Dosage Form: tablet
FULL PRESCRIBING INFORMATION
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 cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed 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 these symptoms have occurred in patients taking Chantix who continued to smoke.
All patients being treated with Chantix should be observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide. These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide, have been reported in some patients attempting to quit smoking while taking Chantix in the postmarketing experience. When symptoms were reported, most were during Chantix treatment, but some were following discontinuation of Chantix therapy.
These events have occurred in patients with and without pre-existing psychiatric disease. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the premarketing studies of Chantix, and the safety and efficacy of Chantix in such patients has not been established.
Advise patients and caregivers that the patient should stop taking Chantix and contact a healthcare provider immediately if agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of Chantix was reported, although in some cases 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 use. Chantix has been demonstrated to increase 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 and Precautions (5.1) and Adverse Reactions 6.2)]
Indications and Usage for Chantix
Chantix is indicated for use as an aid to smoking cessation treatment.
Chantix Dosage and Administration
Usual Dosage for Adults
Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional advice and support. Provide patients with appropriate educational materials and counseling to support the quit attempt.
The patient should set a date to stop smoking. Begin Chantix dosing one week before this date. Alternatively, the patient can begin Chantix dosing and then quit smoking between days 8 and 35 of treatment.
Chantix should be taken after eating and with a full glass of water.
The recommended dose of Chantix 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 |
Patients should be treated with Chantix for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks' treatment with Chantix 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.
Consider a temporary or permanent dose reduction in patients who cannot tolerate the adverse effects of Chantix.
Dosage in Special Populations
Patients with Impaired Renal Function: No dosage adjustment is necessary for patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), the recommended starting dose of Chantix is 0.5 mg once daily. The dose may then be titrated as needed to a maximum dose of 0.5 mg twice a day. For patients with end-stage renal disease undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be administered if tolerated [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Elderly and Patients with Impaired Hepatic Function: No dosage adjustment is necessary for patients with hepatic impairment. 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 Use in Specific Populations (8.5)].
Dosage Forms and Strengths
Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with "Pfizer" on one side and "CHX 0.5" on the other side) and 1 mg (light blue, debossed with "Pfizer" on one side and "CHX 1.0" on the other side)
Contraindications
Chantix is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to Chantix
Warnings and Precautions
Neuropsychiatric Symptoms and Suicidality
Serious neuropsychiatric symptoms have been reported in patients being treated with Chantix [see Boxed Warning and Adverse Reactions (6.2)]. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed 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 these symptoms have occurred in patients taking Chantix who continued to smoke. When symptoms were reported, most were during Chantix treatment, but some were following discontinuation of Chantix therapy.
These events have occurred in patients with and without pre-existing psychiatric disease; some patients have experienced worsening of their psychiatric illnesses. All patients being treated with Chantix should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the premarketing studies of Chantix, and the safety and efficacy of Chantix in such patients has not been established.
Advise patients and caregivers that the patient should stop taking Chantix and contact a healthcare provider immediately if agitation, depressed mood, changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of Chantix was reported, although in some cases 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 use. Chantix has been demonstrated to increase 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.
Angioedema and Hypersensitivity Reactions
There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with Chantix [see Adverse Reactions (6.2), and Patient Counseling Information (17.10)]. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx). There were infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise. Instruct patients to discontinue Chantix and immediately seek medical care if they experience these symptoms.
Serious Skin Reactions
There have been postmarketing reports of rare but serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients using Chantix [see Adverse Reactions (6.2)]. As these skin reactions can be life-threatening, instruct patients to stop taking Chantix and contact a healthcare provider immediately at the first appearance of a skin rash with mucosal lesions or any other signs of hypersensitivity.
Cardiovascular Events
In a controlled clinical trial of Chantix administered to patients with stable cardiovascular disease, with approximately 350 patients per treatment arm, certain cardiovascular events were reported more frequently in patients treated with Chantix than in patients treated with placebo [see Clinical Trials Experience (6.1)]. These included treatment-emergent events (on-treatment or 30 days after treatment) of angina pectoris (13 patients in the varenicline arm vs. 7 in the placebo arm), and the serious cardiovascular events of nonfatal MI (4 vs. 1) and nonfatal stroke (2 vs. 0). During non-treatment follow up to 52 weeks, serious cardiovascular events included nonfatal myocardial infarction (3 vs. 2), need for coronary revascularization (7 vs. 2), hospitalization for angina pectoris (6 vs. 4), transient ischemic attack (1 vs. 0), new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (5 vs. 2). Serious cardiovascular events occurring over the 52 weeks of the study (treatment emergent and non-treatment emergent) were adjudicated by an independent blinded committee. Chantix was not studied in patients with unstable cardiovascular disease or cardiovascular events occurring within two months before screening. Patients should be advised to notify a health care provider of new or worsening symptoms of cardiovascular disease. The risks of Chantix should be weighed against the benefits of its use in smokers with cardiovascular disease. Smoking is an independent and major risk factor for cardiovascular disease. Chantix has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo.
