Varenicline

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Contents 1 Description 2 Mechanism of Action 3 Time Required for Therapeutic Response 4 Pharmacokinetics 5 Special Population Pharmacokinetics 6 Indications and Dosages 6.1 FDA Approved Indications 6.2 Dosage Adjustment 6.3 Dosage Limits 7 Administration 8 Monitoring Parameters 9 Contraindications/Precautions 9.1 Contraindications 9.2 Precautions 9.3 Pregnancy indications 9.4 Breast-feeding indications 10 Drug-Drug, -Food, -Herb Interactions 11 Adverse Reactions/Side Effects 12 Overdosage Measures 13 Product Information and Distribution 14 Patient Information 15 References 16 PUBMED References 16.1 Efficacy Trial Articles 16.2 Pharmacokinetics Articles 17 External Links	This page is not completed and has not been reviewed for accuracy. You are reading a non-certified PubDrug document. This document is incomplete and not ready for final editing, review, and certification. Until this document is certified, any registered PubDrug user may edit its content. Authored by: Tdwalsh 11:55, 18 September 2007 (PDT) Certified by: Thaotran 1:10, 2 October 2007 (PDT) Varenicline quick reference
	Varenicline general drug information
	Pronunciation	ver EN e kleen (.wav file)
	Trade Name(s)	Chantix
	How Supplied	Tablets: 0.5 mg, 1 mg
	Generic Availability	No generics available
	Patent Expiry Date	May 10, 2011
	Classification	Nicotine receptor agonist; Smoking cessation agent
	Schedule	Rx
	Pregnancy Category	C
	Breast-feeding	No human studies exist, but animal studies showed varenicline excreted in breastmilk. Manufacturer recommends either discontinuing the drug or discontinuing breastfeeding.
	Varenicline chemical information
	IUPAC Name	7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3- h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1)
	Empirical Formula	C13H13N3 • C4H6O6
	Molecular Weight	361.35 g/mol
	pharmacokinetic information  |  pharmacogenomic information

Description

Varenicline is a selective α4β2 nicotinic acetylcholine receptor partial agonist. Like other smoking cessation aids (such as nicotine replacement therapy or bupropion), this drug helps maintain abstinence from nicotine by reducing cravings and decreasing the severity of withdrawal symptoms.^[1][2] Clinical trials, involving a total of 3,659 patients^[1], showed superior efficacy for varenicline versus both placebo (43.6% versus 36.9% abstinence after 52 weeks in one study)^[3] and bupropion (43.9% versus 29.8% abstinence during weeks 9 through 12)^[4].

The most common adverse effect during clinical trials was nausea, which was seen in up to 30% of patients. However, the drop-out rate due to nausea was only 3%. This side effect is dose-dependent. For patients who cannot tolerate it at the recommended dose, they may still benefit from a reduced dose. Taking varenicline with food may also help to ameliorate nausea.^[1]

The question of varenicline dependence must be addressed. A small number of patients (lower than 0.001%) experienced euphoria during clinical trials. This is unlikely to be a temptation for potential addicts; however, nausea incidence was markedly increased with single doses of 2 mg or higher. Clinical trials also showed that abrupt discontinuation lead to increased irritability and increased incidence of sleep disturbances – it is difficult to tell whether this indicated physical dependence to varenicline, or was simply the result of uncontrolled nicotine withdrawal.^[1]

Mechanism of Action

Nicotine withdrawal – which is characterized by symptoms such as insomnia, irritability, anxiety and cravings – usually starts between 4 to 6 hours after the last dose of nicotine. (Nicotine’s T_1/2 is around 2 hours.) Nicotine’s addiction potential appears to be related to its action at nicotinic acetylcholine receptors in the brain – when nicotine binds to these receptors, it triggers a cascade which culminates in the release of dopamine. (Dopamine release has been implicated as the cause of several types of drug dependence.) Certain behaviors (such as opening a package of cigarettes) can be so strongly linked to the chemically-rewarding behavior of tobacco use that they can cause a release of dopamine even in the absence of nicotine.^[5]

