Expiration date: 11/2025
Active substance: Varenicline.
Pharmacokinetics:
Absorption in plasma Cmax typically achieved within 3-4 hours after ingestion. In subsequent rounds of healthy volunteers equilibrium state was reached within four days. The drug is almost completely absorbed after oral administration and has a high systemic bioavailability, non-meal time and the reception during the day. After receiving a single dose of 0.1 to 3 mg or repeated administration in a dose of 1 to 3mg / day wore varenicline pharmacokinetics linear.
Distribution
Varenicline is distributed in the tissues and penetrate the BBB entering the brain. The degree of binding to plasma proteins is low (& le20%), regardless of the age and renal function.
Metabolism
Varenicline undergoes minimal transformation: 92% of the dose excreted by the kidneys in unchanged form and less than 10% - in the form of metabolites. Among varenicline metabolites found in urine N-karbamilglyukuronid varenicline and gidroksivareniklin. The plasma varenicline 91% circulates in an unmodified form. Among circulating metabolite detected karbamilglyukuronid varenicline N-and N-glyukozilvareniklin.
Breeding
T1 / 2 - 24 hours. Elimination is carried out mainly by the kidneys by glomerular filtration in combination with active tubular secretion.
Pharmacokinetics in special groups
The pharmacokinetics of varenicline substantially independent of age, race, gender, smoking status, or concomitant therapy.
Impaired renal function. The pharmacokinetics of varenicline did not change in patients with mild renal impairment (Cl creatinine> 50 ml / min and & le80 ml / min). In patients with moderate renal insufficiency (Cl creatinine> 30 ml / min and & le50 ml / min) AUC varenicline increased 1.5 times compared with that of patients with normal renal function (Cl creatinine> 80 ml / min). In patients with severe renal impairment (Cl creatinine <30 ml / min) AUC of varenicline increased 2.1 times. In patients with end-stage renal failure, varenicline was efficiently removed by hemodialysis.
Abnormal liver function. Given the lack of pronounced hepatic metabolism, varenicline pharmacokinetics should not be altered in patients with impaired its function.
Elderly patients. Pharmacokinetics of varenicline in elderly people with normal renal function (aged 65-75 years) is not changed.
Description of the pharmacological actions:
Varenicline with high affinity and selectivity binds & alpha4 & beta2 brain nicotinic acetylcholine receptors, for which it is a partial agonist (but to a lesser degree than nicotine) and an antagonist in the presence of nicotine. Electrophysiological studies in vitro and neurochemical studies in vivo have shown that varenicline binds & alpha4 & beta2 nicotinic acetylcholine receptors and stimulates them, but to a much lesser extent than nicotine. Nicotine competitively binds to the same receptor site to which varenicline has higher affinity. Therefore, varenicline blocks nicotine's ability to effectively stimulate & alpha4 & beta2 receptors and activate the mesolimbic dopamine system - neuronal mechanism that underlies the implementation of the mechanisms of nicotine addiction (getting pleasure from smoking). The effectiveness of varenicline as an agent for the treatment of nicotine addiction due to its partial agonist activity against & alpha4 & beta2 nicotinic receptors, the binding of which reduces the craving for smoking and facilitates display of withdrawal, at the same time leading to a decrease in feelings of pleasure from smoking (antagonism in the presence of nicotine) ..
Testimony:
Nicotine dependence in adults.
Contraindications:
- hypersensitivity to any component of the drug
- end stage renal disease
- pregnancy
- lactation
- age 18 years (insufficient clinical data on the efficacy and safety of the drug in this age group).
Application of pregnancy and breastfeeding:
Due to the fact that an adequate application of varenicline controlled studies in pregnant women were not carried out, the use of the drug is contraindicated in pregnancy.
Data on the allocation of varenicline in breast milk of women there. If necessary, use during lactation, breast-feeding should be discontinued.
Side effect:
Quitting smoking is against the background of varenicline therapy, and without it, ccompanied various symptoms, such as marked depressed mood and dysphoria, insomnia, irritability, feeling of displeasure and anger, anxiety, impaired concentration, restlessness, decrease in heart rate, increased appetite or gain body weight. Quitting smoking on background medical therapy with or without also been accompanied by worsening of psychiatric comorbidity. However, neither in the design of clinical trials of varenicline schemes nor in the analysis of the results has not attempted to distinguish between adverse events associated with the use of the study drug, and adverse events possibly related to the actual nicotine withdrawal syndrome.
According to the results of clinical studies adverse reactions usually appeared during the first week after treatment, were usually mild or moderate, and their frequency is not dependent on age, race or sex of the patient. In patients treated at the recommended dose of varenicline 1 mg 2 times a day after the titration period, the most frequent of the reported adverse events were nausea (28.6%). In the majority of cases nausea occurred early in the treatment, expressed mild to moderate and rarely require discontinuation of the drug.
