Champix

When varenicline (1 mg BID) and NRT (transdermal, 21 mg/day) were co-administered to 24 smokers for 12 days, there was a statistically significant decrease in average systolic blood pressure (mean 2.6 mmHg) measured on the final day of the study. In this study, the incidence of nausea, headache, vomiting, dizziness, dyspepsia and fatigue were greater for the combination of varenicline and NRT than for NRT alone. Due to the partial agonist nicotinic activity of varenicline, it is not anticipated that co-administration with NRT would confer additional benefits compared with CHAMPIX alone, and may result in increased side effects (see Warnings and Precautions, General).

Based on the lack of interaction between varenicline and metformin, interactions between varenicline and other cationic drugs eliminated via hOCT2 are unlikely.

Varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of bupropion (150 mg BID) in 46 smokers. Steady-state pharmacokinetics of varenicline remained unchanged by bupropion co-administration.

Other inhibitors of hOCT2 have not been directly studied. Cimetidine causes greater in vivo drug interactions with renally cleared compounds than other inhibitors of hOCT2. Consequently, co-administration of other inhibitors of hOCT2 with varenicline would not require dosage adjustment in patients with normal renal function or moderate renal impairment. In patients with severe renal impairment, the concomitant use of varenicline and other inhibitors of hOCT2, such as trimethoprim, ranitidine or levofloxacin should be avoided. (See Dosage and Administration, Recommended Dose and Dosage Adjustment, Special Populations, Patients with Impaired Renal Function.)

Varenicline (1 mg BID steady-state) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin in 24 smokers. Prothrombin time (INR) was not affected by CHAMPIX. Smoking-cessation itself may result in changes to warfarin pharmacokinetics (see Warnings and Precautions, General).

In vitro studies demonstrated that varenicline does not inhibit cytochrome P450 enzymes (IC50 >6400 ng/mL). The P450 enzymes tested for inhibition were: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline did not induce the activity of cytochrome P450 enzymes 1A2 and 3A4.

Therefore, varenicline is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes.

Furthermore, since metabolism of varenicline represents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of CHAMPIX (see Action and Clinical Pharmacology, Pharmacokinetics) and therefore a dose adjustment of CHAMPIX should not be required for these types of drugs.

Varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily dose in 18 smokers. Steady-state pharmacokinetics of varenicline remained unchanged by digoxin co-administration.

Based on varenicline pharmacokinetic characteristics, and clinical experience to date, it appears unlikely that CHAMPIX would produce or be subject to clinically meaningful drug interactions.

Drug interaction studies were performed with varenicline and: cimetidine, metformin, digoxin, warfarin, transdermal nicotine and bupropion.

No clinically meaningful pharmacokinetic drug interactions have been identified, other than potential for interaction with cimetidine in patients with severe renal impairment (see Cimetidine).

Safety and efficacy of varenicline in combination with other smoking-cessation therapies, such as bupropion or nicotine replacement therapy, have not been studied.

Oral bioavailability of CHAMPIX is unaffected by food.

CHAMPIX has no known drug-laboratory test interactions.

CHAMPIX has no known drug-herb interactions.

In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (eg, Metformin, see below) are unlikely to be affected by varenicline.

In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter, hOCT2. In patients with normal renal function coadministration with inhibitors of hOCT2 does not require a dose adjustment of CHAMPIX as the increase in systemic exposure to CHAMPIX is not expected to be clinically meaningful except in cases of severe renal impairment, (see Cimetidine, and Other Inhibitors of hOCT2).

Drug-drug interaction studies were limited to approximately two week studies in healthy young adult volunteers who smoked.

When co-administered to 30 smokers, varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of metformin (500 mg BID), which is a substrate of hOCT2. Metformin had no effect on varenicline steady-state pharmacokinetics.

Co-administration of varenicline (2 mg single dose) with an hOCT2 inhibitor, cimetidine (300 mg four times daily (QID) at steady-state) to 12 smokers increased the systemic exposure of varenicline by 29% (90% CI: 21.5%, 36.9%) due to a reduction in varenicline renal clearance. No dosage adjustment is recommended based on concomitant cimetidine administration in subjects with normal renal function or in patients with mild to moderate renal impairment. In patients with severe renal impairment, the concomitant use of cimetidine and varenicline should be avoided. (See Dosage and Administration, Recommended Dose and Dosage Adjustment, Special Populations, Patients with Impaired Renal Function.)