Varenicline is a partial agonist at α4β2 nicotinic acetylcholine receptors. The dopamine release triggered by varenicline is smaller than that triggered by nicotine – this means that the drug helps to alleviate withdrawal symptoms, but does not cause the kind of euphoria associated with nicotine. Varenicline also blocks nicotinic acetylcholine receptors from nicotine activation, which decreases the reward patients receive if they relapse back into tobacco use.^[5]

Time Required for Therapeutic Response

• Initial: Varenicline does not produce a measurable therapeutic response – the drug 'works' if the patient is able to refrain from smoking. Thus, it is hard to judge exactly when it starts to take effect.
• Maximum: As with initial response, the maximum response time is difficult to judge. This presumably occurs when the drug reaches steady state serum concentrations (about four days), though patients are advised not to stop smoking less than one week after starting varenicline.^[1]

Pharmacokinetics

Absorption
Following oral administration of varenicline, plasma concentrations peak in 3-4 hours and steady state is reached after 4 days. The drug exhibits linear pharmacokinetics following both single and repeated doses. Bioavailability is not influenced by food or the time of day a dose is taken.^[1]

Distribution
Varenicline exhibits low plasma protein binding (below 20%), which is not influenced by age or renal function.^[1]

Metabolism
The majority of the dose (92%) is excreted unchanged in the urine. Two metabolites have been observed in humans (2-hydroxyvarenicline and varenicline N-carbamoylglucuronide).^[1][6]

Excretion
According to the manufacturer, the drug’s elimination T_1/2 is approximately 24 hours (some studies suggested ~17 hours ^[6]). The drug appears to be excreted largely via glomerular filtration, though it may also be secreted by the OCT2 organic cation transporter.^[1]

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Special Population Pharmacokinetics

• Renal insufficiency: The majority of the varenicline dose is excreted unchanged in the urine, so renal function plays a role in determining dosage. Pharmacokinetics were unchanged for patients with CrCl between 50 mL/min and 80 mL/min. Drug exposure was increased 1.5 times for patients with CrCl between 30 mL/min and 50 mL/min, and 2.1 times for patients with CrCl below 30 mL/min. Varenicline should be used cautiously in patients with renal insufficiency, and dosage adjustment may be warranted.^[1]
• Hepatic insufficiency: Hepatic insufficiency does not significantly affect varenicline.
• Hemodialysis: Varenicline systemic exposure increases in ESRD patients undergoing a 3-hour session of hemodialysis for three days a week. Hemodialysis has been shown to remove varenicline. A dosage adjustment is recommended in patients undergoing hemodialysis.
• Geriatric: Geriatric patients have displayed similar pharmacokinetics as those seen in younger patients. Given the importance of renal function in varenicline's elimination, this drug should be used cautiously in the elderly.
• Pediatric: A small-scale study in patients between the ages of 12 and 17 showed similar pharmacokinetics as those seen in adults. However, safe and effective doses for this drug for patients under the age of 18 have not been determined – consequently, the manufacturer does not recommend using the drug in this population.
• Gender: Gender does not significantly affect varenicline.

Indications and Dosages

FDA Approved Indications

Management of nicotine withdrawal during smoking cessation^{[1][3][4][7][8]}

• Titration schedule:
  • Treatment should start one week before a patient attempts to stop smoking.
  • Patients should be treated with varenicline for a full twelve weeks.
    • Days 1-3: 0.5 mg po once daily
    • Days 4-7: 0.5 mg po twice daily
    • Days 8-End: 1 mg po twice daily
  • If a patient has successfully stopped smoking at the end of this period, the patient may be placed on another twelve week course to help reduce the risk of relapse.^[3]
  • Patients who failed to stop smoking after the first twelve weeks should not be given another course of varenicline until the underlying causes of the failure have been evaluated and addressed.

Dosage Adjustment

Renal insufficiency: For patients with renal impairment (CrCl < 50 mL/min), the manufacturer recommends a dose of 0.5 mg twice a day. ^[1]
Hemodialysis: For patients undergoing hemodialysis, the manufacturer recommends a dose of 0.5 mg once a day.

