthralgia, back pain, muscle cramps, musculoskeletal pain, and myalgia. Infrequent effects included arthritis, osteoporosis, and increased creatine phosphokinase (CPK) enzymes. Myositis was classified as rare.
The manufacturer categorizes some treatment-emergent adverse reactions occurring during oral varenicline clinical trials as frequent, infrequent, or rare. The incidence of these adverse reactions has not been reported. The following reproductive system disorders are classified as follows: menstrual irregularity (frequent), sexual dysfunction (infrequent), and impotence (erectile dysfunction) (rare).
The manufacturer categorizes some treatment-emergent adverse reactions occurring during oral varenicline clinical trials as frequent, infrequent, and rare. The incidence of these adverse reactions has not been reported by the manufacturer. Renal and urinary effects classified as frequent include polyuria. Infrequent effects include nephrolithiasis, nocturia, urethral syndrome, urine abnormality, and abnormal urinalysis. Acute renal failure (unspecified) and urinary retention are classified as rare.
The manufacturer categorizes some treatment-emergent adverse reactions occurring during oral varenicline clinical trials as frequent, infrequent, or rare. The incidence of these adverse reactions has not been reported. Endocrine effects classified as infrequent include thyroid gland disorders (unspecified) and diabetes mellitus with hyperglycemia. Hypoglycemia is classified as rare.
Some treatment-emergent adverse reactions occurring during oral varenicline clinical trials have been reported by the manufacturer as frequent, infrequent, or rare; the incidence of these adverse reactions has not been reported. Infrequent ocular/visual treatment-emergent adverse reactions include conjunctivitis, xerophthalmia, ocular irritation, ocular pain, blurred vision, and visual impairment. Acquired night blindness, transient blindness, subcapsular cataracts, ocular vascular disorder, photophobia, vitreous floaters, nystagmus, and visual field defect have also rarely been reported with oral varenicline use. The FDA is investigating the potential association between varenicline administration and visual disturbances. The FDA received notification of this possible association via the Adverse Event Reporting System (AERS); however, a causal relationship has not been determined at this time.
The manufacturer categorizes some treatment-emergent adverse reactions occurring during oral varenicline clinical trials as frequent, infrequent, or rare. The incidence of these adverse reactions has not been reported. Otic and labyrinth effects classified as infrequent include tinnitus and vertigo. Hearing loss (deafness) and Meniere's disease are classified as rare.
During 12-week placebo-controlled clinical trials comparing varenicline 0.5 to 1 mg PO twice daily to placebo, the following respiratory effects were reported more frequently in the varenicline groups than the placebo group: rhinorrhea (up to 1% vs 0%), dyspnea (1% to 2% vs 1%), and upper respiratory tract disorder (5% to 7% vs 4%). During other clinical trial evaluations, epistaxis and respiratory disorder (unspecified) were classified as frequent. Infrequent effects included asthma (bronchospasm). Pleurisy was classified as a rare effect.
The manufacturer categorizes some treatment-emergent adverse reactions occurring during oral varenicline clinical trials as frequent, infrequent, or rare. The incidence of these adverse reactions has not been reported. Hematologic and lymphatic effects classified as infrequent include anemia and lymphadenopathy. Leukocytosis, splenomegaly, and thrombocytopenia are classified as rare.
The manufacturer categorizes some treatment-emergent adverse reactions occurring during oral varenicline clinical trials as frequent, infrequent, or rare. The incidence of these adverse reactions has not been reported. General effects not listed elsewhere and classified as frequent include edema and influenza-like illness. Chest discomfort, chills, fever, hypokalemia, and hyperlipidemia are classified as infrequent.
The manufacturer categorizes some treatment-emergent adverse reactions occurring during oral varenicline clinical trials as frequent, infrequent, or rare. The incidence of these adverse reactions has not been reported. Elevated hepatic enzymes are classified as frequent. Gall bladder disorder (e.g., cholecystitis) is classified as rare.