CHAMPIX is given orally with or without food (see Action and Clinical Pharmacology).

Smoking-cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional counselling and/or support services. Physicians should review the patient's overall smoking-cessation plan that includes treatment with CHAMPIX.

There is little clinical experience with doses above the maximum recommended dose of 1 mg BID. The response rates observed for 1 mg BID and 0.5 mg BID were 23% and 19% respectively.

No dosage adjustment is necessary for patients with mild (estimated creatinine clearance >50 mL/min and ≤80 mL/min) to moderate (estimated creatinine clearance ≥30 mL/min and ≤50 mL/min) renal impairment. For patients who experience intolerable adverse events, dosing may be reduced.

For patients with severe renal impairment, the recommended dose of CHAMPIX is 0.5 mg twice daily. Dosing should begin at 0.5 mg once daily for the first 3 days then increased to 0.5 mg twice daily. Based on insufficient clinical experience with CHAMPIX in patients with end-stage renal disease, treatment is not recommended in this patient population (see also Warnings and Precautions, Special Populations, Renal Impairment).

Safety and effectiveness of CHAMPIX in pediatric patients have not been established; therefore, CHAMPIX is not recommended for use in patients under 18 years of age.

To optimize opportunity for the success of the therapy, patients should be titrated up to the maximum recommended dose of 1 mg twice daily, using the following 1-week titration schedule:

Patients who cannot tolerate adverse effects of CHAMPIX may have the dose lowered temporarily or permanently.

The patient should set a date to stop smoking. CHAMPIX dosing should start 1-2 weeks before this date.

Patients should be treated with CHAMPIX for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with CHAMPIX may be considered.

No data are available on the efficacy of an additional 12 week course of treatment for patients who do not succeed in stopping smoking or who relapse after treatment.

Dose tapering may be considered. Regardless of whether the treatment course is 12 or 24 weeks, risk of smoking-cessation relapse is elevated in the period immediately following the end of drug treatment. In addition, dose tapering may help minimize discontinuation symptoms (eg, increase in irritability, urge to smoke, depression, and/or insomnia), observed in up to 3% of patients at the end of treatment.

No dosage adjustment is necessary for elderly patients with normal renal function. However, varenicline is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Warnings and Precautions, Special Populations, Geriatrics (>65 years of age)).

Frequent: menstrual disorder. Infrequent: erectile dysfunction, menorrhagia, vaginal discharge, sexual dysfunction.

Infrequent: conjunctivitis, dry eye, eye irritation, scotoma, scleral discolouration, vision blurred, visual disturbance, eye pain, mydriasis, myopia, lacrimation increased, photophobia. Rare: acquired night blindness, blindness transient, cataract subcapsular, ocular vascular disorder, vitreous floaters.

Infrequent: thyroid gland disorders.

In the paragraphs that follow, the frequency of less commonly reported adverse events from clinical trials is presented. The variability associated with adverse event reporting and the terminology used to describe adverse events limit the value of the quantitative frequency estimates provided. It is important to emphasize that although the events reported occurred during treatment with CHAMPIX, they were not necessarily caused by it. All reported events are included except those already listed in Table 1, those too general to be informative, and those not reasonably associated with the use of the drug. In some cases, separate event terms have been consolidated to facilitate meaningful presentation. Events are further classified within system organ class categories and enumerated in order of decreasing frequency using the following definitions: frequent (occurring in at least 1/100 patients), infrequent (occurring in <1/100 to 1/1000 patients) and rare (occurring in fewer than 1/1000 patients).

The most commonly observed adverse events associated with CHAMPIX (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal dreams, constipation, flatulence, and vomiting.

For patients exposed to the maximum recommended dose of 1 mg BID following initial dosage titration, the incidence of nausea was 30%, compared with 16% in 0.5 mg BID and approximately 10% in placebo-treated patients. Nausea was generally described as mild to moderate and often transient; however, for some subjects, it was persistent throughout the treatment period.