Dosage Limits

• Adults: 1 mg po twice daily^[1]
• Elderly: 1 mg po twice daily
• Adolescents and children: Varenicline is not recommended for use in patients younger than 18 years old

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Administration

• Route: Oral^[1][2]
• Method:
  • Start varenicline therapy one week before stopping smoking
  • Administer each dose with a full glass of water
  • Administer dose after eating to reduce nausea
  • Varenicline tablets should be stored at room temperature (between 15-30°C)

Monitoring Parameters

• None

Contraindications/Precautions

Contraindications

• No absolute contraindications^[1]

Precautions

• Use with care and/or adjust dose in patients with renal impairment^[1]
• Use with care and/or adjust dose in patients undergoing hemodialysis
• Use with care and/or adjust dose in elderly patients
• Varenicline is not indicated for use in patients younger than 18 years old
• This drug is pregnancy category C (see below)
• This drug is not recommended for use in patients who are breastfeeding (see below)

Pregnancy indications

Category C

No studies have evaluated the use of varenicline during pregnancy in humans. Animal studies showed no teratogenic effects at doses up to 15 mg/kg/day in rats or 30 mg/kg/day in rabbits. Rabbit litters exposed to varenicline as fetuses showed low birth weight, though this effect did not manifest itself at a dose of 10 mg/kg/day. Rat litters exposed to varenicline as fetuses displayed reduced fertility and increased auditory startle response. Consequently, varenicline should only be used in pregnant women if the benefit to the mother outweighs the risk to the fetus.^[1]

Breast-feeding indications

Varenicline has been detected in nursing pups in animal studies. (No studies exist to evaluate the risk in humans.) As a result of potential risk to nursing infants, the manufacturer recommends discontinuing varenicline or discontinuing breast-feeding.^[1]

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Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

Adverse Reactions/Side Effects

Varenicline Adverse Reactions Chart

Incidence	Body System	Adverse Reactions
>10%	All	Nausea (16-30%), Insomnia (18-19%), Headaches (15-19%), Abnormal dreams (9-13%)
1-10%	CNS	Dysgeusia (5-8%), Somnolence (3%), Sleep disorder (2-5%), Lethargy (1-2%), Nightmare (1-2%)
	Dermatologic	Rash (1-3%), Pruritis (0-1%)
	GI	Flatulence (6-9%), Constipation (5-8%), Abdominal pain (5-7%), Dry mouth (4-6%), Dyspepsia (5%), Vomiting (1-5%), Increased appetite (3-4%), Decreased appetite/Anorexia (1-2%)
	Respiratory	Upper respiratory tract disorder (5-7%), Dyspnoea (1-2%), Rhinorrhea (0-1%)
	Miscellaneous	Fatigue/malaise/asthenia (4-7%)
<1%	All	Abnormal ECG, Abnormal LFT, Abnormal thought, Acne, Acquired night blindness, Acute coronary syndrome, Acute pancreatitis, Acute renal failure, Aggression, Agitation, Amnesia, Anemia, Angina pectoris, Anxiety, Arrhythmia, Arthritis, Asthma, Athralgia, Atrial fibrillation, Back pain, Balance disorder, Blurred vision, Bradycardia, Bradyphrenia, Cardiac flutter, Cataract subcapsular, Cerebrovascular accident, Chest discomfort, Chest pain, Chills, Convulsion, Cor pulmonale, Coronary artery disease, Deafness, Depression, Dermatitis, Diabetes mellitus, Diarrhea, Disorientation, Dissociation, Disturbance in attention, Dizziness, Drug hypersensitivity, Dry eye, Dry skin, Dysarthria, Dysphagia, Eczema, Edema, Emotional disorder, Enterocolitis, Epistaxis, Erectile dysfunction, Eructation, Erythema, Esophagitis, Euphoric mood, Eye irritation, Eye pain, Facial palsy, Gall bladder disorder, Gastointestinal hemorrhage, Gastric ulcer, Gastritis, Gingivitis, Hallucination, Hot flush, Hyperhidrosis, Hyperkalemia, Hyperlipidemia, Hypersensitivity, Hypertension, Hypoglycemia, Hypokalemia, Hypotension, Influenza-like illness, Intestinal obstruction, Irritability, Leukocytosis, Libido decreased, Lymphadenopathy, Meniere's disease, Menstrual disorder, Mental impairment, Migraine, Mood swings, Mouth ulceration, Multiple sclerosis, Muscle cramp, Muscle enzyme increased, Musculoskeletal pain, Myalgia, Myocardial infarction, Myositis, Nephrolitiasis, Nocturia, Nystagmus, Ocular vascular disorder, Osteoporosis, Palpitations, Parosmia, Peripheral ischemia, Photophobia, Photosensitivity reaction, Pleurisy, Polyuria, Psoriasis, Psychomotor hyperactivity, Psychomotor skills impaired, Psychotic disorder, Pulmonary embolism, Pyrexia, Respiratory disorders, Restless legs syndrome, Restlessness, Sensory disturbance, Sexual dysfunction, Splenomegaly, Suicidal ideation, Syncope, Tachycardia, Thirst, Thrombocytopenia, Thrombosis, Thyroid gland disorders, Tinnitus, Transient blindness, Transient ischemic attack, Tremor, Urethral syndrome, Urinalysis abnormal, Urinary retention, Urine abnormality, Urticaria, Ventricular extrasystoles, Vertigo, Visual disturbance, Visual field defect, Vitreous floaters, Weight increase

