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.[32296] 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.[32296]

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.[32296]

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.[32296]

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.[32296]

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.[32296]

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.[52585] 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.[32296] 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.[32296]

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.[32296]

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).[32296]

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.[32296]

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.[32296]

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.[32296] 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.[32296]

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.[32296]

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.[32296]

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.[32296]

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.[32296]

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.[46658] 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.[46673] 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.[32296]

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%).[67052]

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.[32296]

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%).[32296]

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.[32296]

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.[32296]

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.[32296] [52585]

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.[32296]

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.[32296]

There are no data on the use of intranasal varenicline in pregnant patients to inform any drug associated risk.[67052] 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.[32296] 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.[42078] 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.[32296] [67052] 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.[27500] 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.[67052] 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.[32296]