Infrequent: polydipsia, diabetes mellitus, hyperlipidemia, hypokalemia. Rare: hyperkalemia, hypoglycemia.

Initial dose titration was beneficial in reducing the occurrence of nausea.

An additional 12 weeks of CHAMPIX 1 mg BID was well-tolerated in patients who had completed 12 weeks of treatment and had stopped smoking. Adverse events resulted in treatment discontinuation in 1.7% of patients who received CHAMPIX compared with 1.3% of placebo patients.

Smoking-cessation with or without treatment is associated with various symptoms. For example, dysphoric or depressed mood, insomnia, irritability, frustration or anger, anxiety, difficulty concentrating, restlessness, decreased heart rate, increased appetite or weight gain have been reported in patients attempting to stop smoking.

Frequent: chest pain, influenza like illness, edema, thirst. Infrequent: chest discomfort, chills, circadian rhythm sleep disorder, feeling cold, cyst, pyrexia.

Infrequent: angina pectoris, arrhythmia, atrial fibrillation, bradycardia, ventricular extrasystoles, myocardial infarction, palpitations, tachycardia. Rare: cardiac flutter, coronary artery disease, cor pulmonale, acute coronary syndrome.

Infrequent: tinnitus, vertigo. Rare: deafness, Meniere's disease.

Frequent: epistaxis, respiratory disorders. Infrequent: asthma, cough, hoarseness, pharyngolaryngeal pain, throat irritation, respiratory tract congestion, sinus congestion, post nasal drip, rhinorrhea, snoring. Rare: pleurisy, pulmonary embolism.

Frequent: disturbance in attention, dizziness, sensory disturbance, somnolence. Infrequent: amnesia, coordination abnormal, dysarthria, dysphoria, hypertonia, hypoesthesia, hypogeusia, libido increased, libido decreased, migraine, parosmia, psychomotor hyperactivity, restlessness, restless legs syndrome, syncope, tremor. Rare: balance disorder, cerebrovascular accident, convulsion, facial palsy, mental impairment, multiple sclerosis, nystagmus, psychomotor skills impaired, transient ischemic attack, visual field defect.

The overall pattern and the frequency of adverse events during a 52-week trial with CHAMPIX 1 mg BID (n=251 subjects randomized to CHAMPIX arm, and n=126 to placebo arm) were similar to those described in Table 1, except for the following events which were seen to be increased relative to placebo, as compared to the profile for 12 week drug exposure: nausea (40% vs 8% placebo); and the pooled terms of: abdominal pain (17% vs 3% placebo), and increased blood pressure (11% vs 6% placebo). Few of these events were recorded as severe.

Frequent: polyuria. Infrequent: glycosuria, nephrolithiasis, nocturia, urine abnormality, urethral syndrome. Rare: renal failure acute, urinary retention.

Frequent: hyperhydrosis, rash generalized. Infrequent: acne, dermatitis, dry skin, eczema, erythema, psoriasis, night sweats, urticaria. Rare: photosensitivity reaction.

Frequent: arthralgia, back pain, muscle cramp, musculoskeletal pain, myalgia. Infrequent: arthritis, chest wall pain, costochondritis, joint stiffness, muscle spasms, osteoporosis. Rare: myositis.

Infrequent: bronchitis, nasopharyngitis, sinusitis, fungal infection, viral infection.

Pre-marketing clinical trials included approximately 2300 patients treated for at least 12 weeks, approximately 700 for 6 months, and approximately 100 for one year. In general, onset of adverse events was in the first few weeks of therapy and severity was generally mild to moderate. No differences were observed by age, race or gender with regard to the incidence of adverse reactions, although patient numbers in elderly, and in non-caucasian races were too limited to allow conclusions.

Infrequent: gall bladder disorder.

Frequent: hot flush, hypertension. Infrequent: hypotension, peripheral ischemia, thrombosis.

Infrequent: anemia, lymphadenopathy. Rare: leukocytosis, thrombocytopenia, splenomegaly.

