Varenicline

Varenicline is a smoking cessation aid belonging to the Cholinergic Agonist/Partial Nicotine agonist class.

Varenicline is a partial agonist at nicotinic acetylcholine receptors used to aid smoking cessation.

Varenicline is absorbed well from the gastrointestinal tract. It has a Bioavailability of Approximately 90%. The time taken to reach peak plasma concentration is approximately 3-4 hours. Plasma protein binding of varenicline is low (≤20%) and independent of age and renal function. 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 and active tubular secretion possibly via the organic cation transporter, OCT2.

Varenicline shows side effects like Nausea, constipation, diarrhoea, gas, abdominal pain, vomiting, heartburn, bad taste in the mouth, dry mouth, etc.

Varenicline is available in the form of Oral Tablet and nasal spray.

Varenicline is available in India, UK, EU, Japan, South America, and most of North America. Canada, the USA, and Australia.

Varenicline belongs to the Cholinergic Agonist/Partial Nicotine agonist class and acts as smoking cessation aid.

Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors. The efficacy of Varenicline 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.

The Onset of action of Varenicline is not clinically established.

The Time to peak plasma concentration of Varenicline is approximately 3-4 hours.

Varenicline is available in the form of Oral Tablets and nasal sprays.

Varenicline tablet is taken orally, usually once or twice daily.

Varenicline spray is taken via the nasal route (Insert Nasal spray applicator into a nostril, pointing the tip toward the top of the ear, leaving space between end of the applicator and the wall of nose. Place tongue on the roof of the mouth and breathe gently while pressing the pump to release spray) twice daily.

Varenicline is an effective smoking cessation aid that reduces withdrawal symptoms after smoking has been stopped as well as the craving for nicotine.

Varenicline is a smoking cessation aid belonging to the Cholinergic Agonist/Partial Nicotine agonist class.

Varenicline acts by preventing nicotine stimulation of the mesolimbic dopamine system, the neuronal mechanism underlying reward and reinforcement experienced during smoking. Additionally, it stimulates dopamine activity but to a much lesser extent than nicotine, leading to reduced craving and withdrawal symptoms.

Varenicline is approved for use in the following clinical indications

• Smoking cessation

Varenicline is a partial agonist at nicotinic acetylcholine receptors used to aid smoking cessation.

• Smoking cessation:

Oral: Initial:

Days 1 to 3: 0.5 mg once daily.

Days 4 to 7: 0.5 mg twice daily.

• Dry eye disease:

One spray in each nostril twice daily (~12 hours apart).

Varenicline is available in various strengths as 0.5 mg, 1 mg, 0.5 mg-1 mg; 0.03 mg/inch.

Varenicline is available in the form of Oral Tablets and nasal sprays.

Dosage Adjustment in Kidney Patient

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Initial: 0.5 mg once daily; maximum maintenance dose: 0.5 mg twice daily.

ESRD (receiving hemodialysis): Maximum dose: 0.5 mg once daily.

Varenicline is contraindicated in patients with a known history of severe hypersensitivity reactions or skin reactions to Varenicline.

• CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (e.g., operating machinery, driving). There have been post marketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking varenicline.

• Hypersensitivity reactions

Post-marketing reports of hypersensitivity reactions (including angioedema) and rare cases of serious skin reactions (including Stevens-Johnson syndrome and erythema multiforme) have been reported. Patients should be instructed to discontinue use and contact health care provider if signs/symptoms occur.

• Renal impairment

Use with caution in patients with renal impairment; dosage adjustment is required with severe impairment.

• Psychiatric event

Use of Varenicline may cause mood changes, anxiety, paranoia, delusions, etc., in some patients. Hence it should be administered with caution in patients with a pre-existing psychiatric disorder. Appropriate patient counselling, dose adjustments, or replacement with a suitable alternative may be necessary in some cases.

• Seizures

The use of Varenicline may cause seizures in some patients. Hence, it should be used with extreme caution and appropriate monitoring in patients with a pre-existing seizure disorder. Appropriate dose adjustments or replacement with a suitable alternative may be required in some cases based on the clinical condition.

• Heart diseases

Use of Varenicline may worsen the symptoms of heart diseases. Hence, it should be used with caution and monitoring in patients with pre-existing disease of the heart or the blood vessels. Appropriate dose adjustments or replacement with a suitable alternative may be required in some cases based on the clinical condition.

• Sleepwalking

Use of Varenicline has been associated with incidences of sleepwalking in some rare cases. Hence, caution is advised in patients with a pre-existing condition of somnambulism (sleepwalking). Close monitoring of clinical disease, appropriate dose adjustments, or replacement with a suitable alternative may be required in some cases based on the clinical condition.

• Nausea

Use of Varenicline may cause mild to moderate nausea, which does not require treatment.

