Instructions for use CHAMPIX
Varenicline has linear kinetic parameters with a single dose (at a dose of 0.1 mg to 3 mg) or with repeated use at doses of 1 to 3 mg/day.
Suction
After oral administration, varenicline is almost completely absorbed from the gastrointestinal tract. Bioavailability is high and does not depend on food intake or time of taking the drug. Cmax in plasma is usually achieved within 3-4 hours after oral administration. After repeated oral administration in healthy volunteers, steady state was achieved within 4 days.
Distribution
Varenicline penetrates tissues, including the brain. The apparent Vd at equilibrium is on average 415 l (%CV= 50). Plasma protein binding is low (less than 20%) and is independent of age and the presence of renal impairment.
Metabolism
Varenicline undergoes minimal metabolism with 92% excreted unchanged in urine and less than 10% excreted as metabolites. Small amounts of metabolites in urine include varenicline N-carbamoyl glucuronide and hydroxyvarenicline. In the bloodstream, varenicline constitutes 91% of the drug-associated substance. Small amounts of circulating metabolites include varenicline N-carbamoylglucuronide and N-glucosylvarenicline.
Removal
T1/2 is approximately 24 hours. Through the kidneys, varenicline is eliminated mainly by glomerular filtration simultaneously with active tubular secretion using the organic cation transporter, OCT2.
Pharmacokinetics in special clinical situations
There are no clinically significant differences in the pharmacokinetics of varenicline based on age, race, sex, smoking status, or concomitant drug use, as demonstrated in individual pharmacokinetic studies and in population pharmacokinetic analyses.
Due to the lack of significant metabolism in the liver, the pharmacokinetics of varenicline in patients with impaired liver function should not change.
In individuals with mild renal impairment (estimated creatinine clearance >50 mL/min and <80 mL/min), the pharmacokinetics of varenicline were not altered. In patients with moderate renal impairment (estimated creatinine clearance >30 ml/min and <50 ml/min), the effect of varenicline was increased by 1.5 times compared with individuals with normal renal function. In individuals with severe renal impairment (estimated creatinine clearance <30 ml/min), the effect of varenicline is increased by 2.1 times. In individuals with end-stage renal disease, varenicline was rationally removed by hemodialysis.
The pharmacokinetics of varenicline in elderly patients with normal renal function (aged 65-75 years) are similar to those in young patients. In elderly patients with severe renal impairment, dose adjustment is recommended.
The pharmacokinetics of varenicline when used in children was studied in 22 adolescents aged 12 to 17 years (inclusive). They received varenicline at a single dose of 0.5 mg and 1 mg. The pharmacokinetics of the drug was almost dose-dependent for doses from 0.5 mg to 1 mg. Systemic exposure as assessed by AUC (0-inf) and renal clearance of varenicline were comparable to those in adults.
Experimental animal studies
In rodents, varenicline crosses the placenta and is excreted into breast milk.
Lifetime carcinogenicity studies were performed in mice and rats. There was no evidence of a carcinogenic effect in mice when varenicline was administered by oral gavage for 2 years at doses 47 times the maximum recommended daily dose in humans. Rats were given varenicline by oral gavage at doses of 1, 5, and 15 mg/kg/day for up to 2 years. In male rats (n=65 of each sex per dose group), the incidence of hibernoma (brown adipose tissue tumor) was increased at the intermediate dose (1 tumor) and the highest dose (2 tumors). The clinical significance of these data in humans has not been established. No data have been obtained to support carcinogenicity in female rats.
In experimental animal studies, varenicline was not genotoxic.
Preclinical data indicate that varenicline has stimulant properties, although less pronounced compared to nicotine. In addition, varenicline has demonstrated low dependence potential in human clinical studies.
There was no evidence of impaired fertility in either male or female rats when varenicline succinate was administered at doses 67 and 36 times the maximum recommended daily dose for humans. However, decreased fertility was observed in the offspring of pregnant rats given oral varenicline succinate at a dose 36 times the maximum recommended daily dose in humans. This decrease in fertility in female offspring of treated rats was not observed when the drug was administered orally at a dose 9 times the maximum recommended daily dose in humans.
Varenicline succinate was not teratogenic in rats and rabbits when administered orally at doses 36 and 50 times the maximum recommended daily dose in humans.
There were no adverse effects on the fetus of varenicline succinate in animal reproductive studies. Oral administration of varenicline succinate to pregnant rabbits at a dose 50 times the maximum recommended daily dose in humans resulted in decreased fetal weight; this reduction was not observed after administration of the drug at a dose of 23 times the maximum recommended daily dose in humans. In addition, offspring of pregnant rats treated with varenicline succinate showed decreased fertility and increased auditory start response when administered orally at a dose 36 times the maximum recommended daily dose in humans.
Champix®
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® 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 <10%; infrequent - from ≥ 0.1% to < 1%; rare - from ≥ 0.01% to < 0.1%, very rare - <0.01%, frequency unknown - cannot be determined based on 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 frequent - 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 frequent - headaches; frequent - drowsiness, dizziness, dysgeusia; uncommon - seizures, tremor, lethargy, hypoesthesia; rare - stroke, hypertension, dysarthria, coordination disorders, hypogeusia, sleep-wake rhythm disturbances.
Visual disorders:
uncommon - conjunctivitis, eye pain; rare - scotoma, discoloration of the sclera, mydriasis, photophobia, myopia, increased lacrimation.