Frequent: liver function test abnormal, weight increased. Infrequent: blood pressure increased, electrocardiogram abnormal, electrocardiogram T wave amplitude decreased, electrocardiogram ST segment depression, heart rate increased, platelet count decreased, semen abnormal, C-reactive protein increased, blood calcium decreased, muscle enzyme increased, urine analysis abnormal.

Infrequent: hypersensitivity. Rare: drug hypersensitivity.

Frequent: anxiety, depression, emotional disorder, irritability, restlessness. Infrequent: aggression, agitation, disorientation, dissociation, mood swings, panic reaction, bradyphrenia, thinking abnormal. Rare: euphoric mood, hallucination, psychotic disorder, suicidal ideation, suicide.

Frequent: diarrhea, gingivitis. Infrequent: change of bowel habit, abnormal feces, aphthous stomatitis, gingival pain, tongue coated, dysphagia, enterocolitis, eructation, gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, mouth ulceration, esophagitis. Rare: gastric ulcer, intestinal obstruction, pancreatitis acute.

The following adverse events have been reported during post-approval use of CHAMPIX. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

There have been reports of depressed mood, agitation, hostility, changes in behavior, suicidal ideation and suicide in patients attempting to quit smoking while taking CHAMPIX. Smoking cessation with or without treatment is associated with nicotine withdrawal symptoms and the exacerbation of underlying psychiatric illness. Not all patients had known pre-existing psychiatric illness and not all had completely discontinued smoking. The role of CHAMPIX in these reports is not known (see also Warnings and Precautions, General, Neuropsychiatric Symptoms).

The safety and efficacy of varenicline in pediatric patients have not been established, therefore its use in this patient population is not recommended (see Warnings and Precautions, Special Populations, Pediatrics (<18 years of age)).

No dosage adjustment is necessary for healthy elderly patients. However, varenicline is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Warnings and Precautions, Special Populations, Geriatrics (>65 years of age)).

Consistent with its pharmacological profile, CHAMPIX resulted in increased incidences of nausea and vomiting when given at doses greater than the recommended dose of 1 mg BID.

Varenicline has been shown to be dialyzed in patients with end-stage renal disease (see Action and Clinical Pharmacology, Special Populations and Conditions, Renal Insufficiency), however, there is no experience with dialysis following overdose.

Each capsular, biconvex, light blue film-coated tablet ,debossed with “Pfizer” on one side and “CHX 1.0” on the other side contains: varenicline 1 mg (as tartrate). Nonmedicinal ingredients: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and microcrystalline cellulose; film-coating: hypromellose, polyethylene glycol, titanium dioxide and triacetin. Also contains FD&C Blue #2/Indigo Carmine Aluminum Lake as a colouring agent. Continuation pack: Includes blister strips of 28.

Initial dosing pack: Includes 0.5 mg tablets in blister strips of 11 tablets and 1 mg tablets in blister strips of 14 tablets.

Each capsular, biconvex, white to off-white film-coated tablet, debossed with “Pfizer” on one side and “CHX 0.5” on the other side contains: varenicline 0.5 mg (as tartrate). Nonmedicinal ingredients: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and microcrystalline cellulose; film-coating: hypromellose, polyethylene glycol, titanium dioxide and triacetin. High-density polyethylene (HDPE) bottles of 56.

All patients attempting to quit smoking with CHAMPIX, their families and caregivers should be alerted about the need to monitor for these symptoms. Patients should be instructed to stop taking CHAMPIX and contact their healthcare provider immediately if they have or if their families or caregivers observe depressed mood, agitation, hostility or changes in behavior, that are not typical for the patient, or if the patient has suicidal ideation or suicidal behavior.

Patients with concomitant psychiatric conditions, even if well controlled, or with a history of psychiatric symptoms, should be diligently monitored.

Varenicline succinate has been shown to have an adverse effect on the fetus in animal reproduction studies. Administration of varenicline succinate to pregnant rabbits resulted in reduced fetal weights at an oral dose of 30 mg/kg/day (50 times the human AUC at 1 mg BID); this reduction was not evident following treatment with 10 mg/kg/day (23 times the maximum recommended daily human exposure based on AUC). In addition, in the offspring of pregnant rats treated with varenicline succinate there were decreases in fertility and increases in auditory startle response at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC at 1 mg BID).