Suicidal ideation and attempted/completed suicide have been reported during postmarketing use of oral varenicline. The FDA conducted a postmarketing safety review of data from 1997 to 2007 in the Adverse Event Reporting System (AERS) and found that varenicline was associated with 153 cases of suicidal ideation and behaviors. Of these cases, 76 patients had a prior psychiatric history, 40 patients had no prior psychiatric history, and the psychiatric history was unknown in 37 patients. The median time to onset of symptoms was less than 2 weeks after varenicline initiation. Depression was a co-morbid event in 50% of patients at the time of the reporting, and concomitant psychiatric medications were being used by 39% of the patients. Of the cases considered serious (n = 147), outcomes were categorized as follows: death (13%), hospitalization (13%), life-threatening (21%), disability (6%), intervention required (4%), and other (76%). It should be noted that these outcomes were not mutually exclusive. The FDA subsequently conducted two epidemiological studies which found no difference between hospitalizations due to neuropsychiatric events in patients receiving varenicline compared to nicotine replacement therapy; however, the study designs were limited to hospitalizations and the sample sizes were not sufficient to detect rare events. In an independent analysis of 13,243 documented cases of adverse events involving smoking cessation products, there were 3249 reports of self-injurious behaviors and/or depression of which varenicline use was associated with 90% of those cases compared to bupropion (7%) or nicotine replacement products (3%). There were 295 reports of completed suicides (2.2% of total events) involving smoking cessation products in which the vast majority were associated with varenicline use (92%) compared to bupropion (6%) or nicotine replacement (1%). Self-injurious behaviors and/or depression were reported in 1% of patients (n = 48/4,047) in the comparator group who had received antibiotics. Although patients with schizophrenia, bipolar disorder, and major depression were excluded from premarketing clinical trials, there is limited data available regarding the potential risk of suicidal ideation from a smoking cessation study in patients with stable schizophrenia or schizoaffective disorder. A meta-analysis of 5 randomized, double-blind, placebo controlled trials, including 1,907 patients (1,130 varenicline, 777 placebo) was conducted to assess suicidal ideation and behavior as reported on the Columbia-Suicide Severity Rating Scale (C-SSRS). In 1 small (n = 128) trial, no consistent worsening of schizophrenia or overall changes in extra-pyramidal signs were reported. Although over half of the patients had a lifetime history of suicidal behavior and/or ideation (62% on varenicline vs. 51% on placebo), no patients in the varenicline group reported suicidal behavior and/or ideation at baseline vs. one patient in the placebo group (2%). Suicidal behavior and/or ideation were reported in 11% of the varenicline-treated compared to 9% of the placebo-treated patients during the treatment phase. During the post-treatment phase, suicidal behavior and/or ideation were reported in 11% of patients in the varenicline group and 5% of patients in the placebo group. Many of the patients reporting suicidal behavior and ideation in the follow-up phase had not reported such experiences in the treatment phase. However, no new suicidal ideation or behavior emerged in either treatment group within one week after treatment discontinuation. Although there were no completed suicides, there was one suicide attempt in a varenicline-treated patient. Another trial (n = 525) included patients with a history of depression. The results showed no increase in the incidence of suicidal ideation and/or behavior in patients treated with varenicline compared to patients treated with placebo (RR 0.79, 95% CI 0.46, 1.36). Forty-eight of the 55 patients who reported suicidal ideation or behavior (24 varenicline, 24 placebo) were observed in the two trials that enrolled patients with a history of schizophrenia, schizoaffective disorder, or depression. Few events were observed in the other 3 trials (4 varenicline, 3 placebo). A pooled analysis of 18 double-blind, randomized, placebo-controlled clinical trials, which includes the 5 trials that collected C-SSRS, was conducted to assess the psychiatric safety of oral varenicline. This pooled analysis included 8,521 patients (5,072 varenicline, 3,449 placebo), some of whom had psychiatric conditions at baseline. The results showed a similar incidence of common psychiatric events in patients treated with oral varenicline compared to patients treated with placebo. Four observational studies, each including 10,000 to 30,000 users of oral varenicline in the adjusted analyses, compared the risk of selected serious neuropsychiatric events (neuropsychiatric hospitalizations, fatal and non-fatal self-harm), between varenicline users and prescription NRT or bupropion users. All studies were retrospective cohort studies and included patients with and without a psychiatric history. Two of the studies found no difference in risk of neuropsychiatric hospitalizations between varenicline users and nicotine patch users (HR: 1.14, 95% CI: 0.56 to 2.34 in the first study, and 0.76, 95% CI: 0.40 to 1.46 in the second study). It should be noted that neither study validated the diagnostic codes used to identify outcomes against medical records. A third study reported no difference in risk of psychiatric adverse events diagnosed during an ER visit or inpatient admission between oral varenicline users and bupropion users (HR: 0.85, 95% CI: 0.55 to 1.30). A fourth study examined risk of fatal and non-fatal self-harm in users of varenicline compared