The above data was gathered from Phase 2 and Phase 3 trials. Discontinuation rates for patients (over a three-month period) were as follows:^[1]

• Nausea: 3%
• Insomnia: 1.2%
• Headache: 0.6%
• Abnormal dreams: 0.3%

Overdosage Measures

Overdose symptoms are uncertain – no case of varenicline overdose has been reported. In clinical trials, the most common side effect associated with doses of 2 mg and 3 mg was nausea.
Treatment:

• Supportive care is indicated for overdose patients.
• Experience with ESRD patients shows that varenicline is dialyzed, but there is no reports of dialysis following an overdose.^[1]

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Product Information and Distribution

Note: appearance only available for brand-name product

Dose/form	Drug color(s)	Drug shape	Markings or odor/flavor
0.5 mg tablet	white	biconvex	Pfizer/CHX 0.5
1 mg tablet	blue	biconvex	Pfizer/CHX 1.0

• Inactive ingredients for tablets: microcrystalline cellulose (NF), anhydrous dibasic calcium phosphate (USP), croscarmellose sodium (NF), colloidal silicon dioxide (NF), magnesium stearate (NF), Opadry Clear, and Opadry White (in 0.5 mg tablets) or Opadry Blue (in 1 mg tablets)^[1]

Patient Information

• You should pick a date to stop smoking, then start Chantix one week before this date.^[1]
• You should take Chantix with a full glass of water, after eating (to help reduce nausea).
• The nausea associated with the drug usually does not last long. If it becomes persistently troubling, you should contact your physician.
• You should be familiar with the drug’s dosing schedule. Unless otherwise informed by your physician, Chantix is dosed as follows:
  • 0.5 mg by mouth once daily for three days
  • 0.5 mg by mouth twice daily for four days
  • 1 mg by mouth twice daily for the remainder of your treatment (12 weeks)
• If you start to smoke after starting Chantix, you should continue the regimen and make further attempts to stop smoking.
• You should consider the risks and benefits of this medication before becoming pregnant or breastfeeding.
• Chantix may cause insomnia or drowsiness. You should not drive or operate heavy machinery until you know how this drug affects you.
• If you miss a dose, take it as soon as you remember. If it is close to the time for your next dose, then skip the missed dose and just take your next regular dose.

