CHAMPIX(r) 0.5 mg and 1 mg film-coated tablets. Champix film-coated tablets contain the active ingredient varenicline (as tartrate). Chemical name: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino [2,3-h] [3] benzazepine, (2R, 3R)-2,3-dihydroxybutanedioate (1:1). Chemical structure:
OH
HOOC
R
R
COO
OH
H2 N
N N
Molecular weight: 361.35 Daltons. Molecular formula: C13H13N3 C4H6O6. CAS Registry No: 375815-87-5.
Varenicline tartrate powder is a white to off-white to slightly yellow solid. It is highly soluble in water. The pKa (ionisation constant) for varenicline is 9.2. The octanol-water partition coefficient (Log D) of varenicline tartrate is -1.23 at pH 5, -0.817 at pH 7 and 0.758 at pH 9. Champix contains the following inactive ingredients: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, silica - colloidal anhydrous, magnesium stearate, Opadry(r) White (for 0.5 mg), Opadry(r) Blue (for 1 mg), and Opadry(r) Clear.
Pharmacotherapeutic group: Drugs used in nicotine dependence, ATC code: N07BA. Varenicline is a partial agonist at a4b2 neuronal nicotinic acetylcholine receptors where it binds with high affinity and selectivity to produce an effect sufficient to alleviate symptoms of craving and withdrawal (agonist activity), while simultaneously resulting in blockade of the rewarding and reinforcing effects of smoking by preventing nicotine binding to a4b2 receptors (antagonist activity). Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to a4b2 neuronal nicotinic acetylcholine receptors and stimulates receptor- mediated activity. The maximal activity of varenicline was approximately 30-50% that of nicotine in vitro and ranged from 30-60% that of nicotine in vivo. Varenicline blocks the ability of nicotine to activate the a4b2 receptor and thus to stimulate the central nervous mesolimbic dopamine system, the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds with higher affinity to the a4b2 receptor subtype than to other common nicotinic receptors (>500-fold a3b4, >3,500- fold a7, >20,000-fold a1bgd), or to non-nicotinic receptors and transporters (>2,000-fold).
Absorption
Maximum plasma concentrations of varenicline tartrate occur typically within 3-4 hours after oral administration. Mean (SD) Cmax was 9.22 (2.05) ng/mL at the recommended dose of 1 mg twice daily. Following administration of multiple oral doses to healthy volunteers, steady- state conditions were reached within 4 days. Varenicline tartrate exhibits linear kinetics when given as single or repeated doses. Absorption is virtually complete after oral administration and systemic availability is high. Oral bioavailability of varenicline tartrate is unaffected by food or time-of-day dosing.
Distribution
Plasma protein binding of varenicline tartrate is low (<20%) and independent of both age and renal function. Apparent volume of distribution averaged 415 litres (%CV=50) at steady- state.
Metabolism
Varenicline tartrate undergoes minimal metabolism with 92% eliminated unchanged in the urine.
Elimination
The elimination half-life of varenicline tartrate is approximately 24 hours (individual range 10-58 hr). Renal elimination of varenicline tartrate is primarily through glomerular filtration along with active tubular secretion via the organic cationic transporter, OCT2.
Special Populations
There are no clinically meaningful differences in varenicline tartrate pharmacokinetics due to age, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.
Hepatic Impairment
Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic insufficiency and the potential for clinically meaningful drug interactions between varenicline and metabolic inhibitors/inducers is low.
Renal Impairment
Varenicline tartrate pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance >50mL/min and <=80mL/min); in patients with moderate renal impairment (estimated creatinine clearance >=30mL/min and <=50mL/min), varenicline tartrate exposure increased 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance >80mL/min). In subjects with severe renal impairment (estimated creatinine clearance <30mL/min), varenicline tartrate exposure increased 2.1-fold. In subjects with end-stage-renal disease (ESRD), varenicline tartrate was efficiently removed by haemodialysis. While no dosing adjustment is necessary for patients with mild to moderate renal impairment, a reduced dosing frequency of 1 mg once daily is recommended for patients with severe renal impairment (see DOSAGE AND ADMINISTRATION). Dosing should begin at 0.5 mg once daily for the first 3 days, and then increase to 1 mg once daily.
Elderly (>65 years)
No dosage adjustment is necessary for elderly patients (see DOSAGE AND ADMINISTRATION). A combined single and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline tartrate given once or twice daily to 16 healthy elderly male and female smokers (aged 65-75 years) for 7 consecutive days were similar to that of younger subjects.
Children and Adolescents
Because the safety and effectiveness of varenicline tartrate in paediatric patients have not been established, varenicline is not recommended for use in patients under 18 years of age. Single and multiple-dose pharmacokinetics of varenicline have been investigated in paediatric subjects aged 12 to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied. Steady-state systemic exposure in adolescent patients of bodyweight >55 kg, as assessed by AUC (0-24), was comparable to that noted for the same doses in the adult population. When a 0.5 mg dose was given twice a day, steady- state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight <= 55 kg compared to that seen in the adult population.