Accidental Injury
There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking Chantix. In some cases, the patients reported somnolence, dizziness, loss of consciousness or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving or operating machinery. Advise patients to use caution driving or operating machinery or engaging in other potentially hazardous activities until they know how Chantix may affect them.
Nausea
Nausea was the most common adverse reaction reported with Chantix treatment. Nausea was generally described as mild or moderate and often transient; however, for some patients, it was persistent over several months. The incidence of nausea was dose-dependent. Initial dose-titration was beneficial in reducing the occurrence of nausea. For patients treated to the maximum recommended dose of 1 mg twice daily following initial dosage titration, the incidence of nausea was 30% compared with 10% in patients taking a comparable placebo regimen. In patients taking Chantix 0.5 mg twice daily following initial titration, the incidence was 16% compared with 11% for placebo. Approximately 3% of patients treated with Chantix 1 mg twice daily in studies involving 12 weeks of treatment discontinued treatment prematurely because of nausea. For patients with intolerable nausea, a dose reduction should be considered.
Adverse Reactions
The following serious adverse reactions were reported in postmarketing experience and are discussed in greater detail in other sections of the labeling:
- Neuropsychiatric symptoms and suicidality [see Boxed Warning and Warnings and Precautions (5.1)
- Angioedema and hypersensitivity reactions [see Warnings and Precautions (5.2)]
- Serious skin reactions [see Warnings and Precautions (5.3)]
- Accidental injury [see Warnings and Precautions (5.5)]
In the placebo-controlled studies, the most common adverse events associated with Chantix (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal (vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting.
The treatment discontinuation rate due to adverse events in patients dosed with 1 mg twice daily was 12% for Chantix, compared to 10% for placebo in studies of three months' treatment. In this group, the discontinuation rates that are higher than placebo for the most common adverse events in Chantix-treated patients were as follows: nausea (3% vs. 0.5% for placebo), insomnia (1.2% vs. 1.1% for placebo), and abnormal dreams (0.3% vs. 0.2% for placebo).
Smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and has also been associated with the exacerbation of underlying psychiatric illness.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
During the premarketing development of Chantix, over 4500 subjects were exposed to Chantix, with over 450 treated for at least 24 weeks and approximately 100 for a year. Most study participants were treated for 12 weeks or less.
The most common adverse event associated with Chantix treatment is nausea, occurring in 30% of patients treated at the recommended dose, compared with 10% in patients taking a comparable placebo regimen [see Warnings and Precautions (5.6)].
Table 1 shows the adverse events for Chantix and placebo in the 12-week fixed dose studies with titration in the first week [Studies 2 (titrated arm only), 4, and 5]. Adverse events were categorized using the Medical Dictionary for Regulatory Activities (MedDRA, Version 7.1).
MedDRA High Level Group Terms (HLGT) reported in ≥ 5% of patients in the Chantix 1 mg twice daily dose group, and more commonly than in the placebo group, are listed, along with subordinate Preferred Terms (PT) reported in ≥ 1% of Chantix patients (and at least 0.5% more frequent than placebo). Closely related Preferred Terms such as 'Insomnia', 'Initial insomnia', 'Middle insomnia', 'Early morning awakening' were grouped, but individual patients reporting two or more grouped events are only counted once.
