Vareniklin (Tablets) Instructions for Use

Marketing Authorization Holder

Promomed Rus LLC (Russia)

Manufactured By

Biokhimik, JSC (Russia)

ATC Code

N07BA03 (Varenicline)

Active Substance

Varenicline (Rec.INN registered by WHO)

Dosage Forms

	Varenicline	Film-coated tablets 0.5 mg: 11, 14, 22, 28, 44, 56 or 112 pcs.
		Film-coated tablets 1 mg: 14, 28, 42, 56, 98 or 112 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex; the core on the cross-section is white or almost white.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide.
Film coating 1: hypromellose, triacetin.
Film coating 2: hypromellose, titanium dioxide (E171)

11 pcs. – contour cell packaging (1) – cardboard packs.
11 pcs. – contour cell packaging (2) – cardboard packs.
11 pcs. – contour cell packaging (4) – cardboard packs.
11 pcs. – contour cell packaging (8) – cardboard packs.
11 pcs. – contour cell packaging (1) (in a set with contour cell packaging of 14 tabs. 1 mg – 1 pc.) – cardboard packs.
11 pcs. – contour cell packaging (1) (in a set with contour cell packaging of 14 tabs. 1 mg – 3 pcs.) – cardboard packs.
11 pcs. – contour cell packaging (1) (in a set with contour cell packaging of 14 tabs. 1 mg – 7 pcs.) – cardboard packs.
14 pcs. – polyethylene jars (1) – cardboard packs.
28 pcs. – polyethylene jars (1) – cardboard packs.
56 pcs. – polyethylene jars (1) – cardboard packs.
112 pcs. – polyethylene jars (1) – cardboard packs.

Film-coated tablets from light blue to blue, oval, biconvex; the core on the cross-section is white or almost white.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide.
Film coating 1: hypromellose, triacetin.
Film coating 2: hypromellose, titanium dioxide (E171), macrogol (polyethylene glycol), aluminum lake based on indigo carmine dye (E132) or a ready-made film coating of identical composition.

14 pcs. – contour cell packaging (1) – cardboard packs.
14 pcs. – contour cell packaging (2) – cardboard packs.
14 pcs. – contour cell packaging (4) – cardboard packs.
14 pcs. – contour cell packaging (8) – cardboard packs.
14 pcs. – contour cell packaging (1) (in a set with contour cell packaging of 11 tabs. 0.5 mg – 1 pc.) – cardboard packs.
14 pcs. – contour cell packaging (3) (in a set with contour cell packaging of 11 tabs. 0.5 mg – 1 pc.) – cardboard packs.
14 pcs. – contour cell packaging (7) (in a set with contour cell packaging of 11 tabs. 0.5 mg – 1 pc.) – cardboard packs.
14 pcs. – polyethylene jars (1) – cardboard packs.
28 pcs. – polyethylene jars (1) – cardboard packs.
56 pcs. – polyethylene jars (1) – cardboard packs.
112 pcs. – polyethylene jars (1) – cardboard packs.

Clinical-Pharmacological Group

Drug for the treatment of nicotine dependence

Pharmacotherapeutic Group

Other agents for the treatment of nervous system diseases; agents used for addictive disorders; agents used for nicotine dependence

Pharmacological Action

Agent for the treatment of nicotine dependence. Varenicline binds with high affinity and selectivity to α4β2 nicotinic acetylcholine receptors, for which it is a partial nicotine agonist, i.e., it simultaneously exhibits agonistic activity (but to a lesser extent than nicotine) and antagonism in the presence of nicotine.

Electrophysiological studies in vitro and neurobiochemical studies in vivo have shown that Varenicline binds to and stimulates α4β2 nicotinic acetylcholine receptors, but to a significantly lesser extent than nicotine. Nicotine competitively binds to the same receptor site to which Varenicline has a higher affinity. Thus, Varenicline effectively blocks nicotine’s ability to stimulate α4β2 nicotinic acetylcholine receptors and activate the mesolimbic dopaminergic system – the neuronal mechanism underlying the formation of nicotine dependence (pleasure from smoking).

The efficacy of varenicline as an agent for the treatment of nicotine dependence is due to its partial agonism at α4β2 nicotinic acetylcholine receptors, binding to which reduces the craving for smoking and alleviates withdrawal symptoms (agonistic activity) and simultaneously leads to a reduction in the feeling of pleasure from smoking (antagonism in the presence of nicotine).

Pharmacokinetics

C_max in blood plasma is generally reached within 3-4 hours after oral administration. In subsequent doses in healthy volunteers, steady state was achieved within 4 days. It is almost completely absorbed after oral administration and has high systemic bioavailability, which is not associated with food intake or time of day. After a single dose from 0.1 mg to 3 mg or repeated doses from 1 mg/day to 3 mg/day, the pharmacokinetics of varenicline were linear.

Varenicline is distributed in tissues and crosses the BBB, entering the brain. Plasma protein binding is low (< 20%) and does not depend on age and renal function.