to users of NRT. Although the occurrence of detected suicide was rare during the 3 months after patients initiated any drug treatment (2 cases in 31,260 varenicline users and 6 cases in 81,545 NRT users). This study was limited by several factors, including the fact that these data were captured following public awareness of reports of neuropsychiatric adverse events in varenicline users. Varenicline users had fewer comorbid conditions that could put them at risk for neuropsychiatric adverse events, suggesting that patients with a history of neuropsychiatric illness were preferentially prescribed NRT, and healthier patients were preferentially prescribed oral varenicline. Outcomes examined in these studies did not include the full range of neuropsychiatric adverse events that have been reported during postmarketing use of varenicline, therefore, extreme caution is advisable when using varenicline in those with an underlying psychiatric disorder until the safety and efficacy of varenicline can be formally established in these patient populations. Smoking cessation alone is associated with nicotine withdrawal and has the potential to exacerbate an underlying psychiatric illness. However, not all patients experiencing adverse neuropsychiatric reactions while taking varenicline have had pre-existing psychiatric illness and not all had stopped smoking at the time of the event; therefore, it is currently recommended that all patients receiving varenicline should be monitored for emerging or worsening neuropsychiatric symptoms. Patients and caregivers should be instructed about the importance of monitoring for neuropsychiatric symptoms, and advised to discontinue varenicline and to communicate immediately with the prescriber the emergence of agitation, depression, unusual changes in moods or behavior, or suicidality, or other adverse changes in mood or behavior. A change or discontinuation of the therapeutic regimen should be considered if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
The most frequently reported adverse reaction following administration of varenicline nasal spray during clinical trials was sneezing (82%). Other common adverse reactions included cough (16%), throat irritation (13%), and nasal irritation (8%).
Orally administered varenicline should be avoided in patients with a known hypersensitivity to varenicline or any component of the formulation. Life-threatening hypersensitivity reactions, including angioedema, have occurred. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx). There were infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise. Rarely, serious skin reactions such as Stevens-Johnson syndrome and erythema multiforme have also been reported during postmarketing use of the drug. Patients should be instructed to discontinue the medication and seek immediate medical care if they experience a serious rash with mucosal lesions or any other signs of hypersensitivity.
Patients should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness (e.g., schizophrenia, depression, bipolar disorder) during treatment with orally administered varenicline, due to serious neuropsychiatric symptoms reported during use of the drug. If neuropsychiatric symptoms develop, evaluate the patient for symptom severity and the extent to which the patient is benefiting from treatment, and consider dose reduction or discontinuation, or continued treatment with closer monitoring. In many cases, resolution of symptoms has occurred after discontinuation, although the symptoms can persist; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve Post-marketing reports have included mood or behavioral changes or a psychiatric event such as psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, anxiety, panic, mania, depression, suicidal ideation, suicide attempt, and completed suicide in patients with or without a psychiatric history. Some reported cases may have been complicated by symptoms of nicotine withdrawal, such as depressed mood, in patients who stopped smoking, although most occurred during varenicline treatment. It should be noted that depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by concomitant use of alcohol. Advise patients and caregivers that the patient should stop taking the drug and contact a healthcare provider immediately if agitation, depressed mood, suicidal ideation, suicidal behavior, or other behavioral changes that are not typical for the patient are observed. The boxed warning in the product labeling regarding serious neuropsychiatric effects was removed in December 2016 following results from the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES), which was a large, randomized, double-blind, active- and placebo-controlled smoking cessation clinical trial assessing varenicline, bupropion, and nicotine replacement therapy in patients with (n = 4003) and without (n = 3912) a history of a psychiatric disorder. In the non-psychiatric cohort, fewer patients receiving varenicline reported a serious neuropsychiatric event than patients receiving placebo (0.1% vs. 0.4%). There was a similar incidence of serious neuropsychiatric events between the psychiatric patients receiving varenicline or placebo (0.6% each). In the psychiatric cohort, there were more neuropsychiatric events reported in each treatment group than in the non-psychiatric cohort, and the incidence of events at endpoint was higher in psychiatric patients receiving each of the active treatments than placebo. Risk differences in the psychiatric cohort versus placebo were: 2.7% for varenicline, 2.2% for bupropion, and 0.4% for transdermal nicotine. More patients in the varenicline-treated psychiatric cohort had serious neuropsychiatric events involving a psychiatric hospitalization than in patients receiving placebo (0.5% vs. 0.2%).