The efficacy of CHAMPIX in smoking cessation was demonstrated in three pre-marketing clinical trials in which a total of 2,619 chronic cigarette smokers (>=10 cigarettes per day) received varenicline. Two of these studies were double-blind comparisons between varenicline, bupropion and placebo, assessing critical aspects of smoking cessation, including end-of-treatment and long-term abstinence rates after 12 weeks of treatment. In addition, the effects on reducing craving and withdrawal that can occur during smoking cessation and the reinforcing effects that can perpetuate smoking behaviour were studied. The third study assessed the effect of an additional 12 weeks of treatment on maintaining long-term abstinence.
Two identical double-blind clinical trials prospectively compared the efficacy of CHAMPIX (1 mg twice daily), sustained release bupropion (150 mg twice daily) and placebo in smoking cessation. Patients were treated for 12 weeks and then were followed up for a total study duration of 52 weeks. The CHAMPIX dosage of 1 mg twice daily was achieved using a titration of 0.5 mg once daily for the initial 3 days followed by 0.5 mg twice daily for the next 4 days. The bupropion dosage of 150 mg twice daily was achieved using a 3-day titration of 150 mg once daily. Patients set a date to stop smoking (target quit date, TQD) with dosing starting 1-2 weeks before this date. The primary endpoint of the two studies was the carbon monoxide (CO) confirmed, 4-week continuous quit rate (4W-CQR) from week 9 through week 12. The quit rates are the proportions of all patients treated (i.e., intent-to-treat analysis) who abstained from smoking. The primary endpoint for CHAMPIX demonstrated statistical superiority to bupropion and placebo. Key secondary endpoints for both studies were Continuous Abstinence (CA) from weeks 9-52 and the Long Term Quit Rate (LTQR) at week 52. CA was defined as the proportion of all subjects who did not smoke (not even a puff of a cigarette) from week 9 through week 52 and had an exhaled CO measurement of <=10 ppm. LTQR was defined as the proportion of all subjects treated who were responders for the primary endpoint in the treatment phase and had no more than 6 days of cigarette smoking during the non-treatment phase. In both studies the CO-confirmed 4-week CQR for week 9 through week 12 was superior (p<0.0001) for patients given CHAMPIX compared with the placebo and bupropion groups. Based on this endpoint, the odds of stopping on CHAMPIX were 3.91 (95% CI: 2.74, 5.59) and 3.85 (2.69, 5.50) times those of stopping on placebo in Studies 1 and 2 respectively; the odds of stopping on CHAMPIX were 1.96 (1.42, 2.72) to 1.89 (1.37, 2.61) times those of stopping on bupropion. The 4W-CQR (weeks 9-12), CA (weeks 9-52) and LTQR (week 52) from Studies 1 and 2 are included in the following table:
| Table 1 Continuous Quit Rates, Continuous Abstinence and Long Term Quit Rates for Studies 1 and 2 | ||||||
| Study 1 n=1022 | Study 2 n=1023 | |||||
| 4W CQR | CA wk 9-52 | LTQR wk 52 | 4W CQR | CA wk 9-52 | LTQR wk 52 | |
| CHAMPIX | 44.4% a | 22.1% b | 25.5% c | 44.0% a | 23.0% d | 25.4% e |
| Bupropion | 29.5% | 16.4% | 17.9% | 30.0% | 15.0% | 18.2% |
| Placebo | 17.7% | 8.4% | 9.6% | 17.7% | 10.3% | 12.6% |
a
p <0.0001 vs. placebo and bupropion
b p <0.0001 vs. placebo, p=0.0640 vs. bupropion c p <0.0001 vs. placebo, p=0.0161 vs. bupropion d p <0.0001 vs. placebo, p=0.0062 vs. bupropion e p <0.0001 vs. placebo, p=0.0205 vs. bupropion Based on the key secondary endpoint of carbon monoxide confirmed (not even a puff of a cigarette) Continuous Abstinence from week 9 through week 52 (CA weeks 9-52), the odds of stopping on CHAMPIX were 2.66 (95% CI: 1.72, 4.11) and 3.13 (1.97, 4.97) times those of stopping on placebo in Studies 1 and 2 respectively. For the LTQR at 52 weeks the odds of stopping smoking on CHAMPIX were 3.30 (2.13, 5.11) and 2.40 (1.60, 3.60) times those of stopping on placebo in Studies 1 and 2, respectively.
