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

Active ingredient

Composition

Active ingredient:

Varenicline – 1 mg (in the form of varenicline tartrate 1.71 mg)

Excipients:

Microcrystalline cellulose – 125.13 mg,

calcium hydrophosphate – 66.66 mg,

croscarmellose sodium – 4.00 mg,

colloidal silicon dioxide -1.00 mg,

magnesium stearate – 1.50 mg;

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

How to take, the dosage

The likelihood of successful cessation therapy is increased in patients who are motivated to quit smoking and who receive additional counseling and support.

Champix is taken orally by swallowing the tablets whole and drinking water regardless of meals. The recommended dose of the drug is 1 mg twice daily with dose titration as follows:

Days 1 -3

0.5 mg once daily

Days 4-7

0.5 mg twice daily

Day 8 – end of treatment

1 mg twice daily

The patient must first choose a date to stop smoking. The treatment with Champix usually should be started 1-2 weeks before the selected date. Total duration of treatment with Champix should be 12 weeks.

Patients who successfully quit smoking by the end of the 12th week of treatment may be recommended an additional 12-week course of therapy with varenicline at a dose of 1 mg twice daily to maintain smoking cessation.

For patients who are unable or unwilling to quit abruptly, a gradual approach with varenicline therapy may be considered. In this case, smoking intensity should be reduced during the first 12 weeks of therapy with complete smoking cessation by the end of that period. After that, patients should take varenicline for another 12 weeks for a total treatment period of 24 weeks.

Patients who are appropriately motivated but were not successful in quitting smoking during the previous course of varenicline treatment. or who relapse after successful completion of treatment may retake varenicline treatment, provided that the reasons for the failure of the first attempt have been identified and steps have been taken to address them.

Patients who do not tolerate Varenicline well because of adverse reactions may have the dose reduced to 0.5 mg twice daily temporarily or permanently.

The risk of smoking relapse is increased in people who have recently completed smoking cessation therapy.

Elderly patients

There is no need to adjust the dose of Champix in elderly patients. Elderly patients are more likely to have impaired renal function, so it is reasonable to evaluate it before starting treatment. Renal dosage adjustment is not required in patients with mild renal impairment (creatinine clearance > 50 ml/min and < 80 ml/min) and moderately severe renal impairment (creatinine clearance > 30 ml/min and < 50 ml/min). In patients with moderate renal impairment who do not tolerate adverse reactions to Champix*, the daily dose may be reduced to 1 mg once daily. In patients with severe renal impairment (creatinine clearance < 30 ml/min), the recommended dose of Champix’ is 1 mg once daily. Treatment begins with a dose of 0.5 mg once daily, which is increased after 3 days to 1 mg once daily. Because clinical data on the use of Champix in patients with end-stage renal failure are limited, it is not recommended to prescribe the drug to these patients (see section “Contraindications”).

Hepatic impairment

There is no need to adjust the dose of Champix in patients with hepatic impairment.

Champix* is not recommended for use in children and adolescents under 18 years of age, because there is insufficient information about its safety and effectiveness in this age group.

Interaction

Based on the pharmacological properties and clinical data, varenicline has no clinically significant drug interactions. No dose adjustment of varenicline or the drugs listed below is required when used concomitantly.

In in vitro studies it has been shown that active secretion of varenicline through the kidneys is mediated by the human organic cation transporter (OCT2). No dose adjustment of varenicline is required when used concomitantly with OCT2 inhibitors. as no significant increase in systemic exposure to varenicline tartrate is expected. In vitro studies indicate that varenicline does not alter the pharmacokinetics of drugs that are metabolized by cytochrome P450 isoenzymes. Since clearance of varenicline is metabolized by less than 10%, it is unlikely that substances affecting the activity of cytochrome P45o isoenzymes may affect the pharmacokinetics of varenicline, in connection with which no dose adjustment is required.

Varenicline at therapeutic concentrations does not inhibit renal protein transport in humans. Therefore, varenicline should not affect the pharmacokinetics of drugs whose clearance is due to renal secretion (in particular metformin – see below).
Metformin
Varenicline does not affect the pharmacokinetics of metformin. Metformin does not cause changes in the pharmacokinetics of varenicline.

Cimetidine
Cimetidine causes a 29% increase in the AUC of varenicline by reducing its renal clearance. No dose 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 in equilibrium.

Warfarin
Varenicline does not alter the pharmacokinetics of warfarin and has no effect on prothrombin time (MHO). Cessation of smoking alone may alter warfarin pharmacokinetics.

Alcohol

The data on concomitant use of varenicline and alcohol are limited. Increased toxic effects of alcohol have been reported during post-registration use of varenicline. A causal relationship between these cases and the use of varenicline has not been established.

Performance in combination with other anti-smoking agents

Bupropion

Varenicline does not affect the pharmacokinetics of bupropion in equilibrium.

Nicotine replacement therapy

The concomitant use of varenicline and nicotine patches in smokers for 12 days showed a statistically significant decrease in mean systolic BP {by 2.6 mm Hg) on the last day of the study. At the same time, the incidence of nausea, headache, vomiting, dizziness, dyspepsia and fatigue on combined therapy was higher than on NZT alone.

The safety and effectiveness of varenicline in combination with other tobacco control agents has not been studied.

Special Instructions

The effects of smoking cessation: Physiological changes associated with smoking cessation with or without treatment of Champix may cause disturbances in the pharmacokinetics or pharmacodynamics of some drugs, which may require changes in their doses (eg, theophylline, warfarin and insulin). Smoking causes increase in CYP1A2 activity, so smoking cessation may lead to increased plasma levels of CYP1A2 substrates.