Patients should be advised to use caution when driving or operating machinery or performing other tasks that require mental alertness until they know how varenicline will affect them. There have been reports of motor vehicle accidents, near-miss traffic incidents, and other accidental injuries during the use of orally administered varenicline. In some cases, patients have experienced drowsiness, dizziness, loss of consciousness, or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving or operating machinery. There have also been postmarketing reports of patients experiencing increased effects of ethanol intoxication while taking varenicline. Some cases have described unusual and sometimes aggressive behavior, and have often been accompanied by amnesia of the events. Patients should be advised to reduce their amount of ethanol ingestion while taking varenicline until they know whether the drug affects their tolerance for alcohol. Instruct patients to discontinue varenicline and notify their healthcare provider if they experience somnambulism or other complex sleep-related behaviors. Somnambulism (sleep-walking) has been reported in patients taking varenicline, with some cases describing harmful behavior to self, others, or property.
Seizures have been reported in patients treated with oral varenicline during clinical trials and postmarketing experience. Some patients had no history of seizures, whereas others had a history of seizure disorder that was remote or well-controlled. In most cases, the seizure occurred within the first month of therapy. Weigh this potential risk against the potential benefits before prescribing varenicline in patients with a history of seizures or other factors that can lower the seizure threshold. Tell patients to discontinue varenicline and contact a health care provider immediately if they experience a seizure while on treatment.
A comprehensive evaluation of cardiovascular risk (i.e., randomized controlled trials and meta-analysis) suggests that orally administered varenicline may be associated with a small, increased risk of certain cardiovascular events, such as myocardial infarction or stroke, in patients with cardiac disease. However, because smoking is an independent major risk factor for cardiovascular disease, the health benefits of smoking cessation must be balanced with concerns of potential drug-related cardiac risks. In one smoking cessation trial of patients with stable cardiac disease, nonfatal myocardial infarction and nonfatal stroke occurred more frequently in patients using varenicline than placebo, but the difference was not statistically significant, and all-cause and cardiovascular mortality was lower in patients treated with varenicline. A meta-analysis showed an increased hazard ratio of 1.95 for Major Adverse Cardiovascular Events (MACE) with varenicline, which was not statistically significant. A large postmarketing neuropsychiatric safety outcome trial showed few MACE events; therefore, the findings did not significantly contribute to identifying the cardiac risk of varenicline. Patients should be instructed to seek medical attention if they experience new or worsening cardiac symptoms (such as those suggestive of myocardial infarction or stroke) while receiving varenicline.
Oral varenicline should be used cautiously in patients with renal impairment or renal failure. Varenicline is substantially excreted by the kidneys and the risk of toxic reactions is greater in patients with impaired renal function. Dosage adjustments are necessary in patients with CrCl less than 30 mL per minute and those with end-stage renal disease receiving dialysis.
No overall differences in safety or effectiveness were observed during clinical trials in geriatric patients vs. younger adults. Clinical experience has not identified differences in responses. However, greater sensitivity of some older patients cannot be ruled out. Geriatric patients are more likely to have decreased renal function. Since varenicline is known to be substantially excreted by the kidney and the risk of toxic reactions are greater in patients with impaired renal function, care should be taken when dosing oral varenicline in the elderly; it may be useful to monitor renal function.