In Studies 1 and 2, three aspects of smoking cessation were investigated using validated Patient Reported Outcomes questionnaires: Craving, measured by Brief Questionnaire of Smoking Urges (QSU-Brief) and Minnesota Nicotine Withdrawal Scale (MNWS) Urge to Smoke item; Withdrawal, measured by 4 MNWS subscales; and Reinforcing Effects of Smoking, measured by five Modified Cigarette Evaluation Questionnaire (mCEQ) subscales. Across both Studies 1 and 2, craving and withdrawal were significantly reduced in patients randomised to CHAMPIX in comparison with placebo. CHAMPIX also significantly reduced reinforcing effects of smoking that can perpetuate smoking behaviour in patients who smoke during treatment compared with placebo.
The third study assessed the benefit of an additional 12 weeks of CHAMPIX therapy on the maintenance of abstinence. Patients in this study (n=1,927) received open-label CHAMPIX 1 mg twice daily for 12 weeks. Patients who stopped smoking by week 12 were then randomised to receive either CHAMPIX (1 mg twice daily) or placebo for an additional 12 weeks for a total study duration of 52 weeks. The primary study endpoint was the CO-confirmed continuous abstinence rate from week 13 through week 24 in the double-blind treatment phase. The two key secondary endpoints were the continuous abstinence (CA) rate for week 13 through week 52 and the long-term quit rate (LTQR) at week 52. The key results are summarised in the following table:
| Table 2 Continuous Abstinence and Long Term Quit Rates for Maintenance of Abstinence Study | ||
| CHAMPIX n=602 | Placebo n=604 | |
| CA wk 13-24 | 70.6% * | 49.8% |
| CA wk 13-52 | 44.0% * * | 37.1% |
| LTQR at week 52 | 47.8% * * * | 40.7% |
| *p<0.0001 vs. placebo, * *p=0.0126 vs. placebo, * * *p=0.0119 vs. placebo | ||
This study showed the benefit of an additional 12-week treatment with CHAMPIX 1 mg twice daily for the maintenance of smoking cessation compared to placebo. The odds of maintained abstinence at week 24, following an additional 12 weeks of treatment with CHAMPIX, were 2.47 times those for placebo (95% CI: 1.95, 3.15). Superiority to placebo for continuous abstinence was maintained through week 52 (Odds Ratio = 1.35, 95% CI: 1.07, 1.70).
Varenicline was evaluated in a randomised, double-blind, placebo-controlled study of 703 patients with stable, documented cardiovascular disease (other than or in addition to hypertension) that had been diagnosed for more than 2 months. Patients aged 35 to 75 years were randomised to varenicline 1 mg twice a day or placebo for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Patients treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (47.3 %) compared to patients treated with placebo (14.3%) (odds ratio 6.05; 95% CI 4.13, 8.86; p<0.0001) and from week 9 through 52 (19.8%) compared to patients treated with placebo (7.4%) (odds ratio 3.19; 95% CI 1.97, 5.18; p<0.0001). The key results are summarized in the following table:
| Table 3 Rates of CO-confirmed abstinence for Patients with Cardiovascular Disease | |||
| Varenicline n=353 | Placebo n=350 | Odds ratio (95% CI), p value | |
| CA wk 9-12 | 47.3% | 14.3% | 6.05 (4.13, 8.86) p<0.0001 |
| CA wk 9-52 | 19.8% | 7.4% | 3.19 (1.97, 5.18) p<0.0001 |
Varenicline was evaluated in a randomised, double-blind, placebo-controlled study of patients aged 35 years with mild-to-moderate COPD with post-bronchodilator FEV1/FVC <70% and FEV1 50% of predicted normal value. Patients were randomised to varenicline 1 mg twice daily (N=223) or placebo (N=237) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Patients treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (41.7%) compared to patients treated with placebo (9.3%) and from week 9 through 52 (19.7%) compared to patients treated with placebo (5.9%). The key results are summarised in the following table:
| Table 4 Rates of CO-confirmed abstinence for Patients with Chronic Obstructive Pulmonary Disease | |||
| Varenicline n=223 | Placebo n=237 | Odds ratio (95% CI), p value | |
| CA wk 9-12 | 41.7% | 9.3% | 7.65 (4.51, 12.97) p<0.0001 |
| CA wk 9-52 | 19.7% | 5.9% | 4.19 (2.19, 8.00) p<0.0001 |
The effect of varenicline 1 mg twice a day in a flexible, patient-selected quit date setting was assessed in a double-blind, placebo-controlled study of 651 patients. Patients were randomised 3:1 to varenicline or placebo for a treatment of 12 weeks and a followed up post- treatment for another 12 weeks. In this study, 486 patients received varenicline and 165 received placebo. Patients were instructed to select a quit date after the initial week of dose titration and before the clinical visit at the end of week 5 of treatment. Patients treated with varenicline had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (53.94%) compared to patients treated with placebo (19.4%) (odds ratio 6.03; 95% CI 3.80, 9.56; p<0.0001) and from week 9 through 24 (35.2%) compared to patients treated with placebo (12.73%) (odds ratio 4.45; 95% CI 2.62, 7.55; p<0.0001). Adverse events in this study were quantitatively and qualitatively similar to those observed in premarketing studies. The key results are summarized in the following table:
| Table 5 Rates of CO-confirmed abstinence for Flexible Quit Date Study | |||
| Varenicline n=486 | Placebo n=165 | Odds ratio (95% CI), p value | |
| CA wk 9-12 | 53.9% | 19.4% | 6.03 (3.80, 9.56), p<0.0001 |
| CA wk 9-24 | 35.2% | 12.7% | 4.45 (2.62, 7.55) p<0.0001 |
CHAMPIX is indicated as an aid to smoking cessation in adults over the age of 18 years.