The use of CHAMPIX has not been studied in patients exposed to emetogenic chemotherapy.

The concomitant use of NRT with CHAMPIX (varenicline tartrate) may result in an increase in adverse reactions. In a clinical drug interaction study (N=24), the incidences of nausea, headache, vomiting, dizziness, dyspepsia and fatigue were greater for the combination of NRT and varenicline than for NRT alone (see Drug Interactions). The safety and efficacy of the combination treatment with CHAMPIX and NRT have not been studied. Due to the proposed mechanism of action of varenicline, it is not anticipated that co-administration with NRT would confer additional benefit compared with CHAMPIX alone.

(See also Adverse Reactions, Post-Market Adverse Events).

There have been rare post-marketing reports of serious neuropsychiatric symptoms with CHAMPIX, including depressed mood, agitation, hostility, changes in behaviour, suicidal ideation and suicide, as well as worsening of pre-existing psychiatric illness (previously diagnosed or not).

There are a number of confounding factors which may have contributed, including effects of nicotine withdrawal due to partial or complete smoking discontinuation; concomitant, or history of psychiatric conditions; and the concomitant use of other CNS drugs and/or alcohol. However, there are cases for which these confounding factors did not appear to be present, including cases where symptoms occurred within the first week of initiating CHAMPIX, and prior to initiating smoking cessation. There have been other cases where symptoms developed following cessation of CHAMPIX therapy.

It is not known whether these events are occurring at a rate and severity which is different from the background rate for smoking cessation in the general population, or in the psychiatric population (treated or untreated), or different from the rates for other drugs in the class of smoking cessation.

Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder were excluded from the pre-marketing studies of CHAMPIX and the safety and efficacy of CHAMPIX in such patients has not been studied (see also Special Populations, Use of CHAMPIX in Patients with Concomitant Conditions).

The full consequences of using this product in patients with concomitant illness have not been established, and caution should be exercised (see Special Populations, Use of CHAMPIX in Patients with Concomitant Conditions).

The use of CHAMPIX has not been studied in psychiatric patients. Smoking-cessation with or without pharmacotherapy, has been associated with the exacerbation of underlying psychiatric illness; the impact on this population of a smoking-cessation product with nicotinic partial agonist properties is unknown. Care should be taken with patients with a history of psychiatric illness and patients should be advised accordingly.

There are no adequate data from the use of CHAMPIX in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. CHAMPIX should not be used during pregnancy.

Physiological changes resulting from smoking-cessation, with or without treatment with CHAMPIX, may alter the pharmacokinetics or pharmacodynamics of some drugs for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). As smoking induces cytochrome P450 (CYP) isoenzyme 1A2, smoking-cessation may result in an increase of plasma levels of CYP1A2 substrates.

A multiple dose pharmacokinetic study was conducted in patients with normal renal function, with mild, moderate, or severe renal impairment (estimated creatinine clearance: >80 mL/min, >50 and ≤80 mL/min, ≥30 and ≤50 mL/min, and <30 mL/min, respectively) or end-stage renal disease (ESRD). Varenicline pharmacokinetics was unchanged in subjects with mild renal impairment. Relative to subjects with normal renal function, varenicline exposure increased 1.5-fold in patients with moderate renal impairment and 2.1-fold in patients with severe renal impairment. In subjects with ESRD, varenicline was efficiently removed by hemodialysis. The recommended dose of CHAMPIX is reduced in patients with severe renal impairment. CHAMPIX is not recommended in patients with ESRD. (See Action and Clinical Pharmacology, Special Populations and Conditions, Renal Impairment, and Dosage and Administration, Special Populations, Patients with Impaired Renal Function.)

The use of CHAMPIX has not been studied in patients with epilepsy.

The subjective nicotine-like effects of varenicline were investigated in drug discrimination studies. At 1 mg/kg, there was complete substitution of varenicline for nicotine in a paradigm of nicotine-associated lever pressing for food reward. In an efficacy model, varenicline pretreatment dose-dependently reduced nicotine self administration under a fixed-ratio schedule. Under a progressive ratio schedule rats worked harder for nicotine than for varenicline.