| SYSTEM ORGAN CLASS High Level Group Term Preferred Term | Chantix 0.5 mg BID N=129 | Chantix 1 mg BID N=821 | Placebo N=805 |
|---|---|---|---|
| |||
| GASTROINTESTINAL (GI) | |||
| GI Signs and Symptoms | |||
| Nausea | 16 | 30 | 10 |
| Abdominal Pain * | 5 | 7 | 5 |
| Flatulence | 9 | 6 | 3 |
| Dyspepsia | 5 | 5 | 3 |
| Vomiting | 1 | 5 | 2 |
| GI Motility/Defecation Conditions | |||
| Constipation | 5 | 8 | 3 |
| Gastroesophageal reflux disease | 1 | 1 | 0 |
| Salivary Gland Conditions | |||
| Dry mouth | 4 | 6 | 4 |
| PSYCHIATRIC DISORDERS | |||
| Sleep Disorder/Disturbances | |||
| Insomnia † | 19 | 18 | 13 |
| Abnormal dreams | 9 | 13 | 5 |
| Sleep disorder | 2 | 5 | 3 |
| Nightmare | 2 | 1 | 0 |
| NERVOUS SYSTEM | |||
| Headaches | |||
| Headache | 19 | 15 | 13 |
| Neurological Disorders NEC | |||
| Dysgeusia | 8 | 5 | 4 |
| Somnolence | 3 | 3 | 2 |
| Lethargy | 2 | 1 | 0 |
| GENERAL DISORDERS | |||
| General Disorders NEC | |||
| Fatigue/Malaise/Asthenia | 4 | 7 | 6 |
| RESPIR/THORACIC/MEDIAST | |||
| Respiratory Disorders NEC | |||
| Rhinorrhea | 0 | 1 | 0 |
| Dyspnea | 2 | 1 | 1 |
| Upper Respiratory Tract Disorder | 7 | 5 | 4 |
| SKIN/SUBCUTANEOUS TISSUE | |||
| Epidermal and Dermal Conditions | |||
| Rash | 1 | 3 | 2 |
| Pruritis | 0 | 1 | 1 |
| METABOLISM & NUTRITION | |||
| Appetite/General Nutrit. Disorders | |||
| Increased appetite | 4 | 3 | 2 |
| Decreased appetite/Anorexia | 1 | 2 | 1 |
The overall pattern and frequency of adverse events during the longer-term trials was similar to those described in Table 1, though several of the most common events were reported by a greater proportion of patients with long-term use (e.g., nausea was reported in 40% of patients treated with Chantix 1 mg twice daily in a one-year study, compared to 8% of placebo-treated patients).
Following is a list of treatment-emergent adverse events reported by patients treated with Chantix during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening.
Blood and Lymphatic System Disorders. Infrequent: anemia, lymphadenopathy. Rare: leukocytosis, splenomegaly, thrombocytopenia.
Cardiac Disorders. Infrequent: angina pectoris, arrhythmia, bradycardia, myocardial infarction, palpitations, tachycardia, ventricular extrasystoles. Rare: acute coronary syndrome, atrial fibrillation, cardiac flutter, cor pulmonale, coronary artery disease.
Ear and Labyrinth Disorders. Infrequent: tinnitus, vertigo. Rare: deafness, Meniere's disease.
Endocrine Disorders. Infrequent: thyroid gland disorders.
Eye Disorders. Infrequent: conjunctivitis, dry eye, eye irritation, eye pain, vision blurred, visual disturbance. Rare: acquired night blindness, blindness transient, cataract subcapsular, ocular vascular disorder, photophobia, vitreous floaters.
Gastrointestinal Disorders. Frequent: diarrhea. Infrequent: dysphagia, enterocolitis, eructation, esophagitis, gastritis, gastrointestinal hemorrhage, mouth ulceration. Rare: gastric ulcer, intestinal obstruction, pancreatitis acute.
General Disorders and Administration Site Conditions. Frequent: chest pain, edema, influenza-like illness. Infrequent: chest discomfort, chills, pyrexia.
Hepatobiliary Disorders. Infrequent: gall bladder disorder.
Investigations. Frequent: liver function test abnormal, weight increased. Infrequent: electrocardiogram abnormal, muscle enzyme increased, urine analysis abnormal.
Metabolism and Nutrition Disorders. Infrequent: diabetes mellitus, hyperlipidemia, hypokalemia. Rare: hypoglycemia.
Musculoskeletal and Connective Tissue Disorders. Frequent: arthralgia, back pain, muscle cramp, musculoskeletal pain, myalgia. Infrequent: arthritis, osteoporosis. Rare: myositis.
Nervous System Disorders. Frequent: disturbance in attention, dizziness, sensory disturbance. Infrequent: amnesia, migraine, parosmia, psychomotor hyperactivity, restless legs syndrome, syncope, tremor. Rare: balance disorder, cerebrovascular accident, convulsion, dysarthria, facial palsy, mental impairment, multiple sclerosis, nystagmus, psychomotor skills impaired, transient ischemic attack, visual field defect.
Psychiatric Disorders. Infrequent: disorientation, dissociation, libido decreased, mood swings, thinking abnormal. Rare: bradyphrenia, euphoric mood.
Renal and Urinary Disorders. Frequent: polyuria. Infrequent: nephrolithiasis, nocturia, urethral syndrome, urine abnormality. Rare: renal failure acute, urinary retention.