Hearing and labyrinth disorders:
infrequent - 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 the T waves on the ECG.
Vascular disorders:
infrequent - 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; common - 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, itchy skin; uncommon - erythema, acne, hyperhidrosis, night sweats; rare - severe skin reactions, including Stevens-Johnson syndrome and erythema multiforme, angioedema.
Musculoskeletal and connective tissue disorders:
frequent - 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 - pollakiuria, nocturia; rare - glucosuria, polyuria.
Disorders of the genital organs and breast:
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 in 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.
Champix, 112 pcs., 1 mg, film-coated tablets
The effect of quitting smoking on the body.
Physiological changes that occur after smoking cessation with or without varenicline therapy may affect the pharmacokinetics or pharmacodynamics of some drugs, which may require dose adjustment (for example, theophylline, warfarin and insulin). Since smoking induces the CYP1A2 isoenzyme, smoking cessation may lead to increased plasma concentrations of substrates of this isoenzyme.
Neuropsychiatric disorders.
Analysis of clinical trial data showed no increased risk of developing serious neuropsychiatric disorders with varenicline compared to placebo. In addition, independent observational studies do not support an increased risk of serious neuropsychiatric disorders with varenicline compared with nicotine replacement therapy or bupropion therapy.
During post-marketing use of the drug, there have been reports of neuropsychiatric symptoms, including behavioral or thought disturbances, anxiety, psychosis, mood swings, aggressive behavior, agitation, depressive mood, suicidality and suicidal behavior in patients attempting to quit smoking with varenicline (see section 4.4). "Side effects"). Not all patients had stopped smoking at the time of the onset of these symptoms, and not all patients had previously experienced mental disorders. Physicians should educate patients trying to quit smoking with varenicline about the possibility of developing neuropsychiatric symptoms and consider the need for a gradual dose reduction. Patients, their families, or caregivers should be advised to stop taking varenicline and seek immediate medical attention if behavioral or thinking disturbances, agitation, or depressed mood occur, or if suicidal ideation or suicidal behavior occurs that has not previously occurred. to the patient. In many cases, after discontinuation of the drug, the listed symptoms disappeared, but sometimes the symptoms persisted. Therefore, continued monitoring of patients is recommended until symptoms resolve. Before starting treatment, patients should be encouraged to report any previous mental disorders. It should also be borne in mind that depressive mood, in rare cases in combination with suicidal thoughts or attempts, may accompany smoking cessation. In addition, the process of quitting smoking, with or without pharmacotherapy, is usually associated with exacerbations of existing mental disorders (eg, depression).
Clinical trials have been conducted with varenicline in patients suffering from major depressive disorder without psychotic features, receiving regular antidepressant therapy and/or in patients who have had a major depressive episode within the past two years, with success.
According to the results of assessing the patients' condition on psychiatric scales, there were no differences between the groups of patients receiving varenicline and placebo. There was also no worsening of depression during varenicline therapy in either group of patients. Caution should be used when using varenicline in patients with a history of mental illness.
Cardiovascular diseases.
A meta-analysis of 15 clinical trials with treatment duration ≥12 weeks, including 7002 patients (4190 patients treated with varenicline, 2812 patients treated with placebo) was conducted to systematically evaluate the cardiovascular safety of varenicline.
When using the drug Champix® in patients with cardiovascular diseases, there was a slight increase in the incidence of complications of these diseases. Such complications more often developed in patients with existing cardiovascular diseases. Overall and cardiovascular mortality were lower in patients receiving varenicline. Patients taking varenicline should tell their prescribers if new symptoms of cardiovascular disease develop or worsen existing ones. Patients should seek immediate medical attention if symptoms consistent with myocardial infarction or stroke occur.
Use in patients with stable schizophrenia or schizoaffective disorder.
There are limited data on the use of varenicline in patients with stable schizophrenia or schizoaffective disorder. Caution should be used when using varenicline in patients with a history of mental illness.
Epilepsy.
There is no data on the use of Champix® in patients with epilepsy.
While using the drug Champix®, seizures developed (both with and without a history of seizures). If you have a history of seizures or other conditions that lower the seizure threshold, caution should be exercised when using Champix®. A causal relationship between the use of varenicline and the development of seizures has not been established.
Completion of therapy.
Completion of varenicline treatment in 3% of patients was accompanied by increased irritability, smoking urges, depression and/or insomnia. Patients should be warned about such complications and the possibility of dose reduction should be discussed.
Angioedema and hypersensitivity reactions.
There are reports of hypersensitivity reactions, including angioedema, in patients taking varenicline. Clinical symptoms of this complication include swelling of the face, mouth (tongue, lips, gums), neck (larynx and pharynx), and extremities. In addition, there are rare reports of the development of life-threatening angioedema, the treatment of which may require emergency medical intervention due to the risk of impaired respiratory function. Patients should immediately stop taking varenicline and contact their healthcare provider if any symptoms of hypersensitivity reactions develop.
Severe skin reactions.
There have been rare reports of severe life-threatening skin reactions, including Stevens-Johnson syndrome and erythema multiforme, in patients taking varenicline. Since these reactions can be life-threatening, you should stop using Champix® at the first signs of a rash or skin reaction and immediately inform your doctor.
Impact on the ability to drive vehicles and operate machinery.
Given that varenicline may cause dizziness and drowsiness, patients are advised not to drive, use machinery, or perform other potentially hazardous tasks until they have assessed their response to the drug.