There are no data on the use of intranasal varenicline in pregnant patients to inform any drug associated risk. Available data from orally administered varenicline have not suggested an increased risk for major birth defects in exposed infants following maternal exposure as compared with mothers who smoke. Overall, however, available study results cannot definitively establish or exclude any varenicline-associated risk during pregnancy. In 1 population-based observational study using national registries from Denmark and Sweden where pregnancy and birth outcomes were compared among patients exposed to varenicline, patients who smoked during pregnancy, and non-smoking pregnant patients, the prevalence of major malformations was similar in all groups. The prevalence of other adverse perinatal outcomes in the varenicline-exposed cohort was not greater than in the cohort of patients who smoked. Study limitations included the inability to capture malformations from pregnancies without a live birth and misclassifications of outcomes, varenicline exposure, or smoking exposure. Other small epidemiological studies did not identify an association between varenicline use during pregnancy and major malformations. Smoking during pregnancy causes increased risks of orofacial clefts, premature rupture of membranes, placenta previa, placental abruption, ectopic pregnancy, fetal growth restriction and low birth weight, stillbirth, preterm delivery and shortened gestation, neonatal death, sudden infant death syndrome and reduction of lung function in infants. It is not known whether smoking cessation with varenicline during pregnancy reduces these risks. Non-pharmacologic smoking cessation efforts are used to help reduce the proportion of patients who continue to smoke in late pregnancy, thereby reducing adverse perinatal outcomes. Nicotine replacement treatment is used during pregnancy only if the likelihood of smoking cessation justifies the potential risk of the treatment or the risk that the patient will continue to smoke. The potential effects of varenicline on labor and delivery are not known.
There are no data on the presence of varenicline in human milk, the effects on the breast-fed infant, or the effects on human milk production. In animal studies varenicline was present in milk of lactating rats. However, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The lack of clinical data during lactation precludes a clear determination of the risk of varenicline to an infant during lactation. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for varenicline and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. If varenicline use is required, breast-feeding women should monitor their infant for seizures and excessive vomiting, which are adverse reactions that have occurred in adults that may be clinically relevant in a breast-feeding infant. The decision of whether to use a pharmacologic method for smoking cessation in a woman who is breast-feeding should be evaluated in comparison to the risks associated with passive exposure of the infant to tobacco smoke. Nicotine replacement products may be considered as an alternate smoking cessation treatments to varenicline in breast-feeding mothers if supportive cessation interventions are ineffective. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Safety and efficacy of intranasal varenicline in pediatric patients have not been established. Additionally, orally administered varenicline is not recommended for children or adolescents because its efficacy in these populations has not been demonstrated. Varenicline did not improve continuous abstinence rates at weeks 9 through 12 of treatment compared to placebo in a randomized, double-blind study of 312 patients 12 to 19 years of age, who smoked an average of at least 5 cigarettes per day, had a Fagerstrom Test for Nicotine Dependence score of at least 4, and at least 1 previous failed attempt to quit. The safety profile of varenicline was similar to that of adults.
For tobacco cessation (smoking cessation) as an adjunct to psychosocial interventions:
Adults: 0.5 mg PO once daily on days 1 to 3, then 0.5 mg PO twice daily on days 4 to 7, and then 1 mg PO twice daily for a total of 12 weeks. An additional 12 weeks of treatment for a total of 24 weeks is recommended for successful quitters to increase likelihood of long-term abstinence. Another attempt at treatment is recommended for those who fail to stop smoking or relapse when factors contributing to the failed attempt have been addressed.
For the treatment of the signs and symptoms of dry eye disease:
Adults: 1 spray (0.03 mg) in each nostril twice daily, approximately 12 hours apart. If a dose is missed, resume regular dosing at the next scheduled dosing time.
Maximum Dosage Limits:
2 mg per day PO; 0.12 mg (4 sprays) intranasally per day.
2 mg per day PO; 0.12 mg (4 sprays) intranasally per day.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is necessary for patients with hepatic impairment.
Patients with Renal Impairment Dosing
CrCl 30 mL per minute or more: No dosage adjustment needed.
CrCl less than 30 mL per minute: Initially, 0.5 mg PO once per day. Max: 0.5 mg PO twice daily.
Varenicline is removed by hemodialysis. A maximum dose of 0.5 mg PO once daily may be given if well tolerated in patients with end-stage renal disease on hemodialysis.
Cimetidine: (Minor) Inhibitors of OCT2 (e.g., cimeditine) may increase the exposure of varenicline but these changes may not necessitate a dose adjustment of varenicline as the increase in systemic exposure is not expected to be clinically meaningful. Administration cimetidine (300 mg four times daily), with varenicline (2 mg single dose) to 12 smokers increased the systemic exposure of varenicline by 29% due to a reduction in varenicline renal clearance. In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter OCT2. Another H2 antagonist may be preferable to cimetidine in patients taking varenicline.
Ethanol: (Major) Patients should be advised to avoid alcohol while taking varenicline as it may affect their tolerance for alcohol. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by a patient's concomitant use of alcohol. There have been postmarketing reports of patients experiencing increased alcohol intoxication while taking varenicline. Some cases described unusual and sometimes aggressive behavior, and were often accompanied by amnesia for the events.