Hypersensitivity to the active substance or to any of the excipients.
Physiological changes resulting from smoking cessation, with or without treatment with CHAMPIX, may alter pharmacokinetics or pharmacodynamics of some drugs, for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). As smoking induces CYP1A2, smoking cessation may result in an increase of plasma levels of CYP1A2 substrates. Smoking cessation, with or without pharmacotherapy, has been associated with the exacerbation of underlying psychiatric illness (e.g. depression). Care should be taken with patients with a history of psychiatric illness and patients should be advised accordingly. There is no clinical experience with CHAMPIX in patients with epilepsy. At the end of treatment, discontinuation of CHAMPIX was associated with an increase in irritability, urge to smoke, depression, and/or insomnia in up to 3% of patients. The prescriber should inform the patient accordingly.
Serious neuropsychiatric symptoms have occurred in patients being treated with CHAMPIX. Some cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking; however, some of these symptoms have occurred in patients who continued to smoke. Although a causal association between CHAMPIX and these symptoms has not been established, in some reports the association cannot be excluded. Patients being treated with CHAMPIX and their families should be alerted to the need to monitor for neuropsychiatric symptoms including changes in behaviour or thinking, anxiety, psychosis, mood swings, agitation, aggression, depressed mood, suicidal ideation and suicidal behaviour. Doctors should discuss the efficacy and safety profile of CHAMPIX with patients attempting to quit smoking with CHAMPIX and advise them of the possible emergence of neuropsychiatric symptoms. These symptoms, as well as worsening of pre-existing psychiatric illness, have been reported in patients attempting to quit smoking while taking CHAMPIX in the post-marketing experience. Patients and their families should be advised that the patient should stop taking CHAMPIX and contact a health care professional immediately if changes in behaviour or thinking, agitation or depressed mood, that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behaviour. In many post-marketing cases, resolution of symptoms after discontinuation of CHAMPIX was reported, although in some cases the symptoms persisted; therefore, ongoing follow up should be provided until symptoms resolve. Patients and their families should be encouraged to report any history of psychiatric illness prior to initiating treatment. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the pre-marketing studies of CHAMPIX and the safety and efficacy of CHAMPIX in such patients has not been established.
There have been post-marketing reports of hypersensitivity reactions including angioedema in patients treated with CHAMPIX. Clinical signs included swelling of the face, mouth (tongue, lips and gums), neck (throat and larynx) and extremities. There were rare reports of life- threatening angioedema requiring urgent medical attention due to respiratory compromise. Patients experiencing these symptoms should discontinue treatment with CHAMPIX and contact a health care provider immediately (see ADVERSE EFFECTS, Post-Marketing Experience).
There have also been post-marketing reports of rare but severe cutaneous reactions, including Stevens-Johnson Syndrome and Erythema Multiforme in patients using CHAMPIX. As these skin reactions can be life-threatening, patients should discontinue treatment at the first sign of rash or skin reaction and contact a healthcare provider immediately (see ADVERSE EFFECTS, Post-Marketing Experience).
In a post-marketing randomised, controlled study of 703 patients with stable cardiovascular disease, deaths and serious cardiovascular events occurring over the 52 weeks of the study (treatment-emergent and non-treatment-emergent) were adjudicated by a blinded, independent committee. Certain cardiovascular events were reported more frequently in patients treated with varenicline. The following adjudicated treatment-emergent events (on-treatment or up to 30 days after treatment) occurred with a frequency 1% in either treatment group: nonfatal myocardial infarction (1.1% vs. 0.3% for varenicline and placebo, respectively), and hospitalisation for angina pectoris (0.6% vs 1.1%). During non-treatment follow up to 52 weeks, adjudicated events with a frequency >=1% included need for coronary revascularisation (2.0% vs. 0.6%), hospitalisation for angina pectoris (1.7% vs. 1.1%), and new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiring coronary revascularisation underwent the procedure as part of management of nonfatal MI and hospitalisation for angina. Cardiovascular death occurred in 0.3% of patients in the varenicline arm and 0.6% of patients in the placebo arm over the course of the 52 week study. No causal relationship between these events and varenicline has been established. Smoking is an independent and major risk factor for cardiovascular disease. Patients should be advised to seek medical attention in the event of new or worsening symptoms of cardiovascular disease. Patients with known cardiovascular disease require ongoing assessment and management of other risk factors for cardiovascular disease. (See CLINICAL TRIALS -Cardiovascular Disease Study).