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References

1. ↑ ^{1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21} Chantix® (varenicline) package insert. New York, NY: Pfizer, Inc.; 2007 May.
2. ↑ ^2.0 2.1 Zierler-Brown SL and Kyle JA. New drug approvals: oral varenicline for smoking cessation. Ann Pharmacother. 2007 January; 41:95-99.
3. ↑ ^{3.0 3.1 3.2} Tonstad S, Tønnesen P, Hajek P, Williams KE, Billing CB, Reeves KR. Effect of maintenance therapy with varenicline on smoking cessation. JAMA. 2006 July 5; 296(1):64-71.
4. ↑ ^4.0 4.1 Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion and placebo for smoking cessation. JAMA. 2006 July 5; 296(1):56-63.
5. ↑ ^5.0 5.1 Foulds J. The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline. Int J of Clin Pract. 2006 May; 60(5):571-576.
6. ↑ ^6.0 6.1 Obach RS, Reed-Hagen AE, Krueger SS, Obach BJ, O’Connell TN, Zandi KS, et al. Metabolism and disposition of varenicline, a selective α4β2 acetylcholine receptor partial agonist, in vivo and in vitro. Drug Metab Dispos. 2006 January; 34(1):121-130.
7. ↑ Goyal A, Tricoci P, Melloni C, Mills JS, Thomas KL, Adams GL, et al. Highlights from the American Heart Association Scientific Sessions, November 13 to 16, 2005, Dallas TX. Am Heart J. 2006 February; 151(2):295-307.
8. ↑ Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing C, et al. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation. JAMA. 2006 July 5; 296(1):47-55.

PUBMED References

Efficacy Trial Articles

1. Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, et al. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation. JAMA. 2006 July 5; 296(1):47-55.
2. Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion and placebo for smoking cessation. JAMA. 2006 July 5; 296(1):56-63.
3. Nakamura M, Oshima A, Fujimoto Y, Maruyama N, Ishibashi T and Reeves KR. Efficacy and tolerability of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, in a 12-week randomized, placebo-controlled, dose-response study with a 40-week follow-up for smoking cessation in Japanese smokers. Clin Ther. 2007 June; 29(6):1040-1056.
4. Nides M, Oncken C, Gonzales D, Rennard S, Watsky EJ, Anziano R, et al. Smoking cessation with varenicline, a selective α4β2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo-and bupropion-controlled trial with 1-year follow-up. Arc Intern Med. 2006 August; 166:1561-1568.
5. Oncken C, Gonzales D, Nides M, Rennard S, Watsky E, Billing CB, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med. 2006 August; 166(15):1571-1577.
6. Tonstad S, Tønnesen P, Hajek P, Williams KE, Billing CB, Reeves KR. Effect of maintenance therapy with varenicline on smoking cessation. JAMA. 2006 July 5; 296(1):64-71.
7. Tsai ST, Cho HJ, Cheng HS, Kim CH, Hsueh KC, Billing CB Jr., et al. A randomized, placebo-controlled trial of varenicline, a selective α4β2 nicotinic acetylcholine receptor partial agonist, as a new therapy for smoking cessation in Asian smokers. Clin Ther. 2007 June; 29(6):1027-1039.

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Pharmacokinetics Articles

1. Faessel HM, Gibbs MA, Clark DJ, Rohrbacher K, Stolar M and Burstein AH. Multiple-dose pharmacokinetics of the selective nicotinic receptor partial agonist, varenicline, in healthy smokers. J Clin Pharmacol. 2006 December; 46(12):1439-1448.
2. Faessel HM, Smith BJ, Gibbs MA, Gobey JS, Clark DJ, and Burstein AH. Single-dose pharmacokinetics of the selective nicotinic receptor partial agonist, varenicline, in healthy smokers. 2006 September; 46(9):991-998.
3. Obach RS, Reed-Hagen AE, Krueger SS, Obach BJ, O’Connel TN, Zandi KS, et al. Metabolism and disposition of varenicline, a selective α4β2 acetylcholine receptor partial agonist, in vivo and in vitro. Drug Metab Dispos. 2006, January; 34(1):121-130.

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External Links

Clinical treatment guidelines

• CDC’s Best Practices for Comprehensive Tobacco Control Programs
• Smoking cessation guidelines from the American Heart Association
• Smoking cessation guidelines from the University of Michigan Health System

Patient information pages

• Smokefree.gov, a US-government-sponsored smoking cessation page
• Smoking cessation information from the National Cancer Institute

Other resources

• Smoking cessation information from Roswell Park

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