Champix, 1 mg 28 pcs

Pharmacotherapeutic group:

Nicotine addiction treatment.

ATX code:N07BA03

Pharmacodynamics

Varenicline binds with high affinity and selectivity to a4p2 nicotinic acetylcholine receptors in the brain, against which it is both a partial agonist (but less so than nicotine) and an antagonist in the presence of nicotine. In vitro electrophysiological and in vivo neurochemical studies have shown that varenicline binds to and stimulates a4p2 nicotinic acetylcholine receptors, but to a much lesser extent than nicotine. Nicotine competitively binds to the same receptor site to which varenicline has a higher affinity. Thus, varenicline effectively blocks the ability of nicotine to stimulate receptors and activate the mesolimbic dopamine system, a neuronal mechanism that underlies the mechanisms of nicotine addiction (the pleasure of smoking). Varenicline is highly selective and binds more to the a4p2 receptor subtype than to other nicotinic receptor subtypes (aZp4, a7, afub) or other receptors and transport proteins. The efficacy of varenicline as a treatment for nicotine dependence is due to its partial agonism to the a4[}2 nicotinic receptors, binding to which reduces cravings for smoking and facilitates the onset of withdrawal, while leading to a reduction in feelings of pleasure from smoking (antagonism in the presence of nicotine).

When used in adult patients, varenicline has been shown to reduce smoking cravings and withdrawal symptoms. Increasing the duration of varenicline to 24 weeks (an additional 12 weeks to the standard course) increased its effectiveness. Varenicline was also effective for smoking cessation when repeatedly used in patients who had previously stopped smoking with varenicline. Varenicline was also effective when patients chose their own smoking cessation date (a “flexible” regimen).

Varenicline was effective for smoking cessation in patients with chronic obstructive pulmonary disease, including long-term follow-up (52 weeks from treatment initiation), in cardiology patients with acute and chronic cardiovascular disease (including hospitalized patients with acute coronary syndrome – unstable angina and ST-segment elevation myocardial infarction), both for complete smoking cessation and for reducing the number of cigarettes smoked. The efficacy and safety of varenicline for smoking cessation in patients with a history of psychiatric illness has been demonstrated.

Pharmacokinetics

Intake

The maximum plasma concentration of varenicline (Cm;iX) is generally reached 3-4 h after oral administration. On subsequent doses in healthy volunteers, the equilibrium state was reached within 4 days. The drug is almost completely absorbed after oral administration and has high systemic bioavailability unrelated to food intake and time of administration during the day. After a single dose of 0.1 mg to 3 mg or repeated doses of 1 mg/day to 3 mg/day, the pharmacokinetics of varenicline were linear.

Distribution

Varenicline is distributed in tissues and penetrates the thematoencephalic barrier, reaching the brain. The degree of binding to plasma proteins is low (< 20%) and is independent of age and renal function. The apparent volume of distribution in the equilibrium state is 415 l. In rodents varenicline penetrates into breast milk and passes through the placental barrier.

Metabolism

Varenicline undergoes minimal transformation: 92% of the dose is excreted unchanged by the kidneys and less than 10% as metabolites. Among the metabolites of varenicline, N-carbamyl glucuronide of varenicline and hydroxyvarenicline are found in urine. In blood plasma varenicline is 91% circulating unchanged. Among the circulating metabolites, N-carbamylglucuronide varenicline and N-glucosyl varenicline were found. In vitro studies have demonstrated that varenicline does not inhibit cytochrome P450 isoenzymes (inhibitory concentration 50 > 6400 ng/ml). The following cytochrome P450 isoenzymes were tested: 1A2. 2A6, 2B6, 2C8. 2C9, 2CI9. 2D6. 2E1, and ZA4/5. It was also shown in human hepatocytes in vitro that varenicline does not induce the activity of cytochrome P450 isoenzymes IA2 and WA4. Thus, it is unlikely that varenicline will affect drugs that are predominantly metabolized by cytochrome P450 isoenzymes. Excretion

The elimination half-life (T’/;) of varenicline is approximately 24 h. Renal excretion of varenicline is primarily by glomerular filtration combined with active tubular secretion via organic cationic carrier proteins OCT2.