A combined single and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily (QD) or BID to 16 healthy elderly male and female smokers (aged 65-75 years) for 7 consecutive days was similar to that of younger subjects. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Varenicline is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Dosage and Administration, Special Populations, Geriatrics (>65 years of age)).

The use of CHAMPIX has not been studied in patients with irritable bowel syndrome or other GI problems.

The rewarding potential of varenicline (1 mg and 3 mg doses) was compared with that of amphetamines in subjects experienced with psychomotor stimulants. The pattern for both smokers and non-smokers was consistent with a profile of a drug that, while having some pharmacological activity, did not produce amphetamine-like subjective effects.

Nausea was the most common adverse event associated with CHAMPIX treatment. Nausea was generally described as mild or moderate and often transient; however, for some subjects, it was persistent over several months. The incidence of nausea was dose-dependent. Initial dose-titration was beneficial in reducing the occurrence of nausea. Nausea was reported by approximately 30% of patients treated with CHAMPIX 1 mg BID after an initial week of dose titration. In patients taking CHAMPIX 0.5 mg BID, the incidence of nausea was 16% following initial titration. Approximately 3% of subjects treated with CHAMPIX 1 mg BID in studies involving 12 weeks of treatment discontinued treatment prematurely because of nausea. For patients with intolerable nausea, dose reduction should be considered.

There was no evidence of impairment of fertility in either male or female Sprague-Dawley rats administered varenicline succinate up to 15 mg/kg/day (67 and 36 times, respectively, the maximum recommended human daily exposure based on AUC at 1 mg BID). However, a decrease in fertility was noted in the offspring of pregnant rats who were administered varenicline succinate at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC at 1 mg BID). This decrease in fertility in the offspring of treated female rats was not evident at an oral dose of 3 mg/kg/day (9 times the maximum recommended human daily exposure based on AUC at 1 mg BID).

Safety and efficacy of CHAMPIX in pediatric patients have not been established; therefore, CHAMPIX is not recommended for use in patients under 18 years of age.

CHAMPIX may cause dizziness and somnolence and therefore patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that CHAMPIX does not affect them adversely.

Varenicline was not genotoxic, with or without metabolic activation, in the following assays: Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenetic aberrations in vivo in rat bone marrow and in vitro in human lymphocytes.

Lifetime carcinogenicity studies were performed in CD-1 mice and Sprague Dawley rats. There was no evidence of a carcinogenic effect in mice administered varenicline by oral gavage for 2 years at doses up to 20 mg/kg/day (47 times the maximum recommended human daily exposure based on the area under the curve (AUC). Rats were administered varenicline (1, 5, and 15 mg/kg/day) by oral gavage for 2 years. In male rats (n=65 per sex per dose group), incidences of hibernoma (tumor of the brown fat) was increased at the mid dose (1 tumor, 5 mg/kg/day, 23 times the maximum recommended human daily exposure based on AUC) and at the maximum dose (2 tumors, 15 mg/kg/day, 67 times the maximum recommended human daily exposure based on AUC). The clinical relevance of this finding to humans has not been established. There was no evidence of carcinogenicity in female rats.

Animal studies have shown that varenicline can be transferred to nursing pups. It is not known whether varenicline is excreted in human milk. Because many drugs are excreted in human milk and because the potential for adverse reactions in nursing infants from CHAMPIX is unknown, a decision should be made whether to discontinue nursing or to discontinue the drug.

Due to the absence of significant hepatic metabolism, varenicline tartrate pharmacokinetics should be unaffected in patients with hepatic insufficiency, except in the case that there is accompanying renal compromise (see Dosage and Administration). The potential for clinically meaningful drug interactions between varenicline and metabolic inhibitors/inducers is low.

A combined single and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once or twice daily to 16 healthy elderly male and female smokers (aged 65-75 years) for 7 consecutive days was similar to that of younger subjects.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Dosage and Administration, Special Populations, Geriatrics).

