Varenicline Tartrate

Approved Indications:

• Smoking Cessation Aid (Primary Use):
  Varenicline Tartrate is indicated as an aid to smoking cessation treatment in adults. It is used to help people quit smoking by reducing craving and withdrawal symptoms, and decreasing the rewarding effects of nicotine.

Off-label/Clinically Accepted Uses:

• Smoking Cessation in Patients with Psychiatric Disorders:
  Used with caution in patients with schizophrenia, bipolar disorder, or major depressive disorder, under close psychiatric supervision.
• Smoking Cessation in Patients with Cardiovascular Disease:
  Considered effective and generally safe for helping patients with stable cardiovascular disease quit smoking.

Adults:

• Standard Dose Regimen:
• Days 1–3: 0.5 mg once daily
• Days 4–7: 0.5 mg twice daily
• Day 8 onward (for 12 weeks): 1 mg twice daily
• Extended Therapy:
  For patients successfully abstaining at the end of 12 weeks, an additional 12-week course (1 mg twice daily) may be prescribed to enhance long-term abstinence.

Initiation Guidelines:

• Patients should start Varenicline 1 week before their planned quit date, or choose a flexible quit date between Days 8 and 35 of treatment.

Special Populations:

• Renal Impairment:
• Moderate impairment (CrCl 30–59 mL/min): No dose adjustment necessary.
• Severe impairment (CrCl <30 mL/min): Initial dose 0.5 mg once daily; maximum dose 0.5 mg twice daily.
• End-stage renal disease on hemodialysis: Maximum dose 0.5 mg once daily.
• Hepatic Impairment:
  No dose adjustment necessary.
• Elderly Patients (≥65 years):
  No routine dose adjustment unless renal function is impaired.

Route of Administration:
Oral. Tablets should be taken after eating with a full glass of water.

Varenicline is a partial agonist at the α4β2 subtype of the nicotinic acetylcholine receptors (nAChRs). It binds with high affinity to these receptors in the brain, leading to moderate, sustained release of dopamine that helps reduce nicotine cravings and withdrawal symptoms. At the same time, by partially stimulating the receptor and preventing nicotine from binding, it blocks the full reinforcing effects of nicotine. This dual action—partial agonism and competitive antagonism—helps smokers quit by diminishing both withdrawal symptoms and nicotine reward.

• Absorption:
  Rapidly absorbed after oral administration. Peak plasma concentrations occur within 3–4 hours. Food does not significantly affect bioavailability.
• Bioavailability:
  Approximately 90% (absolute), unaffected by food.
• Distribution:
  Volume of distribution is about 5.8 L/kg. Plasma protein binding is negligible (~<20%).
• Metabolism:
  Minimal hepatic metabolism; over 90% of the drug is excreted unchanged in the urine.
• Half-life:
  Elimination half-life is approximately 24 hours.
• Excretion:
  Primarily renal via glomerular filtration and active tubular secretion.

• Pregnancy:
  Classified as Pregnancy Category C (FDA). Animal studies have shown adverse effects on the fetus, and there are no adequate, well-controlled studies in pregnant women. Use only if the potential benefit justifies the potential risk.
• Lactation:
  Varenicline is excreted into breast milk in animal studies. The effects on nursing infants are unknown; caution is advised, and alternative smoking cessation methods may be considered.

• Primary Class: Smoking Cessation Aid
• Subclass: Partial Nicotinic Receptor Agonist (α4β2 subtype)

• Known hypersensitivity to varenicline tartrate or any component of the formulation
• History of serious allergic or skin reactions (e.g., Stevens-Johnson Syndrome) to varenicline
• Concurrent use with other smoking cessation therapies (e.g., nicotine patches), unless supervised

• Neuropsychiatric Events:
  Serious neuropsychiatric symptoms (e.g., suicidal ideation, depression, hostility) may occur; monitor patients with psychiatric illness closely.
• Seizures:
  Cases of seizures reported, particularly during the first month; use caution in individuals with seizure history.
• Cardiovascular Events:
  Use with caution in patients with pre-existing cardiovascular disease.
• Hypersensitivity Reactions:
  Reports of angioedema, Stevens-Johnson Syndrome, and other serious skin reactions.
• Impairment of Driving or Operation of Machinery:
  May cause dizziness, somnolence, or loss of consciousness; patients should avoid such activities until they know how varenicline affects them.
• Renal Impairment:
  Dose adjustment required; monitor renal function in elderly and renal-compromised patients.

Common Side Effects:

• Gastrointestinal: Nausea (most common), constipation, flatulence, vomiting
• Neurological: Headache, insomnia, abnormal dreams, dizziness, somnolence
• Psychiatric: Depression, irritability, anxiety

Serious Adverse Effects:

• Neuropsychiatric symptoms: Suicidal ideation, aggression, agitation, hallucinations
• Cardiovascular: Chest pain, palpitations (rare)
• Allergic Reactions: Rash, angioedema, hypersensitivity reactions

Rare/Severe Effects:

• Stevens-Johnson Syndrome
• Seizures
• Visual disturbances
• Loss of consciousness

• Nicotine Replacement Therapy (NRT):
  Concomitant use may increase side effects (nausea, headache, dizziness); coadministration requires close monitoring.
• Alcohol:
  May enhance the neuropsychiatric side effects of varenicline. Some patients reported increased intoxication or aggressive behavior with alcohol.
• Cimetidine (in severe renal impairment):
  Increases plasma concentration of varenicline due to reduced clearance.
• Mechanism of Interactions:
  Varenicline has minimal metabolism and does not significantly interact with CYP450 enzymes, thus low potential for major CYP-mediated interactions.

• FDA Label Update:
  The boxed warning on serious neuropsychiatric side effects was removed in 2016, but caution is still advised.
• EMA (European Medicines Agency):
  Continued recommendation for monitoring mental health symptoms during treatment, especially in patients with psychiatric history.
• Discontinuation Notice (Some Regions):
  Temporary recalls occurred due to nitrosamine impurities in certain batches; reformulated or alternative batches have since become available.
• Guideline Positioning:
  Varenicline is recommended as first-line pharmacologic therapy for smoking cessation in most international guidelines (e.g., NICE, WHO, AHRQ).

• Storage Temperature: Store below 25°C (77°F).
• Light & Moisture Protection: Store in a dry place, protect from moisture.
• Handling Precautions: No special handling required. Keep in original packaging until use.
• Do Not Freeze.
• Tablets should not be split or crushed.