Consumption of alcohol is not recommended while receiving this medicine since it may decrease your tolerance towards alcohol and increase the risk of severe adverse effects. Avoid performing activities requiring high mental alertness like driving a vehicle or operating heavy machinery if alcohol and this medicine are used together.

There are no data on the presence of varenicline in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies varenicline was present in milk of lactating rats. However, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The lack of clinical data during lactation precludes a clear determination of the risk of Varenicline to an infant during lactation; however, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Varenicline and any potential adverse effects on the breastfed child from Varenicline or from the underlying maternal condition.

Pregnancy Category C

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Common

Nausea , vomiting, Nervous system: Abnormal dreams, depressed mood, headache, insomnia, irritability, Acute myocardial infarction, angina pectoris, chest pain, peripheral edema, Skin rash, Menstrual disease, weight gain, Abdominal pain, anorexia, constipation, decreased appetite, diarrhea, dysgeusia, dyspepsia, flatulence, gastroesophageal reflux disease, increased appetite, toothache, xerostomia, Abnormal hepatic function tests, Agitation, anxiety, disturbance in attention, dizziness, drowsiness, emotional disturbance, fatigue, hostility, lethargy, malaise, nightmares, sleep disorder, cardiac arrhythmia, cardiac flutter, cerebrovascular accident, chest discomfort, coronary artery disease, ECG abnormality, edema, flushing, ophthalmic vascular disease, palpitations, pulmonary embolism, syncope, tachycardia, thrombosis, tremor, Blurred vision, cataract (subcapsular), conjunctivitis, eye irritation, eye pain, night blindness, nystagmus disorder, photophobia, transient blindness, visual field defect, vitreous opacity, xerophthalmia, Deafness, Meniere's disease, tinnitus, Acute kidney injury, nephrolithiasis, polyuria, Allergic rhinitis, asthma.

Rare

Erythema multiforme, Stevens-Johnson syndrome, Hyperglycemia, Angioedema, Aggressive behavior, behavioral changes, delusion, depression, hallucination, homicidal ideation, lack of concentration, loss of consciousness, mania, panic, paranoid ideation, psychosis, somnambulism, suicidal, suicidal ideation.

• 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.

The common side effects of Varenicline include the following

Common side effects

Nausea, constipation, diarrhea, gas, abdominal pain, vomiting, heartburn, bad taste in the mouth, dry mouth, increased or decreased appetite, toothache, trouble falling asleep or staying asleep, unusual dreams or nightmares, headache, lack of energy, back, joint, or muscle pain, abnormal menstrual cycles.

Rare side effects

Swelling of the face, throat, tongue, lips, gums, eyes, neck, hands, arms, feet, ankles, or lower legs, hoarseness, difficulty swallowing or breathing, rash, swollen, red, peeling, or blistering skin, blisters in the mouth, pain, squeezing, or pressure in the chest, pain or discomfort in one or both arms, back, neck, jaw, or stomach, shortness of breath, sweating, nausea, vomiting, or light-headedness with chest pain, slow or difficult speech, sudden weakness or numbness of an arm or leg, especially on one side of the body, calf pain while walking, seizures, sleepwalking.

• Pregnancy

Pregnancy Category C

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

• Nursing Mothers

There are no data on the presence of varenicline in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies varenicline was present in milk of lactating rats. However, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The lack of clinical data during lactation precludes a clear determination of the risk of Varenicline to an infant during lactation; however, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Varenicline and any potential adverse effects on the breastfed child from Varenicline or from the underlying maternal condition.

• Pediatric Use

Safety and effectiveness of Varenicline in pediatric patients have not been established.

• Geriatric Use

No dosage adjustment is recommended for elderly patients.

• Pharmacodynamic

Varenicline is a partial nicotinic acetylcholine receptor agonist, designed to partially activate this system while displacing nicotine at its sites of action in the brain.

• Pharmacokinetics

Absorption

Varenicline is absorbed well from the gastrointestinal tract. It has Bioavailability of Approximately 90%. Time taken to reach peak plasma concentration is approximately 3-4 hours.

Distribution

Plasma protein binding of varenicline is low (≤20%) and independent of both age and renal function.

Metabolism and Excretion

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.

1. Faessel HM, Obach RS, Rollema H, Ravva P, Williams KE, Burstein AH. A review of the clinical pharmacokinetics and pharmacodynamics of varenicline for smoking cessation. Clinical pharmacokinetics. 2010 Dec;49:799-816.

2. Ravva P, Gastonguay MR, Tensfeldt TG, Faessel HM. Population pharmacokinetic analysis of varenicline in adult smokers. British journal of clinical pharmacology. 2009 Nov;68(5):669-81.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021928s040lbl.pdf
• https://www.rxlist.com/varenicline/generic-drug.htm
• https://www.drugs.com/mtm/varenicline.html
• https://go.drugbank.com/drugs/DB01273
• https://reference.medscape.com/drug/chantix-varenicline-343212