Varenicline oral: ahfs detailed monograph

Varenicline Oral: AHFS Detailed Monograph http://www.medscape.com/druginfo/monograph?cid=med&drugid=144.
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Varenicline Oral
Monograph - Varenicline tartrate
Class: AUTONOMIC DRUGS, MISCELLANEOUS(12:92) Sections: Introduction | Uses | Dosage and Administration | Cautions | Drug Interactions | Description | Advice to
Patients | Preparations
Introduction
Varenicline is a selective α4β2 nicotinic acetylcholine receptor partial agonist. •Smoking Cessation
Varenicline is used as an adjunct in the cessation of cigarette smoking. Varenicline received priority review from the US Food and Drug Administration (FDA); such status is granted to drugs that represent an important improvement over existing therapies in effectiveness and/or patient compliance or a reduction in adverse effects. Safety and efficacy of varenicline as an adjunct for smoking cessation have been established in 6 placebo-controlled oractive-comparator studies in 3659 patients (mean age: 43 years; 79–96% white; mean smoking history: about 25 years)who smoked at least 10 cigarettes daily (mean: about 21 cigarettes daily). Patients were treated with varenicline inconjunction with weekly 10-minute counseling (including provision of an educational pamphlet). Abstinence wasdetermined by patients’ self-report and verified by weekly measurements of expiratory carbon monoxide. Treatment wasinitiated 1 week prior to the target cessation date.
In 2 such studies in patients who received varenicline (flexible dosages of 0.5–2 mg daily or fixed dosages of 1 or 2 mgdaily) or placebo for 12 weeks and then were followed for 40 weeks post-treatment, continuous abstinence rates of 40–51or 12%, respectively, during weeks 9–12 of treatment and 19–23 or 4–8%, respectively, during weeks 9–52 werereported.
In 2 randomized, double-blind, multicenter studies in patients who received varenicline (1 mg twice daily),extended-release bupropion (150 mg twice daily), or placebo for 12 weeks and then were followed for 40 weeksposttreatment, continuous abstinence rates during weeks 9–12 of treatment were higher with varenicline (44%) than withbupropion (30%) or placebo (17–18%); abstinence rates during weeks 9–52 were 21–23% with varenicline, 14–16% withbupropion, and 8–10% with placebo.
In a randomized, double-blind, maintenance-of-abstinence study, patients with a history of chronic smoking who hadsuccessfully quit smoking by the end of 12 weeks of open-label varenicline therapy were randomized to receive eithervarenicline (1 mg twice daily) or placebo for an additional 12 weeks. The additional 12 weeks of varenicline therapy (inthose who achieved cessation of smoking) resulted in higher continuous abstinence rates during weeks 13–24 and during28 weeks of posttreatment follow-up compared with placebo. Reported rates of abstinence for varenicline versus placebowere 70% versus 50% during weeks 13–24, and 54% versus 39%, respectively, during 28 weeks of posttreatment. Someclinicians state that since only individuals who had quit smoking by the end of the first 12 weeks of the study wererandomized to receive the drug for an additional 12 weeks, about 33% of the participants (for whom the drug does notappear to be effective) were eliminated from the second phase, and thus the relapse prevention results may havelimitations.
In these studies, the urge to smoke was less severe in individuals receiving varenicline than in those receiving placebo. Efficacy and safety of varenicline given in conjunction with other smoking cessation therapies (e.g., bupropion, nicotine replacement therapy) have not been established. Varenicline Oral: AHFS Detailed Monograph http://www.medscape.com/druginfo/monograph?cid=med&drugid=144.