Reproductive System and Breast Disorders. Rare: sexual dysfunction. Frequent: menstrual disorder. Infrequent: erectile dysfunction.
Respiratory, Thoracic and Mediastinal Disorders. Frequent: epistaxis, respiratory disorders. Infrequent: asthma. Rare: pleurisy, pulmonary embolism.
Skin and Subcutaneous Tissue Disorders. Frequent: hyperhidrosis. Infrequent: acne, dry skin, eczema, erythema, psoriasis, urticaria. Rare: photosensitivity reaction.
Vascular Disorders. Frequent: hot flush. Infrequent: thrombosis.
Chantix has also been studied in a trial conducted in patients with stable cardiovascular disease, a trial conducted in patients with chronic obstructive pulmonary disease (COPD) and a trial conducted in generally healthy patients (similar to those in the premarketing studies) in which they were allowed to select a quit date between days 8 and 35 of treatment ("alternative quit date instruction trial").
In the trial of patients with stable cardiovascular disease, more types and a greater number of cardiovascular events were reported compared to premarketing studies. Treatment-emergent (on-treatment or 30 days after treatment) cardiovascular events reported with a frequency ≥ 1% in either treatment group in this study were angina pectoris (3.7% and 2.0% for varenicline and placebo, respectively), chest pain (2.5% vs. 2.3%), peripheral edema (2.0% vs. 1.1%), hypertension (1.4% vs. 2.6%), and palpitations (0.6 % vs. 1.1%). 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. The following treatment-emergent adjudicated events occurred with a frequency ≥1% in either treatment group: nonfatal MI (1.1% vs. 0.3% for varenicline and placebo, respectively), and hospitalization for angina pectoris (0.6% vs. 1.1%). During non-treatment follow up to 52 weeks, the adjudicated events included need for coronary revascularization (2.0% vs. 0.6%), hospitalization 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 revascularization underwent the procedure as part of management of nonfatal MI and hospitalization 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.
Adverse events in the trial of patients with COPD and in the alternative quit date instruction trial were quantitatively and qualitatively similar to those observed in premarketing studies.
Postmarketing Experience
The following adverse events have been reported during post-approval use of Chantix. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
There have been reports of depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide in patients attempting to quit smoking while taking Chantix [see Boxed Warning, Warnings and Precautions (5.1)]. 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.
There have been reports of hypersensitivity reactions, including angioedema [see Warnings and Precautions (5.2)].
There have also been reports of serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients taking Chantix [see Warnings and Precautions (5.3)].
There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischemic and hemorrhagic events in patients taking Chantix. 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.
Drug Interactions
Based on varenicline characteristics and clinical experience to date, Chantix has no clinically meaningful pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].
Use With Other Drugs for Smoking Cessation
Safety and efficacy of Chantix in combination with other smoking cessation therapies have not been studied.
Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) 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 twice daily) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue was greater for the combination than for NRT alone. In this study, eight of twenty-two (36%) patients treated with the combination of varenicline and NRT prematurely discontinued treatment due to adverse events, compared to 1 of 17 (6%) of patients treated with NRT and placebo.
Effect of Smoking Cessation on Other Drugs
Physiological changes resulting from smoking cessation, with or without treatment with Chantix, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) for which dosage adjustment may be necessary.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C.
There are no adequate and well-controlled studies of Chantix use in pregnant women. In animal studies, Chantix caused decreased fetal weights, increased auditory startle response, and decreased fertility in offspring. Chantix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In reproductive and developmental toxicity studies, pregnant rats and rabbits received varenicline succinate during organogenesis at oral doses up to 15 and 30 mg/kg/day, respectively. These exposures were 36 (rats) and 50 (rabbits) times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 1 mg twice daily. While no fetal structural abnormalities occurred in either species, reduced fetal weights occurred in rabbits at the highest dose (exposures 50 times the human exposure at the MRHD based on AUC). Fetal weight reduction did not occur at animal exposures 23 times the human exposure at the MRHD based on AUC.
In a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate from organogenesis through lactation. These resulted in exposures up to 36 times the human exposure (based on AUC) at the MRHD of 1 mg twice daily. Decreased fertility and increased auditory startle response occurred in offspring.
Nursing Mothers
It is not known whether Chantix is excreted in human milk. In animal studies varenicline was excreted in milk of lactating animals. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Chantix, 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.
Pediatric Use
Safety and effectiveness of Chantix in pediatric patients have not been established.
Geriatric Use
A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65–75 yrs) 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 (2.2)].