The linearity/non-linearity of varenicline pharmacokinetics

The pharmacokinetics of varenicline are linear with single (0.1 to 3 mg) and multiple (I to 3 mg/day) administration. Pharmacokinetics in Special Groups

Pharmacokinetic studies and population pharmacokinetic analysis have shown that varenicline pharmacokinetics are not significantly affected by age, race, sex, smoking status, or concomitant therapy. Renal dysfunction

The pharmacokinetics of varenicline was not altered in patients with mild renal dysfunction (creatinine clearance > 50 ml/min and < 80 ml/min). In patients with moderately severe renal impairment (creatinine clearance > 30 ml/min and < 50 ml/min) AUC of varenicline increased 1.5 times compared to that in patients with normal renal function (creatinine clearance > 80 ml/min). In patients with severe renal impairment (creatinine clearance < 30 ml/min) varenicline AUC increased 2.1-fold. In patients with terminal renal failure varenicline was effectively removed by hemodialysis.

Hepatic dysfunction

In view of the absence of marked metabolism of varenicline in the liver, the pharmacokinetics of varenicline should not be altered in patients with impaired liver function.

Elderly patients

The pharmacokinetics of varenicline in elderly patients with normal renal function (age 65 to 75 years) are not altered. For recommendations on the use of varenicline in elderly patients with impaired renal function, see “Dosage and administration”.

Indications

The drug Champix® is intended for use as a means of smoking cessation in adults from the age of 18 years onwards without age restrictions.

Pharmacological effect

Pharmacotherapeutic group:

nicotine addiction treatment.

ATX code:N07BA03

Pharmacodynamics

Varenicline binds with high affinity and selectivity to the α4β2 nicotinic acetylcholine receptors of the brain, for which it is both a partial agonist (but to a lesser extent than nicotine) and an antagonist in the presence of nicotine. In vitro electrophysiological studies and in vivo neurochemical studies 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 for which varenicline has a higher affinity. Thus, varenicline effectively blocks the ability of nicotine to stimulate receptors and activate the mesolimbic dopamine system – a neuronal mechanism that underlies the mechanisms of formation of nicotine addiction (getting pleasure from smoking). Varenicline is highly selective and binds to a greater extent to the a4p2 receptor subtype than to other nicotinic receptor subtypes (a3p4, a7, afub) or other receptors and transport proteins. The effectiveness of varenicline as a treatment for nicotine addiction is due to its partial agonism at α4[}2 nicotinic receptors, binding to which reduces the craving for smoking and facilitates the manifestation of the withdrawal syndrome, while simultaneously leading to a decrease in the feeling of pleasure from smoking (antagonism in the presence of nicotine).

When used in adult patients, varenicline has demonstrated a reduction in smoking cravings and withdrawal symptoms. Increasing the duration of varenicline administration to 24 weeks (an additional 12 weeks to the standard course) led to an increase in its effectiveness. Varenicline was also effective for smoking cessation when given repeatedly in patients who had previously stopped smoking with varenicline. Varenicline was also effective when patients chose their own smoking cessation date (“flexible” dosing schedule).

Varenicline was effective for smoking cessation in patients with chronic obstructive pulmonary disease, including during long-term follow-up (52 weeks from the start of treatment), in cardiac patients with acute and chronic cardiovascular diseases (including those hospitalized with acute coronary syndrome – unstable angina and myocardial infarction with and without ST-segment elevation), both for complete cessation of smoking and for reducing the number of cigarettes smoked. 11The effectiveness and safety of the use of varenicline for smoking cessation in patients with a history of psychiatric diseases has been demonstrated.

Pharmacokinetics

Suction

The maximum concentration of varenicline (Cm;iX) in the blood plasma is usually achieved 3-4 hours after oral administration. With subsequent doses in healthy volunteers, steady state was achieved within 4 days. The drug is almost completely absorbed after oral administration and has high systemic bioavailability, not related to food intake and time of administration during the day. After a single dose of 0.1 mg to 3 mg or repeated doses of 1 mg/day to 3 mg/day, the pharmacokinetics of varenicline were linear.

Distribution

Varenicline is distributed in tissues and penetrates the thematic-brain barrier, entering the brain. The degree of binding to plasma proteins is low (<20%) and does not depend on age and renal function. The apparent volume of distribution at steady state is 415 l. In rodents, varenicline passes into breast milk and crosses the placental barrier.