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

There is no experience of using Champix in patients with epilepsy. Cancellation of Champix after treatment termination 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 gradual reduction of the dose.

Impact on the ability to drive and use machinery
CAMPIX has a small to moderate effect on the ability to drive and use complex machinery. CAMPIX may cause dizziness and drowsiness and, accordingly, may affect the ability to drive and use complex machinery. Patients are advised not to drive, operate complex machinery, or perform other potentially hazardous tasks until they have evaluated their response to the medication.

Contraindications

Younger than 18 years of age (insufficient clinical data on the efficacy and safety of the drug in this age group).

Pregnancy and lactation.
Terminal stage of renal failure.

Pregnancy

. There was a moderate amount of data on pregnant women (outcomes assessment results for 300 to 1000 pregnancies) that indicated no toxic effects of varenicline on the fetus/newborn leading to physical malformations.

Animal studies have shown reproductive toxicity. Use during pregnancy is contraindicated as a precautionary measure.

Breastfeeding

There are no reports of varenicline being excreted with breast milk in women. Varenicline has been shown to be excreted in breast milk in animal studies. As a precautionary measure, use in breastfeeding is contraindicated.

Fertility

There are no clinical data on the effect of varenicline on fertility. Preclinical studies have shown no adverse effects of varenicline on fertility in standard rat studies. Women of childbearing age should refrain from planning a pregnancy during treatment with varenicline.

Side effects

Smoking cessation, both with and without therapy, was accompanied by various symptoms, in particular, a decrease in mood and dysphoria, insomnia, irritability, frustration and anger, anxiety, impaired concentration, motor restlessness, decreased heart rate, increased appetite or weight gain were noted. Smoking cessation with or without drug therapy was also accompanied by exacerbation of concomitant psychiatric disorders. When developing the design of the clinical trials of Champix’1 and analyzing their results, no distinction was made between adverse events possibly related to the use of the study drug and those actually associated with nicotine withdrawal. Adverse reactions are based initially on the evaluation of registration studies and were supplemented with data from 18 placebo-controlled registration and post-marketing studies including approximately 5,000 patients taking varenicline.

In the clinical trials, adverse reactions generally appeared within the first week of treatment initiation, were generally mild to moderate in severity, and their frequency was independent of patient age, race, or sex.

In patients receiving Champix at the recommended dose of 1 mg twice daily after the titration period, the most frequent reported adverse effect was nausea (28.6%). In most cases, nausea occurred in the early stages of therapy, was mild to moderate in severity, and rarely required discontinuation of the drug. The following reactions of organs and systems are also possible during the use of Champix (frequency rating criteria: very common >10%; common – from >1% to <10%; infrequent – from >0,1% to <1%; rare – from >0,01% to <0.1%, very rare – <0.01%, frequency unknown – cannot be determined from the available data):

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

Blood and lymphatic system disorders: rare – decreased number of platelets.

Mechanism and nutrition disorders: frequent – weight gain, decreased appetite, increased appetite; infrequent – hyperglycemia; rare – diabetes mellitus, polydipsia.

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

Nervous system disorders: very frequent – headaches; frequent – sleepiness, dizziness, dysgeusia; infrequent – seizures, tremor, lethargy, hypoesthesia; rare – stroke, hypertension, dysarthria, coordination disorders, hypogeusia, sleep and wakefulness rhythm disorders.

Visual organ disorders: infrequent – conjunctivitis, eye pain; rare – scotoma, sclera color changes, mydriasis, photophobia, myopia, increased tear production.

Hearing and labyrinth disorders: infrequent – ear noise.

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

Vascular disorders: infrequent – high blood pressure, blood rush.

Respiratory system disorders, thoracic and mediastinal organs:
frequent – shortness of breath, cough; infrequent – inflammation of the upper airways, airway hyperemia, dysphonia, allergic rhinitis, pharyngeal irritations, maxillary sinus mucous membranes edema, upper airway cough syndrome, rhinorrhea; rare – larynx pain, snoring.

Gastrointestinal disorders: very frequent – nausea; frequent – gastroesophageal reflux, vomiting, constipation, diarrhea, gas, abdominal pain, toothache, dyspepsia, bloating, dry mouth; infrequent – hematochezia, gastritis, disorders of habitual bowel emptying rhythm, belching, aphthous stomatitis, gum pain; rare – vomiting with blood, stool changes, coated tongue.

Skin and subcutaneous tissue disorders: frequent – rash, pruritus;
infrequent – erythema, acne, hyperhidrosis, night sweats; rare – severe skin reactions, including Stevens Johnson syndrome and erythema multiforme, angioedema.

Muscular and connective tissue disorders: frequent – arthralgia, myalgia, back pain; infrequent – muscle spasms, chest pain related to the skeletal musculature; rare – ankylosis, rib chondritis.

Renal and urinary tract disorders: infrequent – gullakiuria, nycturia; rare – glucosuria, polyuria.

Gender and mammary gland disorders: infrequent – menorrhagia; rare – menorrhagia, sexual functional disorders.

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

Impact on the results of laboratory and instrumental studies: frequent – abnormal biochemical parameters of liver function; rare – abnormal results of seminal fluid analysis, increased C-reactive protein, decreased blood calcium levels.

* Estimation of frequency by post-registration observational study in cohorts.

Overdose

Pregnancy use

There have been no adequately and strictly controlled studies on the safety of Champix in pregnancy, so the prescription of the drug is contraindicated.

It is unknown whether varenicline is excreted with breast milk in humans. If it is necessary to use the drug during lactation, breastfeeding should be stopped.