Plasma protein binding of varenicline is low (≤20%) and independent of both age and renal function.

There were no clinically meaningful differences seen in varenicline tartrate pharmacokinetics due to being elderly, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.

Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral doses of varenicline to healthy volunteers, steady-state conditions were reached within 4 days. Varenicline exhibits linear kinetics when given as single (0.1 to 3 mg) or repeated (1 to 3 mg/day) doses. In a mass balance study, absorption of varenicline is virtually complete after oral administration and systemic availability is high. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing.

The efficacy of CHAMPIX in smoking-cessation is believed to be a result of varenicline's partial agonist activity at the α4β2 nicotinic acetylcholine receptor (ie agonist activity to a lesser degree than nicotine), while simultaneously preventing nicotine binding (ie antagonist activity).

In vitro, varenicline binds with higher affinity to the α4β2 receptor subtype than to other common nicotinic receptors (>500-fold α3β4; >3500-fold α7; >20,000-fold α1βγδ), or to non-nicotinic receptors and transporters (>2000-fold).

Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline acts as a partial agonist at α4β2 nicotinic acetylcholine receptors. In the absence of nicotine, varenicline's agonist activity is at a significantly lower level than nicotine, but sufficient to activate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking. In the presence of nicotine, which competes for the same human α4β2 nicotinic acetylcholine receptor (nAChR) binding site, varenicline prevented nicotine from activating the α4β2 receptor, since it has higher affinity for this site and this prevented full stimulation of the central nervous mesolimbic dopamine system.

Varenicline is also a partial agonist at α3β4 receptors, but a full agonist at α7 receptors and a full agonist at 5-HT3 receptors.

Varenicline has moderate affinity for the 5-HT3 serotonergic receptor (Ki=350 nM), at which it acts as a weak, full agonist (EC₅₀=0.96 µM). Varenicline-induced nausea shortly after dosing, when gastrointestinal levels are predicted to be temporarily high, may be due to activation of this peripheral receptor, in addition to a possible role for peripheral α3β4 and/or central α4β2 nAChRs.

The elimination half-life of varenicline tartrate is approximately 24 hours. Renal elimination of varenicline is the major elimination route, primarily through glomerular filtration along with active tubular secretion via the organic cationic transporter, OCT2.

Varenicline tartrate pharmacokinetics were studied in subjects with normal, mild, moderate, severe renal impairment and end-stage renal disease (n=6 per arm), following 0.5 mg once daily administration for 12 days.

Varenicline pharmacokinetics were essentially unchanged in subjects with mild renal impairment (estimated creatinine clearance >50 mL/min and ≤80 mL/min).

In patients with moderate renal impairment (estimated creatinine clearance ≥30 mL/min and ≤50 mL/min), varenicline exposure [AUCτ] increased 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance >80 mL/min).

In subjects with severe renal impairment (estimated creatinine clearance <30 mL/min), varenicline exposure [AUCτ] was increased 2.1-fold.

In subjects with end-stage renal disease (ESRD), undergoing a three hour session of hemodialysis for three days a week, varenicline exposure [AUCτ] was increased 2.7-fold; varenicline was efficiently removed by hemodialysis (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Special Populations, Patients with Impaired Renal Function).

Varenicline tartrate undergoes minimal metabolism, with approximately 92% of recovered drug-related entity in urine being unchanged varenicline. Metabolite profiles (for circulation and urine) were similar for smokers and non-smokers, and are from the following minor routes of metabolism: N-carbomyl glucuronidation, N-formylation and conjugation with a hexose sugar.

When 22 adolescent smokers aged 12 to 17 years (inclusive) received a single 0.5 mg and 1 mg dose of varenicline the pharmacokinetics of varenicline was approximately dose proportional between the 0.5 mg and 1 mg doses. Systemic exposure, as assessed by AUC_0-∞, and renal clearance of varenicline tartrate were comparable to those of an adult population. An increase of 30% in C_max and a shorter elimination half-life (10.9 h) were observed in adolescents compared with adults.

Because the safety and effectiveness of varenicline in pediatric patients have not been established, varenicline is not recommended for use in patients under 18 years of age.