Metabolism

Varenicline undergoes minimal transformation: 92% of the dose is excreted unchanged by the kidneys and less than 10% in the form of metabolites. Among the metabolites of varenicline, varenicline N-carbamylglucuronide and hydroxyvarenicline were found in the urine. In blood plasma, 91% of varenicline circulates unchanged. Among the circulating metabolites, N-carbamylglucuronide varenicline and N-glucosylvarenicline were found. In vitro studies have demonstrated that varenicline does not inhibit cytochrome P450 isoenzymes (inhibitory concentration 50 > 6400 ng/ml). The following cytochrome P450 isoenzymes were tested: 1A2. 2A6, 2B6, 2S8. 2С9, 2CI9. 2D6. 2E1, and ZA4/5. It was also shown in vitro in human hepatocytes that varenicline does not induce the activity of cytochrome P450 isoenzymes IA2 and ZA4. Therefore, varenicline is unlikely to affect drugs that are predominantly metabolized by cytochrome P450 isoenzymes. Removal

The half-life (T’/;) of varenicline is about 24 hours. Excretion of varenicline by the kidneys is carried out mainly by glomerular filtration in combination with active tubular secretion through organic cationic OCT2 transporter proteins.

Linearity/nonlinearity of varenicline pharmacokinetics

The pharmacokinetics of varenicline is linear with a single dose (from 0.1 to 3 mg) and multiple doses (from 1 to 3 mg/day). Pharmacokinetics in special groups

Pharmacokinetic studies and population pharmacokinetic analyzes have shown that the pharmacokinetics of varenicline are not significantly affected by age, race, gender, smoking status, or concomitant therapy. Renal dysfunction

The pharmacokinetics of varenicline did not change in patients with mild renal impairment (creatinine clearance > 50 ml/min and 30 ml/min and 80 ml/min). In patients with severe renal impairment (creatinine clearance <30 ml/min), the AUC of varenicline increased 2.1-fold. In patients with end-stage renal disease, varenicline was effectively removed by hemodialysis.

Liver dysfunction

Given the lack of significant metabolism of varenicline in the liver, the pharmacokinetics of varenicline should not change in patients with impaired liver function.

Elderly patients

The pharmacokinetics of varenicline in elderly people with normal renal function (age 65 to 75 years) is unchanged. Recommendations for the use of varenicline in elderly patients with impaired renal function are listed in the section “Dosage and Administration”.

Special instructions

Effects of smoking cessation: Physiological changes associated with smoking cessation while taking Champix or without treatment may cause changes in the pharmacokinetics or pharmacodynamics of some drugs, which may require changes in their dose (for example, theophylline, warfarin and insulin). Smoking increases CYP1A2 activity, so cessation of smoking may increase plasma levels of CYP1A2 substrates.

Smoking cessation with or without pharmacotherapy was accompanied by exacerbation of psychiatric diseases (for example, depression). Caution must be exercised in patients with a history of psychiatric disorders. Patients should be warned about the possibility of exacerbation of such diseases when smoking cessation.

There is no experience with the use of Champix in patients with epilepsy. Discontinuation of Champix after completion of treatment in 3% of patients was accompanied by increased irritability, craving for smoking, depression and/or insomnia. The physician should inform the patient about the possible occurrence of such reactions and consider the possibility of gradually reducing the dose.

Impact on the ability to drive a car and use equipment
Champix has a slight or moderate effect on the ability to drive a car and use complex equipment. Champix may cause dizziness and drowsiness and, accordingly, affect the ability to drive a car and use complex equipment. Patients are not advised to drive, use sophisticated machinery, or perform other potentially hazardous tasks until they have assessed their response to the drug.

Active ingredient

Varenicline

Composition

Active substance:

varenicline – 1 mg (as varenicline tartrate 1.71 mg)

Excipients:

microcrystalline cellulose – 125.13 mg,

calcium hydrogen phosphate – 66.66 mg,

croscarmellose sodium – 4.00 mg,

colloidal silicon dioxide -1.00 mg,

magnesium stearate – 1.50 mg;

film coating: opadry transparent YS-2-19114-A (contains hypromellose and triacetin) – 1.00 mg; opadry blue 03B90547 (contains hypromellose, titanium dioxide, macrogol and aluminum varnish based on indigo carmine) – 8.00 mg.

Pregnancy

There have been no adequate and strictly controlled studies on the safety of Champix during pregnancy, therefore the use of the drug is contraindicated.

It is not known whether varenicline is excreted into breast milk in humans. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Contraindications

Hypersensitivity to any component of the drug.