For additional information on smoking cessation, see Guidelines under Uses: Smoking Cessation, in Nicotine 12:92 andBupropion 28:16.04.92. Dosage and Administration
•Administration
Varenicline is administered orally. The drug should be taken after eating and with a full glass of water. •Dosage
Dosage of varenicline tartrate is expressed in terms of varenicline. Smoking Cessation
The recommended adult dosage of varenicline as an adjunct in smoking cessation is 0.5 mg once daily ondays 1–3, 0.5 mg twice daily on days 4–7, and 1 mg twice daily from day 8 through the end of 12 weeks oftreatment. Therapy should be initiated 1 week before the target smoking cessation date. Titration of thedosage during the initial week of treatment has been shown to reduce the incidence of drug-relatednausea. The dosage of varenicline may be reduced temporarily or permanently in patients who experienceintolerable adverse effects. In patients who have successfully stopped smoking by the end of 12 weeks oftreatment, an additional 12 weeks of varenicline therapy is recommended to increase the likelihood oflong-term abstinence.
Patients who have been unable to quit smoking during 12 weeks of initial treatment or those who have relapsed after varenicline therapy should be encouraged to make another attempt to quit smoking, once factors responsible of such failure have been identified and addressed. •Special Populations
No dosage adjustment is needed in patients with mild to moderate renal impairment. In patients with severe renal impairment (creatinine clearance less than 30 mL/minute), an initial dosage of 0.5 mg once daily is recommended; dosage may be titrated as needed to a maximum of 0.5 mg twice daily. A maximum dosage of 0.5 mg once daily, if well-tolerated, is recommended in patients with end-stage renal disease who are undergoing hemodialysis. No dosage adjustment is needed in patients with hepatic impairment. Because geriatric patients are more likely to have decreased renal function, dosage should be selected cautiously; it may be useful to monitor renal function in such patients. Cautions
•Contraindications
The manufacturer states that there are no known contraindications to the use of varenicline. •Warnings/Precautions
Varenicline Oral: AHFS Detailed Monograph http://www.medscape.com/druginfo/monograph?cid=med&drugid=144.
Major Toxicities
Nausea, usually mild or moderate, dose-related, often transient (although may persist for several months), is the most common adverse effect, occurring in about 30% of patients, and has required discontinuance of the drug in about 3% of those receiving varenicline (1 mg) twice daily. Initial titration of varenicline dosage (see Dosage and Administration: Dosage) reduces the incidence of nausea. Dosage reduction should be considered in patients experiencing intolerable nausea. Specific Populations
Pregnancy.
Lactation.
Varenicline is distributed into milk in animals. Not known whether varenicline is distributed into human milk. Discontinue nursing or the drug, taking into account the importance of the drug to the woman. Pediatric Use.
Safety and efficacy not established in patients younger than 18 years of age and use of the drug in this age group is not recommended. Geriatric Use.
No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out. Because geriatric patients are more likely to have decreased renal function, dosage should be selected cautiously; it may be useful to monitor renal function in such patients. Renal Impairment.
Varenicline should be used with caution in patients with moderate to severe renal impairment and in patients with end-stage renal disease undergoing hemodialysis. Exposure to the drug was increased in patients with such impairment. Dosage adjustment is recommended for patients with creatinine clearance less than 30 mL/minute. (See Dosage and Administration: Special Populations.) •Common Adverse Effects
Adverse effects reported in 5% or more of adults receiving varenicline 1 mg twice daily in clinical trials include nausea, abdominal pain, flatulence, dyspepsia, vomiting, constipation, dry mouth, insomnia, abnormal dreams, sleep disorders, headache, dysgeusia, fatigue/malaise/asthenia, and upper respiratory tract disorders. Drug Interactions
Physiological changes resulting from smoking cessation (with or without varenicline) may alter the pharmacokinetics or pharmacodynamics of some drugs (e.g., theophylline, warfarin, insulin); dosage adjustment may be required. The manufacturer states that clinical experience in patients receiving varenicline with other drugs has not revealed evidence of clinically important interactions. •Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Pharmacokinetic interactions unlikely with drugs metabolized by or affecting cytochrome P-450 (CYP) isoenzymes. In Varenicline Oral: AHFS Detailed Monograph http://www.medscape.com/druginfo/monograph?cid=med&drugid=144.
