CHANTIX®
(varenicline) Tablets
WARNING:
Serious neuropsychiatric events, including, but not limited to depression, suicidal ideation, suicide attempt and completed suicide have been reported in patients taking CHANTIX. Some reported cas may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depresd mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of the symptoms have occurred in patients taking CHANTIX who continued to smoke.d day
All patients being treated with CHANTIX should be obrved for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depresd mood, and suicide-related events, including ideation, behavior, and attempted suicide. The symptoms, as well as worning of pre-existing psychiatric illness and completed suicide have been reported in some patients attempting to quit smoking while taking CHANTIX in the post-marketing experience. When symptoms were reported, mo
st were during CHANTIX treatment, but some were following discontinuation of CHANTIX therapy.
The events have occurred in patients with and without pre-existing psychiatric dia. Patients with rious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the pre-marketing studies of CHANTIX and the safety and efficacy of CHANTIX in such patients has not been established.
Advi patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, hostility, depresd mood, or changes in behavior or thinking that are not typical for the patient are obrved, or if the patient develops suicidal ideation or suicidal behavior. In many post-marketing cas, resolution of symptoms after discontinuation of CHANTIX was reported, although in some cas the symptoms persisted; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
The risks of CHANTIX should be weighed against the benefits of its u. CHANTIX has been demonstrated to increa the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial.
(See WARNINGS/Neuropsychiatric Symptoms and Suicidality,
PRECAUTIONS/Information for Patients, and ADVERSE REACTIONS/Post-Marketing Experience)
DESCRIPTION
谭凯文CHANTIX® tablets contain the active ingredient, varenicline (as the tartrate salt), which is a partial agonist lective for α4β2 nicotinic acetylcholine receptor subtypes.
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Varenicline, as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid with the following chemical name: 7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine, (2R ,3R )-2,3-dihydroxybutanedioate (1:1). It is highly soluble in water. Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of C 13H 13N 3 • C 4H 6O 6. The chemical structure is: CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debosd with "Pfizer " on one side and "CHX 0.5" on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debosd with "Pfizer " on one side and "CHX 1.0" on the other side. Each 0.5 mg CHANTIX tablet contains 0.85 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free ba; each 1mg CHANTIX tablet contains 1.71 mg of varenicline tartrate equivalent to 1 mg of varenicline free ba. The
following inactive ingredients are included in the tablets: microcrystalline cellulo, anhydrous
dibasic calcium phosphate, croscarmello sodium, colloidal silicon dioxide, magnesium
stearate, Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg), and Opadry® Clear. CLINICAL PHARMACOLOGY
Mechanism Of Action
Varenicline binds with high affinity and lectivity at α4β2 neuronal nicotinic acetylcholine receptors. The efficacy of CHANTIX in smoking cessation is believed to be the result of
varenicline’s activity at a sub-type of the nicotinic receptor where its binding produces agonist
activity, while simultaneously preventing nicotine binding to α4β2 receptors.
fullcalendarElectrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated
activity, but at a significantly lower level than nicotine. Varenicline blocks the ability of nicotine to activate α4β2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly lective and binds more potently to α4β2 receptors than to other common nicotinic receptors (>500-fold α3β4, >3500-fold α7, >20,000-fold α1βγδ), or to nonmrdt
nicotinic receptors and transporters (>2000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.
Pharmacokinetics
Absorption/Distribution
Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral dos of varenicline, steady-state conditions were reached within 4 days. Over the recommended dosing range, varenicline exhibits linear pharmacokinetics after single or repeated dos. In a mass balance study, absorption of varenicline was virtually complete after oral administration and systemic availability was high. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing. Plasma protein binding of varenicline is low (≤20%) and independent of both age and renal function. Metabolism/Elimination
The elimination half-life of varenicline is approximately 24 hours. Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular cretion possibly via the organic cation transporter, OCT2.
Pharmacokinetics In Special Patient Populations
There are no clinically meaningful differences in varenicline pharmacokinetics due to age, race, gender, smoking status, or u of concomitant medications, as demonstrated in specific pharmacoki
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netic studies and in population pharmacokinetic analys.
Renal Impairment
Varenicline pharmacokinetics were 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 incread 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance >80 mL/min). In subjects with vere renal impairment (estimated creatinine clearance <30 mL/min), varenicline exposure was incread 2.1-fold. In subjects with end-stage-renal dia (ESRD) undergoing a three hour ssion of hemodialysis for three days a week, varenicline exposure was incread 2.7-fold following 0.5 mg once daily administration for 12 days. The plasma C max and AUC of varenicline noted in this tting were similar to healthy subjects receiving about 1 mg twice daily. Caution is warranted with the u of CHANTIX in subjects with renal impairment (See DOSAGE AND ADMINISTRATION). Additionally, in subjects with ESRD, varenicline was efficiently removed by hemodialysis (See OVERDOSAGE).国家教育部考试中心
Geriatric
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A combined single and multiple-do pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given QD or BID to 16 healthy elderly male and female smokers (aged 65-75 yrs) for 7 concutive days was similar to that of younger subjects. Pediatric
Becau the safety and effectiveness of CHANTIX in pediatric patients have not been established, CHANTIX is not recommended for u in patients under 18 years of age.