Varenicline undergoes minimal transformation: 92% of the dose is excreted by the kidneys unchanged and less than 10% as metabolites. Among the metabolites of varenicline found in urine are varenicline N-carbamoylglucuronide and hydroxyvarenicline. In blood plasma, Varenicline circulates 91% unchanged. Among the circulating metabolites found are varenicline N-carbamoylglucuronide and varenicline N-glucoside.

T_1/2 of varenicline is about 24 hours. The renal excretion of varenicline occurs mainly through glomerular filtration combined with active tubular secretion.

In patients with moderate renal impairment (CrCl > 30 ml/min and ≤ 50 ml/min), the AUC of varenicline increased 1.5-fold compared to that in patients with normal renal function (CrCl > 80 ml/min). In patients with severe renal impairment (CrCl < 30 ml/min), the AUC of varenicline increased 2.1-fold. In patients with end-stage renal disease, Varenicline was effectively removed by hemodialysis.

Indications

Nicotine dependence in adults.

ICD codes

Dosage Regimen

Take orally. The initial dose is 500 mcg once a day. Dose titration is carried out according to a special scheme. The recommended dose is 1 mg twice a day.

The course of treatment is 12 weeks. For patients who have successfully quit smoking by the end of the 12th week, an additional course of treatment with the drug at a dose of 1 mg twice a day for 12 weeks is recommended.

Patients who are unable to quit smoking during the initial 12-week course of treatment or who relapse after treatment should be advised to make another attempt, provided that the reasons for the failure of the first attempt have been identified and measures have been taken to address them.

For patients with severe renal impairment (CrCl < 30 ml/min), the recommended dose is 1 mg once a day. Treatment is started with a dose of 500 mcg once a day, which is increased after 3 days to 1 mg once a day.

Adverse Reactions

Most frequently – nausea (28.6%).

From the digestive system: very common – nausea; common – vomiting, constipation, diarrhea, abdominal bloating, stomach discomfort, dyspepsia, flatulence, dry mouth; rare – vomiting blood, blood in stool, gastritis, gastroesophageal reflux disease, abdominal pain, intestinal disorders, stool changes, belching, aphthous stomatitis, gum soreness, coated tongue, changes in liver function tests.

From the nervous system: very common – unusual dreams, insomnia, headache; common – drowsiness, dizziness, dysgeusia; rare – panic reaction, bradyphrenia, thinking impairment, mood swings, tremor, coordination impairment, dysarthria, motor restlessness, dysphoria, hypoesthesia, apathy.

From the metabolism: common – increased appetite; rare – anorexia, decreased appetite, polydipsia, increased body weight, decreased blood calcium concentration.

From the cardiovascular system: rare – increased BP, ST segment depression on ECG, decreased T wave amplitude on ECG, increased heart rate, atrial fibrillation, palpitations.

From the senses: rare – scotoma, change in sclera color, eye pain, pupil dilation, photophobia, myopia, increased lacrimation, tinnitus, decreased taste sensation.

From the respiratory system: rare – shortness of breath, cough, hoarseness, pharyngeal and laryngeal pain, pharyngeal irritation, respiratory congestion, nasal sinus congestion, nasopharyngeal exudation, rhinorrhea, snoring.

Dermatological reactions: rare – generalized rash, erythema, pruritus, acne, hyperhidrosis, increased night sweating.

From the musculoskeletal system: rare – joint stiffness, muscle spasms, chest wall pain, costochondritis.

From the urinary system: rare – glucosuria, nocturia, polyuria.

From the reproductive system: rare – menorrhagia, vaginal discharge, sexual dysfunction, increased libido, decreased libido, sperm changes.

Infections: rare – bronchitis, nasopharyngitis, sinusitis, fungal infections, viral infections.

Other: common – fatigue; rare – chest discomfort, chest pain, fever, feeling cold, asthenia, circadian sleep rhythm disturbance, malaise, cyst, decreased platelet count, increased C-reactive protein level.

Contraindications

End-stage renal failure; children and adolescents under 18 years of age; pregnancy, lactation (breastfeeding); hypersensitivity to varenicline.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Special Precautions

Physiological changes that occur after smoking cessation with or without varenicline treatment may alter the pharmacokinetics or pharmacodynamics of some drugs, for which dose adjustment may be required (e.g., for theophylline, warfarin, and insulin).

Completion of varenicline treatment in 3% of patients was accompanied by increased irritability, craving for smoking, depression, and/or insomnia.

During post-registration use of the drug, reports have been received of the occurrence of neuropsychiatric disorders, including behavioral disturbances, agitation, depressed mood, suicidal ideation and suicidal behavior in patients receiving Varenicline for smoking cessation.

Effect on ability to drive vehicles and operate machinery

Varenicline may cause dizziness and drowsiness, so patients are advised not to drive automobiles and engage in other potentially hazardous activities until their individual response to Varenicline has been assessed.

Drug Interactions

Cimetidine causes a 29% increase in the AUC of varenicline due to a decrease in its renal clearance.

With simultaneous use of varenicline and nicotine-containing patches for 12 days in smokers, a statistically significant decrease in mean systolic BP (by 2.6 mm Hg) was detected on the last day of the study. At the same time, the frequency of nausea, headache, vomiting, dizziness, dyspepsia and fatigue during combination therapy was higher than during nicotine replacement therapy alone.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.