Patients should be advised to use caution driving or operating machinery until they know how quitting smoking and/or CHAMPIX may affect them.
It is not expected that varenicline tartrate would impair fertility. Varenicline did not impair fertility in rats at oral doses producing plasma concentrations up to 40 times the human plasma Cmax at the maximal recommended dose of 1 mg twice daily. Offspring of treated rats have shown decreased fertility (see Use in Pregnancy).
Pregnancy Category: B3 The safety of varenicline tartrate in human pregnancy has not been established. The use of CHAMPIX in pregnant women is not recommended. There was no evidence of teratogenicity following oral administration of varenicline to rats and rabbits during organogenesis with systemic exposure (plasma AUC) up to 36 times the human plasma AUC at the maximal recommended dose of 1 mg twice daily. In animal reproduction studies, varenicline has been shown to have adverse effects on the foetus and offspring. Oral administration of varenicline to pregnant rabbits during organogenesis resulted in reduced foetal weights at systemic exposure (plasma AUC) 50 times the human plasma AUC at the maximal recommended dose; the no-effect exposure was 23 times the clinical exposure. Oral administration of varenicline to pregnant rats from early gestation until weaning resulted in reduced fertility, increased auditory startle response and decreased rearing in offspring at maternal plasma concentrations 40 times the human plasma Cmax at the maximal recommended dose; the no-effect exposure was 17 times clinical exposure. Women of child bearing potential: Where drug therapy is initiated, treatment should be timed such that the course is completed before conception.
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 effects in nursing infants from CHAMPIX is unknown, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Varenicline is excreted in the milk of lactating rats. Oral administration of varenicline to pregnant rats from early gestation until weaning was associated with adverse effects in offspring (see Use in Pregnancy). The clinical significance of this finding is unknown.
Safety and effectiveness of CHAMPIX in paediatric patients have not been established; therefore, CHAMPIX is not recommended for use in patients under 18 years of age (see PHARMACOLOGY, Pharmacokinetics).
No dosage adjustment is necessary for elderly patients (see PHARMACOLOGY, Pharmacokinetics). Because elderly patients are more likely to have decreased renal function, prescribers should consider the renal status of an elderly patient.
Carcinogenicity studies were performed in mice and rats at respective oral doses of varenicline up to 20 mg/kg/day and 15 mg/kg/day for 2 years, with respective systemic drug exposure (Cmax) up to 130 and 50 times the human plasma Cmax at the maximal recommended dose of 1 mg twice daily. There was no evidence of carcinogenicity in mice or female rats. Male rats showed increased incidences of hibernoma (a rare tumour of brown fat) at systemic exposures of 25 times the human Cmax (incidence 1/65 rats) and 50 times the human Cmax (incidence 2/65 rats); the no-effect exposure was 10 times the human Cmax. The clinical relevance of this finding has not been established.
Varenicline had no genotoxic effects, with or without metabolic activation, based on the following assays: Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenic aberrations in vivo in rat bone marrow and in vitro in human lymphocytes.
Based on varenicline characteristics and clinical experience to date, varenicline has no known clinically meaningful drug interactions. No dosage adjustment of varenicline or co- administered drugs listed below is recommended. In vitro studies demonstrate that varenicline tartrate does not inhibit cytochrome P450 enzymes (IC50> 6,400 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 was shown not to induce the activity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, varenicline tartrate is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes.
In vitro
studies demonstrate that varenicline tartrate does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (e.g. metformin - see below) are unlikely to be affected by varenicline tartrate.
In vitro
studies demonstrate that active renal secretion of varenicline tartrate is mediated by the human organic cation transporter, OCT2. Co-administration with inhibitors of OCT2 does not require a dose adjustment of CHAMPIX as the increase in systemic exposure to varenicline tartrate is not expected to be clinically meaningful (see cimetidine interaction below). Furthermore since metabolism of varenicline tartrate contributes to less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of varenicline tartrate (see PHARMACOLOGY, Pharmacokinetics) and therefore a dose adjustment of CHAMPIX would not be required.
Metformin:
Varenicline tartrate (1 mg twice daily) did not affect the pharmacokinetics of metformin (500 mg twice daily), which is a substrate of OCT2. Metformin had no effect on varenicline pharmacokinetics.
Cimetidine:
Co-administration of an OCT2 inhibitor, cimetidine (300 mg four times daily), with varenicline (2 mg single dose) increased the systemic exposure of varenicline by 29% 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.
Digoxin:
Varenicline tartrate (1 mg twice daily) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily dose.