Age under 18 years (insufficient clinical data on the effectiveness and safety of the drug in this age group).

Pregnancy and lactation.
End stage renal failure.

Use during pregnancy and breastfeeding

Pregnancy

A moderate amount of data was obtained from pregnant women (outcomes from 300 to 1000 pregnancies) indicating that varenicline does not cause fetal/newborn toxicity resulting in malformations.

Animal studies have revealed toxic effects on the reproductive system. As a precaution, use during pregnancy is contraindicated.

Breast-feeding

There is no information about the excretion of varenicline into breast milk in women. In animal studies, varenicline has been shown to be excreted in breast milk. As a precaution, use during breastfeeding is contraindicated.

Fertility

There are no clinical data on the effects of varenicline on fertility. Preclinical studies have shown no negative effects of varenicline on fertility in standard rat studies. Women of childbearing potential should avoid planning pregnancy while being treated with varenicline.

Side Effects

Smoking cessation, both with and without therapy, is accompanied by various symptoms, in particular, decreased mood and dysphoria, insomnia, irritability, feelings of displeasure and anger, anxiety, impaired concentration, restlessness, decreased heart rate, increased appetite or weight gain. Smoking cessation with or without drug therapy was also accompanied by exacerbation of concomitant mental disorders. When developing the design of clinical trials of the drug Champix’1 and during the analysis of their results, no distinction was made between adverse events possibly associated with the use of the study drug and those actually associated with nicotine withdrawal syndrome. Adverse reactions were based initially on the evaluation of registration studies and were supplemented by data from 18 placebo-controlled registration and post-marketing studies involving approximately 5000 patients taking varenicline.

According to the results of clinical studies, adverse reactions usually appeared in the first week after the start of treatment, were usually mild or moderate, and their frequency did not depend on the age, race or gender of the patient.

In patients receiving Champix at the recommended dose of 1 mg twice daily after the titration period, the most common adverse effect reported was nausea (28.6%). In most cases, nausea occurred in the early stages of therapy, was mild or moderate, and rarely required discontinuation of the drug. While taking the drug Champix, the following reactions from organs and systems are also possible (frequency assessment criteria: very frequent > 10%; frequent – from > 1% to 0.1% to 0.01% to < 0.1%, very rare - < 0.01%, frequency unknown - cannot be determined based on the available data):

Infectious and parasitic diseases: very common – nasopharyngitis; common – bronchitis, sinusitis; uncommon – fungal infections, viral infections.

Blood and lymphatic system disorders: rare – low platelet count.

Metabolic and nutritional disorders: frequent – weight gain, decreased appetite, increased appetite; uncommon – hyperglycemia; rare – diabetes mellitus, polydipsia.

Mental disorders: very common – unusual dreams, insomnia; infrequent – suicidal behavior, aggressiveness, panic reaction, thinking disorders, anxiety, mood swings, depression*, states of fear*, hallucinations*, increased libido, decreased libido; rare – psychosis, somnambulism, behavioral deviations, dysphoria, bradyphrenia.

Nervous system disorders: very common – headaches; frequent – drowsiness, dizziness, dysgeusia; uncommon – seizures, tremor, lethargy, hypoesthesia; rare – stroke, hypertension, dysarthria, coordination disorders, hypogeusia, sleep-wake rhythm disturbances.

Violations of the organ of vision: infrequent – conjunctivitis, eye pain; rare – scotoma, discoloration of the sclera, mydriasis, photophobia, myopia, increased lacrimation.

Hearing and labyrinthine disorders: uncommon – tinnitus.

Cardiac disorders: uncommon – myocardial infarction, angina pectoris, tachycardia, palpitations, increased heart rate; rare – atrial fibrillation, depression of the ST interval on the ECG. reduced amplitude of T waves on the ECG.

Vascular disorders: uncommon – high blood pressure, flushing.

Disorders of the respiratory system, chest and mediastinal organs:
frequent – shortness of breath, cough; uncommon – inflammation of the upper respiratory tract, hyperemia of the respiratory tract, dysphonia, allergic rhinitis, pharyngeal irritation, swelling of the mucous membranes of the maxillary sinuses, cough syndrome of the upper respiratory tract, rhinorrhea; rare – pain in the larynx, snoring.