When 22 pediatric patients aged 12 to 17 years (inclusive) received a single 0.5 mg and 1 mgdo of varenicline, the pharmacokinetics of varenicline was approximately do proportional between the 0.5 mg and 1 mg dos. Systemic exposure, as assd by AUC(0-∞), and renal clearance of varenicline were comparable to tho of an adult population.
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Hepatic Impairment
Due to the abnce of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic insufficiency.
Drug-Drug Interactions
Drug interaction studies were performed with varenicline and digoxin, warfarin, transdermal nicotine,
bupropion, cimetidine and metformin. No clinically meaningful pharmacokinetic drug- drug interactions have been identified.
In vitro studies demonstrated that varenicline does not inhibit the following cytochrome P450 enzymes (IC50 >6400 ng/mL): 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline does not induce the cytochrome P450 enzymes 1A2 and 3A4.
In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal cretion (e.g. metformin - e below) are unlikely to be affected by varenicline.
In vitro studies demonstrated the active renal cretion of varenicline is mediated by the human organic cation transporter, OCT2. Co-administration with inhibitors of OCT2 may not require a do adjustment of CHANTIX as the increa in systemic exposure to CHANTIX is not expected to be clinically meaningful (e Cimetidine interaction below). Furthermore, since metabolism of varenicline reprents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of CHANTIX (e Pharmacokinetics) and therefor
e a do adjustment of CHANTIX would not be required. Metformin: 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 OCT2. Metformin had no effect on varenicline steady-state pharmacokinetics.
Cimetidine: Co-administration of an OCT2 inhibitor, cimetidine (300 mg QID), with varenicline (2 mg single do) to 12 smokers incread the systemic exposure of varenicline by 29% (90% CI: 21.5%, 36.9%) due to a reduction in varenicline renal clearance.
Digoxin: Varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily do in 18 smokers.
Warfarin: Varenicline (1 mg BID) did not alter the pharmacokinetics of a single 25 mg do of (R, S)-warfarin in 24 smokers. Prothrombin time (INR) was not affected by varenicline. Smoking cessation itlf may result in changes to warfarin pharmacokinetics (e PRECAUTIONS).
U with other therapies for smoking cessation:
Bupropion: Varenicline (1 mg BID) did not alter the steady-state pharmacokinetics of bupropion
(150 mg BID) in 46 smokers. The safety of the combination of bupropion and varenicline has not been established.
Nicotine replacement therapy (NRT): Although co-administration of varenicline (1 mg BID) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of naua, headache, vomiting, dizziness, dyspepsia and fatigue was greater for the combination than for NRT alone. In this study, eight of twenty-two (36%) subjects treated with the combination of varenicline and NRT prematurely discontinued treatment due to adver events, compared to 1 of 17 (6%) of subjects treated with NRT and placebo.
Safety and efficacy of CHANTIX in combination with other smoking cessation therapies have not been studied.
CLINICAL STUDIES
The efficacy of CHANTIX in smoking cessation was demonstrated in six clinical trials in which a total of 3659 chronic cigarette smokers (≥10 cigarettes per day) were treated with CHANTIX. In all clinical studies, abstinence from smoking was determined by patient lf-report and verified by measurement of exhaled carbon monoxide (CO≤10 ppm) at weekly visits. Among the CHANTIX treat
ed patients enrolled in the studies, the completion rate was 65%. Except for the initial Pha 2 study (Study 1) and the maintenance of abstinence study (Study 6), patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. Most subjects enrolled in the trials were white (79% - 96%). All studies enrolled almost equal numbers of men and women. The average age of subjects in the studies was 43 years. Subjects on average had smoked about 21 cigarettes per day for an average of approximately 25 years.
In all studies, patients were provided with an educational booklet on smoking cessation and received up to 10 minutes of smoking cessation counling at each weekly treatment visit according to Agency for Healthcare Rearch and Quality guidelines. Patients t a date to stop smoking (target quit date, TQD) with dosing starting 1 week before this date.
Initiation of Abstinence
infocenter>hard是什么意思Study 1: This was a six-week do-ranging study comparing CHANTIX to placebo. This study provided initial evidence that CHANTIX at a total do of 1 mg per day or 2 mg per day was effective as an aid to smoking cessation.
Study 2: This study of 627 subjects compared CHANTIX 1 mg per day and 2 mg per day with placeb
o. Patients were treated for 12 weeks (including one week titration) and then were followed for 40 weeks post-treatment. CHANTIX was given in two divided dos. Each do of CHANTIX was given in two different regimens, with and without initial do titration, to explore the effect of different dosing regimens on tolerability. For the titrated groups, dosage was titrated up over the cour of one week, with full dosage achieved starting with the cond week of dosing. The titrated and nontitrated groups were pooled for efficacy analysis.
Forty five percent of subjects receiving CHANTIX 1 mg per day (0.5 mg BID) and 51% of subjects receiving 2 mg per day (1 mg BID) had CO-confirmed continuous abstinence during