Warfarin:
Varenicline tartrate (1 mg twice daily) did not alter the pharmacokinetics of a single 25 mg dose of (R,S)-warfarin. Prothrombin time (INR) was not affected by varenicline tartrate. Smoking cessation itself may result in changes to warfarin pharmacokinetics (see PRECAUTIONS).
Bupropion:
Varenicline tartrate (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily).
Nicotine Replacement Therapy (NRT):
When varenicline (1 mg twice daily) and nicotine replacement therapy (transdermal 21 mg/day) were co-administered to smokers (N=24) for 12 days, there was a statistically significant decrease in average systolic blood pressure (mean
mmHg) measured on the final day of the study. In this study, the incidence of nausea, headache, vomiting, dyspepsia, fatigue and dizziness was greater for the combination than for NRT alone. Safety and efficacy of CHAMPIX in combination with other smoking cessation therapies have not been studied.
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. No attempt has been made in either the design or the analysis of the CHAMPIX studies to distinguish between adverse effects associated with study drug treatment or those possibly associated with nicotine withdrawal. Clinical trials included approximately 4,000 patients treated with CHAMPIX for up to 1 year (average exposure 84 days). In general, where adverse events occurred, onset was in the first week of therapy; severity was generally mild to moderate and there were no differences by age, race or gender with regard to the incidence of adverse effects. The treatment discontinuation rate was 11.4% for varenicline compared with 9.7% for placebo. In this group, the discontinuation rates for the most common adverse events in varenicline treated patients were as follows: nausea (2.7% vs. 0.6% placebo), headache (0.6% vs. 1.0% for placebo), insomnia (1.3% vs. 1.2% for placebo), and abnormal dreams (0.2% vs. 0.2% for placebo). Table 6 includes the most frequently occurring events (at a rate of >=1% and an incidence higher than that for placebo). These data are derived from a pooled database of studies in which patients were randomised to receive 12 weeks of treatment using the recommended dosage regimen.
| Table 6 Adverse Events Considered Treatment-Related and Reported in Studies at a Rate >=1% and at an Incidence Higher than Placebo, Conducted Using the Recommended Dosage Regimen | ||
| Percentage of Patients Reporting Event | ||
| CHAMPIX N=821 | Placebo N=805 | |
| Gastrointestinal Disorders | 28.6 | 8.8 |
| Nausea | ||
| Constipation | 5.8 | 2.2 |
| Flatulence | 5.1 | 2.5 |
| Dry mouth | 5.6 | 4.1 |
| Dyspepsia | 3.8 | 1.5 |
| Vomiting | 4.1 | 0.7 |
| Abdominal Distension | 1.3 | 0.4 |
| Stomach Discomfort | 1.1 | 0.5 |
| General Disorders and Administration Site Conditions Fatigue | 4.6 | 3.9 |
| Metabolism and Nutrition Disorders Increased Appetite | 1.7 | 1.2 |
| Nervous System Disorders | 10.1 | 8.4 |
| Headache | ||
| Dizziness | 5.2 | 4.6 |
| Dysgeusia | 5.0 | 3.6 |
| Somnolence | 3.0 | 2.1 |
| Psychiatric Disorders | 13.8 | 10.6 |
| Insomnia | ||
| Abnormal Dreams | 12.4 | 4.5 |
| Sleep Disorder | 4.8 | 2.9 |
In the listings below all adverse effects, which occurred at a rate lower than 1% and greater than placebo are listed by system organ class and frequency (uncommon (>=1/1,000, <1/100).