No dosage adjustment is recommended for elderly patients.
Renal Impairment
Varenicline is substantially eliminated by renal glomerular filtration along with active tubular secretion. Dose reduction is not required in patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), and for patients with end-stage renal disease undergoing hemodialysis, dosage adjustment is needed. [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Drug Abuse and Dependence
Controlled Substance
Varenicline is not a controlled substance.
Dependence
Humans: Fewer than 1 out of 1000 patients reported euphoria in clinical trials with Chantix. At higher doses (greater than 2 mg), Chantix produced more frequent reports of gastrointestinal disturbances such as nausea and vomiting. There is no evidence of dose-escalation to maintain therapeutic effects in clinical studies, which suggests that tolerance does not develop. Abrupt discontinuation of Chantix was associated with an increase in irritability and sleep disturbances in up to 3% of patients. This suggests that, in some patients, varenicline may produce mild physical dependence which is not associated with addiction.
In a human laboratory abuse liability study, a single oral dose of 1 mg varenicline did not produce any significant positive or negative subjective responses in smokers. In non-smokers, 1 mg varenicline produced an increase in some positive subjective effects, but this was accompanied by an increase in negative adverse effects, especially nausea. A single oral dose of 3 mg varenicline uniformly produced unpleasant subjective responses in both smokers and non-smokers.
Animals: Studies in rodents have shown that varenicline produces behavioral responses similar to those produced by nicotine. In rats trained to discriminate nicotine from saline, varenicline produced full generalization to the nicotine cue. In self-administration studies, the degree to which varenicline substitutes for nicotine is dependent upon the requirement of the task. Rats trained to self-administer nicotine under easy conditions continued to self-administer varenicline to a degree comparable to that of nicotine; however in a more demanding task, rats self-administered varenicline to a lesser extent than nicotine. Varenicline pretreatment also reduced nicotine self-administration.
Overdosage
In case of overdose, standard supportive measures should be instituted as required.
Varenicline has been shown to be dialyzed in patients with end stage renal disease [see Clinical Pharmacology (12.3)], however, there is no experience in dialysis following overdose.
Chantix Description
Chantix tablets contain varenicline (as the tartrate salt), which is a partial agonist selective for α4β2 nicotinic acetylcholine receptor subtypes.
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 C13H13N3 • C4H6O6. 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 debossed with "Pfizer" on one side and "CHX 0.5" on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed 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 base; each 1mg Chantix tablet contains 1.71 mg of varenicline tartrate equivalent to 1 mg of varenicline free base. The following inactive ingredients are included in the tablets: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg), and Opadry® Clear.
Chantix - Clinical Pharmacology
Mechanism of Action
Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors. The efficacy of Chantix in smoking cessation is believed to be the result of varenicline's activity at α4β2 sub-type of the nicotinic receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to these receptors.
Electrophysiology 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 selective 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 non-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 doses of varenicline, steady-state conditions were reached within 4 days. Over the recommended dosing range, varenicline exhibits linear pharmacokinetics after single or repeated doses. In a mass balance study, absorption of varenicline was virtually complete after oral administration and systemic availability was ~90%. 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 secretion 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 use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.
Renal Impairment: Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance >50 mL/min and ≤80 mL/min). In subjects with moderate renal impairment (estimated creatinine clearance ≥30 mL/min and ≤50 mL/min), varenicline exposure 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 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 was increased 2.7-fold following 0.5 mg once daily administration for 12 days. The plasma Cmax and AUC of varenicline noted in this setting were similar to those of healthy subjects receiving 1 mg twice daily. [see Dosage and Administration (2.2), and Use in Specific Populations (8.6)]. Additionally, in subjects with ESRD, varenicline was efficiently removed by hemodialysis [see Overdosage (10)].
Geriatric Patients: A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65–75 yrs) for 7 consecutive days was similar to that of younger subjects.
Pediatric Patients: Because the safety and effectiveness of Chantix in pediatric patients have not been established, Chantix is not recommended for use in patients under 18 years of age. Single and multiple-dose pharmacokinetics of varenicline have been investigated in pediatric patients 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 0.5 mg BID was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight ≤ 55 kg compared to that noted in the adult population.
Hepatic Impairment: Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic impairment.
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 secretion (e.g., 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 OCT2. Co-administration with inhibitors of OCT2 (e.g., cimeditine [see below]) may not necessitate a dose adjustment of Chantix as the increase in systemic exposure to Chantix is not expected to be clinically meaningful. 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 Chantix [see Clinical Pharmacology (12.3)
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