Gastrointestinal disorders: very common – nausea; frequent – gastroesophageal reflux, vomiting, constipation, diarrhea, gas, abdominal pain, toothache, dyspepsia, bloating, dry mouth; infrequent – hematochezia, gastritis, disturbances in the usual rhythm of bowel movements, belching, aphthous stomatitis, pain in the gums; rare – vomiting with blood, changes in stool, coated tongue.

Disorders of the skin and subcutaneous tissues: frequent – rash, itching;
uncommon – erythema, acne, hyperhidrosis, night sweats; rare – severe skin reactions, including Stevens Johnson syndrome and erythema multiforme, angioedema.

Musculoskeletal and connective tissue disorders: common – arthralgia, myalgia, back pain; infrequent – muscle spasms, chest pain related to skeletal muscles; rare – ankylosis, chondritis of the ribs.

Renal and urinary tract disorders: uncommon – gyllakiuria, nocturia; rare – glucosuria, polyuria.

Disorders of the genital organs and mammary gland: uncommon – menorrhagia; rare – leucorrhoea, sexual functional disorders.

General disorders and disorders at the injection site: frequent – chest pain, fatigue; uncommon – chest complaints, illness with flu-like symptoms, fever, pyrexia. asthenia, malaise; rare – feeling of cold, cyst.

Influence on the results of laboratory and instrumental studies: frequent – deviation from the norm of biochemical indicators of liver function; rare – abnormal results of seminal fluid analysis, increased levels of C-reactive protein, decreased levels of calcium in the blood.

*Rate estimates based on post-registration observational study cohorts.

Interaction

Based on pharmacological properties and clinical data, varenicline does not have clinically significant drug interactions. No dose adjustment is required for varenicline or the drugs listed below when used concomitantly.

In vitro studies have shown that active renal secretion of varenicline is mediated by the human organic cation transporter (OCT2). When used concomitantly with OCT2 inhibitors, no dosage adjustment of varenicline is required. since a significant increase in systemic exposure to varenicline tartrate is not expected. In vitro studies indicate that varenicline does not alter the pharmacokinetics of drugs that are metabolized by cytochrome P450 isoenzymes. Since varenicline clearance is less than 10% due to metabolism, it is unlikely that substances affecting the activity of cytochrome P45o isoenzymes could affect the pharmacokinetics of varenicline, and therefore no dosage adjustment is required.

Varenicline at therapeutic concentrations does not inhibit renal protein transport in humans. Therefore, varenicline should not affect the pharmacokinetics of drugs that are cleared by renal secretion (in particular, metformin – see below).
Metformin
Varenicline does not affect the pharmacokinetics of metformin. Metformin does not change the pharmacokinetics of varenicline.

Cimetidine
Cimetidine causes an increase in the AUC of varenicline by 29% due to a decrease in its renal clearance. No dosage adjustment is required in patients with normal renal function or in patients with mild to moderate renal impairment. In patients with severe renal impairment, concomitant use of cimetidine and varenicline should be avoided.

Digoxin
Varenicline does not affect the pharmacokinetics of digoxin at steady state.

Warfarin
Varenicline does not change the pharmacokinetics of warfarin and does not affect prothrombin time (MHO). Smoking cessation itself may alter the pharmacokinetics of warfarin.

Alcohol

Data on the concomitant use of varenicline and alcohol are limited. During post-marketing use of varenicline, cases of increased toxic effects of alcohol have been reported. A causal relationship between these cases and the use of varenicline has not been established.

Use in combination with other anti-smoking products

Bupropion

Varenicline does not affect the pharmacokinetics of bupropion at steady state.

Nicotium replacement therapy

When varenicline and nicotine patches were used concomitantly in smokers for 12 days, a statistically significant decrease in mean systolic blood pressure was found (by 2.6 mmHg). Art.) on the last day of the study. Moreover, the incidence of nausea, headache, vomiting, dizziness, dyspepsia and fatigue during combination therapy was higher than during NRT alone.

The safety and effectiveness of varenicline in combination with other anti-tobacco medications have not been studied.

Overdose

There were no cases of varenicline overdose in registration clinical studies. In case of overdose, symptomatic therapy should be used. Varenicline is eliminated by hemodialysis in patients with severe renal impairment, but there is no experience with the use of hemodialysis in overdose.

Storage conditions

At 15–30 °C

Shelf life

2 years

Manufacturer

R-Pharm Germany GmbH, Germany