| System Organ Class | Adverse Drug Effects |
| Infections and Infestations | |
| Uncommon | Bronchitis, nasopharyngitis, sinusitis, fungal infection, viral infection |
| Metabolism and Nutrition Disorders | |
| Uncommon | Anorexia, decreased appetite, polydipsia |
| Psychiatric Disorders | |
| Uncommon | Panic reaction, bradyphrenia, thinking abnormal, mood swings |
| Nervous System Disorders | |
| Uncommon | Tremor, coordination abnormal, dysarthria, hypertonia, restlessness, dysphoria, hypoaesthesia, hypogeusia, lethargy, libido increased, libido decreased, convulsion + |
| Cardiac Disorders | |
| Uncommon | Atrial fibrillation, palpitations |
| Vascular Disorders | |
| Uncommon | Hot flush, varicose vein |
| Eye Disorders | |
| Uncommon | Scotoma, scleral discolouration, eye pain, mydriasis, photophobia, myopia, lacrimation increased |
| Ear and Labyrinth Disorders | |
| Uncommon | Tinnitus |
| Respiratory, Thoracic and Mediastinal Disorders | |
| Uncommon | Dyspnoea, cough, hoarseness, pharyngolaryngeal pain, throat irritation, respiratory tract congestion, sinus congestion, post nasal drip, rhinorrhoea, snoring |
| Gastrointestinal Disorders | |
| Uncommon | Haematemesis, haematochezia, gastritis, gastro-oesophageal reflux disease, abdominal pain, change of bowel habit, salivary hypersecretion, abnormal faeces, eructation, aphthous stomatitis, gingival pain, tongue coated |
| Skin and Subcutaneous Tissue Disorders | |
| Uncommon | Rash generalised, erythema, pruritus, acne, hyperhidrosis, night sweats |
| Musculoskeletal and Connective Tissue Disorders | |
| Uncommon | Joint stiffness, muscle spasms, chest wall pain, costochondritis |
| Renal and Urinary Disorders | |
| Uncommon | Glycosuria, nocturia, polyuria |
| System Organ Class | Adverse Drug Effects |
| Reproductive System and Breast Disorders | |
| Uncommon | Menorrhagia, vaginal discharge, sexual dysfunction |
| General Disorders and Administration Site Conditions | |
| Uncommon | Chest discomfort, chest pain, pyrexia, feeling cold, asthenia, circadian rhythm sleep disorder, malaise, cyst |
| Investigations | |
| Uncommon | Blood pressure increased, electrocardiogram ST segment depression, electrocardiogram T wave amplitude decreased, heart rate increased, liver function test abnormal, platelet count decreased, weight increased, semen abnormal, C-reactive protein increased, blood calcium decreased. |
Special populations+
Studies have been conducted on patients with cardiovascular disease (CV) and chronic obstructive pulmonary disease (COPD). Safety analyses included all subjects who received at least one dose of the study drug. (See CLINICAL TRIALS and PRECAUTIONS, Cardiovascular Events). The most commonly reported adverse events (incidence 2% in the varenicline group and at an incidence higher than placebo) considered treatment related in studies in patients with CV disease and COPD are shown below in Table 7 and Table 8 respectively.
| Table 7 Adverse Events Considered Treatment Related and Reported at a Rate >=2% and at an Incidence Higher than Placebo in the CVD Study | ||
| Percentage of Patients Reporting Event | ||
| CHAMPIX N=353 | Placebo N=350 | |
| Gastrointestinal Disorders | 27.8 | 7.4 |
| Nausea | ||
| Vomiting | 6.8 | 0.9 |
| Constipation | 5.1 | 1.4 |
| Diarrhoea | 4.5 | 2.9 |
| Dyspepsia | 4.0 | 2.3 |
| Abdominal Pain Upper | 3.7 | 2.0 |
| Dry mouth | 3.1 | 1.7 |
| Flatulence | 2.3 | 2.0 |
| Abdominal Distension | 2.0 | 0.9 |
| General Disorders and Administration Site Conditions Fatigue | 5.1 | 2.3 |
| Nervous System Disorders | 10.2 | 8.0 |
| Headache | ||
| Dizziness | 4.8 | 2.9 |
| Dysgeusia | 4.5 | 2.0 |
| Psychiatric Disorders | 9.6 | 4.9 |
| Insomnia | ||
| Abnormal Dreams | 7.9 | 1.7 |
| Sleep Disorder | 3.1 | 1.4 |
CVD= cardiovascular disease. Patients are only counted once per treatment in each row. Includes data up to 30 days after last dose of study drug.
| Table 8 Adverse Events Considered Treatment-Related and Reported at a Rate >=2% and at an Incidence Higher than Placebo in the COPD Study | ||
| Percentage of Patients Reporting Event | ||
| CHAMPIX N=248 | Placebo N=251 | |
| Gastrointestinal Disorders | 26.6 | 6.8 |
| Nausea | ||
| Flatulence | 6.9 | 4.8 |
| Vomiting | 6.0 | 0.8 |
| Dry mouth | 4.8 | 1.6 |
| Constipation | 3.6 | 1.6 |
| Dyspepsia | 3.2 | 0.4 |
| Abdominal Pain | 2.8 | 0.4 |
| Diarrhoea | 2.8 | 1.6 |
| Gastrooesophageal reflux disease | 2.8 | 1.2 |
| General Disorders and Administration Site Conditions | 3.6 | 0 |
| Fatigue | ||
| Irritability | 2.0 | 1.2 |
| Metabolism and Nutrition Disorders Decreased Appetite | 2.0 | 0 |
| Nervous System Disorders | 6.5 | 4.8 |
| Headache | ||
| Dysgeusia | 2.8 | 2.4 |
| Psychiatric Disorders | 9.3 | 2.4 |
| Abnormal Dreams | ||
| Insomnia | 8.5 | 3.2 |
COPD= chronic obstructive pulmonary disease. Patients are only counted once per treatment in each row. Includes data up to 30 days after last dose of study drug.