vitro studies indicate that varenicline does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5 in vitro. The drug also does not induce CYP isoenzymes 1A2 or 3A4. •Drugs Eliminated by Renal Secretion
Clinically important pharmacokinetic interaction (requiring dosage reduction of varenicline) unlikely. •Bupropion
Pharmacokinetic interaction unlikely. Safety of combined use of bupropion and varenicline not established. •Cimetidine
Potential pharmacokinetic interaction (increased plasma concentration of varenicline secondary to a reduction in renal clearance). •Digoxin
•Nicotine
Pharmacokinetic interaction unlikely. Increased incidence of adverse effects (nausea, headache, vomiting, dizziness, dyspepsia, fatigue) and increased rate of discontinuance of combination (varenicline and transdermal nicotine replacement) therapy compared with those receiving transdermal nicotine and placebo. Safety and efficacy of varenicline in combination with other smoking cessation therapies have not been studied. •Warfarin
Pharmacokinetic interaction unlikely. Warfarin pharmacokinetics may be affected by smoking cessation. Description
Varenicline is a selective α4β2 nicotinic acetylcholine receptor partial agonist. The drug binds with high affinity andselectivity to α4β2 nicotinic acetylcholine receptors located in the brain and stimulates receptor-mediated activity, but at asubstantially lower level than nicotine; this low-level receptor stimulation and subsequent moderate, sustained release ofmesolimbic dopamine are thought to reduce craving and withdrawal symptoms associated with smoking cessation.
Varenicline also blocks the ability of nicotine to activate α4β2 receptors, preventing nicotine-induced stimulation of the mesolimbic dopaminergic system and thereby reducing the reinforcement and reward effects of cigarette smoking. Varenicline is eliminated principally in urine as unchanged drug. Renal elimination of the drug occurs primarily throughglomerular filtration along with active tubular secretion. In vitro studies indicate that varenicline does not induce Varenicline Oral: AHFS Detailed Monograph http://www.medscape.com/druginfo/monograph?cid=med&drugid=144.
cytochrome P-450 (CYP) isoenzymes 1A2 or 3A4 or inhibit major CYP isoenzymes; in addition, the drug does not inhibit human renal transport proteins in vitro. (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.) Advice to Patients
Importance of providing educational materials and counseling to support attempt to quit smoking. Patients should be instructed to read the patient information leaflet before initiation of varenicline therapy and every time the prescription is refilled since the information may have been revised. Advise patients to set a date to quit smoking and to start varenicline therapy 1 week prior to the quit date. Importance of taking varenicline after eating and with a full glass of water. Importance of encouraging patients to continue to attempt to quit smoking if they have early lapses after the set quit date. Importance of informing patients that some medications may require dosage adjustment due to effects of smoking cessation. Importance of informing clinician in case of troubling, persistent nausea or insomnia (clinician may recommend dosagereduction). Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise women who are or plan to become pregnant or plan to breast-feed of risks of smoking and risks and benefits of using varenicline to aid in smoking cessation. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses; some drugs may require dosage adjustment due to effects of smoking cessation. Importance of informing patients of other important precautionary information. (See Cautions.) Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed andpublished, the manufacturer’s labeling should be consulted. It is essential that the manufacturer’s labeling be consultedfor more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory testinterferences, and acute toxicity.
Preparations
Varenicline Tartrate
Strength
11 Tablets, film-coated, Varenicline Tartrate 0.5 mg (of varenicline) Chantix® Pack (available as dose/cards for first
month of therapy), Pfizer
Varenicline Tartrate 1 mg (of varenicline) Chantix®, Pfizer
Chantix® (available as 4 cards of 14 tablets and
regular packaging), Pfizer
Varenicline Oral: AHFS Detailed Monograph http://www.medscape.com/druginfo/monograph?cid=med&drugid=144.

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