Varenicline is a partial agonist of nicotinic acetylcholine (nACh) receptors alpha4-beta2, alpha4alpha6-beta2, alpha3-beta4, alpha3alpha5-beta4, and full alpha7. These receptors are believed to be the site whereby nicotine exerts its effects. Similar to most abused substances, nicotine increases dopamine release in the nucleus accumbens and prefrontal cortex. Cravings for nicotine are stimulated by low levels of mesolimbic dopamine during periods of abstinence. Varenicline is effective because it partially stimulates alpha4-beta2 receptors to produce a modest level of mesolimbic dopamine thereby diminishing nicotine cravings and withdrawal symptoms. This mesolimbic dopamine level is lower than that produced by nicotine. Varenicline also has the added benefit of blocking the effects of nicotine by occupying receptor sites. By blocking receptors, varenicline reduces the pharmacologic reward of nicotine in cases where a patient relapses and uses tobacco. Varenicline binds with high affinity and selectivity to these nACh receptors. Varenicline also binds with moderate affinity to 5-HT3 (serotonin) receptors.
The exact mechanism by with varenicline treats the symptoms of dry eye disease is unknown; however, it is believed to occur through binding to the heteromeric sub-type(s) of nACh receptors. By binding to these receptors, varenicline activates the trigeminal parasympathetic pathway resulting in increased production of basal tear film.
Varenicline is administered orally and intranasally. Twenty percent or less of varenicline is plasma protein bound and is independent of both age and renal function. Metabolism is minimal. Approximately 92% of an administered dose is excreted unchanged in the urine. Elimination via the kidneys is primarily through glomerular filtration along with active tubular secretion by the human organic cation transporter, OCT2. The elimination half-life is about 24 hours for the oral formulation and 19 hours +/- 10 hours for the intranasal formulation.
Affected cytochrome P450 isoenzymes and drug transporters: none
Based on in vitro studies, varenicline does not inhibit cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. It does not induce CYP1A2 or CYP3A4.
Varenicline is almost completely absorbed, and systemic availability is high with oral administration. The maximum plasma concentration (Cmax) occurs within 3 to 4 hours and steady-state is reached in about 4 days after multiple doses. Food or time-of-day do not affect varenicline oral bioavailability.
Following nasal administration of 0.12 mg (i.e., 0.06 mg spray in each nare), varenicline was detected in the plasma within 5 minutes and achieved peak concentration within 2 hours. The mean Cmax and systemic exposure (AUC) were 0.34 ng/mL and 7.46 ng x hour/mL, respectively. The AUC following the 0.12 mg intranasal dose was approximately 7.5% of the exposure observed following a 1 mg oral dose.
Because varenicline is not hepatically metabolized, the pharmacokinetics of varenicline are not affected by hepatic impairment.
In patients with moderate (CrCl 30 to 49 mL/minute) to severe (CrCl less than 30 mL/minute) renal impairment, systemic exposure to varenicline was increased 1.5- and 2.1-fold, respectively, compared to patients with normal renal function (CrCl more than 80 mL/minute). End-stage renal disease (ESRD) patients receiving 0.5 mg PO once daily for 12 days and undergoing a 3-hour hemodialysis session 3 days a week had a 2.7-fold increase in varenicline systemic exposure. The varenicline plasma Cmax and AUC in these ESRD patients were similar to those seen in healthy subjects receiving about 1 mg PO twice daily. Varenicline is efficiently removed by hemodialysis.
Steady-state systemic exposure (AUC) in adolescent patients weighing more than 55 kg was comparable to that noted in the adult population. Mean exposure was approximately 40% higher in adolescent patients weighing 55 kg or less.
Based on pharmacokinetic studies and population pharmacokinetic analyses, no clinically meaningful differences exist in varenicline pharmacokinetics due to age.
Based on pharmacokinetic studies and population pharmacokinetic analyses, no clinically meaningful differences exist in varenicline pharmacokinetics due to gender.
Based on pharmacokinetic studies and population pharmacokinetic analyses, no clinically meaningful differences exist in varenicline pharmacokinetics due to race.
Based on pharmacokinetic studies and population pharmacokinetic analyses, no clinically meaningful differences exist in varenicline pharmacokinetics due to smoking status or use of concomitant medications.