Post-Marketing Experience
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 neuropsychiatric symptoms such as depressed mood, agitation, hallucinations, changes in behaviour or thinking, anxiety, psychosis, mood swings, aggressive behaviour, 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 discontinued smoking. The role of CHAMPIX in these reports is not known (see PRECAUTIONS). There have also been reports of hypersensitivity reactions, such as angioedema and of rare but severe cutaneous reactions, including Stevens-Johnson Syndrome and Erythema Multiforme in patients taking CHAMPIX (see PRECAUTIONS). There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischaemic and haemorrhagic events in patients taking CHAMPIX. In the majority of the reported cases, patients had pre-existing cardiovascular disease and/or other risk factors. Although smoking is a risk factor for MI and CVA, based on temporal relationship between medication use and events, a contributory role of varenicline cannot be ruled out. There have also been post- marketing reports of diabetes mellitus and hyperglycaemia+.
Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided with additional advice and support. The recommended dose of CHAMPIX is 1 mg twice daily following a 1-week titration as follows:
| Days 1 - 3: | 0.5 mg once daily |
| Days 4 - 7: | 0.5 mg twice daily |
| Day 8 - End of Treatment: | 1 mg twice daily |
The patient should set a date to stop smoking. CHAMPIX dosing should start 1 - 2 weeks before this date. Alternatively, a flexible approach to quitting smoking may be adopted. Patients can begin varenicline dosing and then quit smoking between days 8 and 35 of treatment (see CLINICAL TRIALS, Flexible Quit Date Study).+ CHAMPIX tablets should be swallowed whole with water. CHAMPIX can be taken with or without food. 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 at 1 mg twice daily is recommended to further increase the likelihood of long-term abstinence. Patients who do not succeed in stopping smoking during 12 weeks of initial therapy, or who relapse after treatment, should be encouraged to make another attempt once factors contributing to the failed attempt have been identified and addressed. Dose tapering of CHAMPIX is not required at the end of treatment.
No dosage adjustment is necessary for patients with mild to moderate renal impairment. For patients with severe renal impairment, the recommended dose of CHAMPIX is 1 mg once daily. Dosing should begin at 0.5 mg once daily for the first 3 days then increase to 1 mg once daily (see PHARMACOLOGY, Pharmacokinetics). Based on insufficient clinical experience with Champix in patients with end stage renal disease, treatment is not recommended in this patient population (see PHARMACOLOGY, Pharmacokinetics, Special Populations).
No dosage adjustment is necessary for patients with hepatic impairment (see PHARMACOLOGY, Pharmacokinetics).
No dosage adjustment is necessary for elderly patients (see PHARMACOLOGY, Pharmacokinetics). Because elderly patients are more likely to have decreased renal function, prescribers should consider the renal status of an elderly patient.
Safety and effectiveness of CHAMPIX in paediatric patients have not been established; therefore, CHAMPIX is not recommended for use in patients under 18 years of age (see PHARMACOLOGY, Pharmacokinetics).
No cases of overdose were reported in pre-marketing clinical trials. In case of overdose, standard supportive measures should be instituted as required. Varenicline has been shown to be dialysed in patients with end stage renal disease (see PHARMACOLOGY, Pharmacokinetics); however, there is no experience in dialysis following overdose. Contact the Poisons Information Centre for advice on the management of an overdose.
CHAMPIX is supplied for oral administration in two strengths:
0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with "Pfizer" on one side and "CHX 0.5" on the other side
1 mg capsular biconvex, light blue film-coated tablet debossed with "Pfizer" on one side and "CHX 1.0" on the other side.
Champix tablets are presented in PVC or Aclar/PVC blisters with aluminium foil backing, or high-density polyethylene (HDPE) bottles with polypropylene child resistant closure and an aluminium foil/polyethylene induction seal, in the following pack sizes (not all presentations marketed): Initiation Pack containing 11 x 0.5 mg film-coated tablets and 42 x 1 mg film-coated tablets in blisters within a secondary heat sealed wallet Composite Carton containing 11 x 0.5 mg film-coated tablets and 42 x 1 mg film-coated tablets in blisters. This carton contains two heat sealed wallets. The first heat sealed wallet consists of an initial dosing pack containing 11 x 0.5 mg tablets and 14 x 1 mg tablets. The second heat sealed wallet consists of 28 x 1 mg tablets. Continuation pack containing 56 x 1 mg film-coated tablets in blisters within a carton or secondary heat sealed wallet. Composite Pack containing one blister of 11 x 0.5 mg film-coated tablets and a second blister of 14 x 1 mg film-coated tablets in a carton or a heat sealed wallet. Blisters containing 28 or 140 x 1 mg film-coated tablets in a carton or secondary heat sealed card packaging. Bottle containing 56 x 1 mg film-coated tablets.
Shelf Life: 2 years. Store below 30degC..
Pfizer Australia Pty Ltd ABN 50 008 422 348 38 - 42 Wharf Road West Ryde NSW 2114
Prescription only medicine (S4)
15 February 2007.
4 September 2013.
+
Please note change(s) to Product Information.
Registered trademark.