The frequency of discontinuation due to adverse events was 11.4% for varenicline group and 9.7% for the placebo group. The frequency of discontinuation due to major adverse reactions was as follows: nausea - 2.7 and 0.6% in the varenicline and placebo groups, respectively, headache - 0.6 and 1.0% of insomnia - 1.3 and 1.2% uncommon dreams - 0.2 and 0.2%.
While taking varenicline also have the following response from the organs and systems with the following gradation of frequency: very often - & ge1 / 10 often - & ge1 / 100 but <1/10 rarely - & ge1 / 1000 but <1/100.
Infection: rare - bronchitis, nasopharyngitis, sinusitis, fungal infections, viral infections.
Disorders of metabolism and nutrition: often - increased appetite rarely - anorexia, decreased appetite, polydipsia.
Psychiatric disorders: very common - abnormal dreams, insomnia rarely - a panic reaction, bradifreniya, thought disorder, mood swings.
Neurological disorders: very often - headache often - somnolence, dizziness, dysgeusia rare - tremors, impaired coordination, dysarthria, hypertonia, restlessness, dysphoria, hypoesthesia, decreased taste sensation, lethargy, increased, decreased libido.
Changes in the heart: rarely - atrial fibrillation, palpitations.
Changes in the organ of vision: rarely - scotoma, change color of the sclera, pain in the eyeball, mydriasis, photophobia, myopia, lacrimation increased.
Changes in the organ of hearing, and the vestibular system: rarely - ringing in the ears.
Changes in the respiratory system, thoracic and mediastinal disorders: rarely - shortness of breath, cough, hoarseness, sore throat and larynx, throat irritation, congestion in the respiratory tract congestion in the sinuses, exudation in the nasopharynx, rhinorrhea, snoring.
Gastrointestinal disorders: very often - nausea often - vomiting, constipation, diarrhea, bloating, stomach discomfort, dyspepsia, flatulence, dry mouth, rarely - vomiting blood, blood in the stool, gastritis, gastroesophageal reflux disease, abdominal pain , intestinal disorders, stools, belching, aphthous stomatitis, sore gums, coated tongue.
Changes in the skin and subcutaneous tissue disorders: rare - generalized rash, erythema, pruritus, acne, hyperhidrosis, night sweats.
The changes in the musculoskeletal system and connective tissue disorders: rarely - joint stiffness, muscle spasms, pain in the chest wall, costochondritis.
Changes in the kidneys and urinary tract: rarely - Glycosuria, nocturia, polyuria.
Changes in the reproductive system and breast cancer: rarely - menorrhagia, vaginal discharge, sexual dysfunction.
General and local reactions: often - fatigue, rarely - chest discomfort, chest pain, fever, feeling cold, asthenia, circadian rhythm sleep, malaise, cyst.
Research results: rarely - increased blood pressure, ST-segment depression on electrocardiogram, decrease in T-wave amplitude in the ECG, increase in heart rate, changes in liver function, a decrease in platelet count, weight gain, changes in sperm, elevated levels of C-reactive protein, reduced calcium levels in blood.
Quitting smoking during therapy with or without accompanied by the development of nicotine withdrawal symptoms and the exacerbation of psychiatric comorbidity. During post-marketing studies in patients trying to quit smoking using varenicline, recorded cases of depressed mood, agitation, behavioral disorders, suicidal thoughts and suicide attempts. Since these events are recorded as a result of voluntary Posts population of uncertain size, it is not always possible to ascertain their frequency or a causal relationship to the action of the drug. Not all patients described in these reports, had a history of mental illness, and not all of them have stopped smoking. Varenicline role in the development of the reactions described in these messages is not known.
Also registered cases of hypersensitivity reactions such as angioedema and facial swelling.
Drug Interactions:
Clinically significant interactions with other drugs varenicline is not revealed. No dose adjustment of varenicline or the following preparations, while the application is not required.
in vitro studies suggest that varenicline does not alter the pharmacokinetics of drugs which are metabolized by the action of cytochrome P450 isoenzymes. Since varenicline clearance less than 10% at the expense of metabolism, it is unlikely that a substance influencing on the activity of cytochrome P450 isoenzymes, can affect the pharmacokinetics of varenicline, and therefore the dose correction is not required.
Varenicline therapeutic concentrations does not inhibit the renal transport proteins in humans. Therefore, varenicline should not affect the pharmacokinetics of drugs which the clearance by renal secretion (eg metformin).
Metformin. Varenicline has no effect on the pharmacokinetics of metformin. Metformin does not cause changes in the pharmacokinetics of varenicline.
Cimetidine causes an increase in AUC of varenicline by 29% due to the decrease in its renal clearance.
Digoxin. Varenicline has no effect on the pharmacokinetics of digoxin in the equilibrium state.
Warfarin. Varenicline did not alter the pharmacokinetics of warfarin, and does not affect the prothrombin time (INR). Smoking cessation itself may result in changes in the pharmacokinetics of warfarin.
Use in combination with other anti-smoking
Bupropion. Varenicline not affect the pharmacokinetics of bupropion in the equilibrium state.
Nicotine replacement therapy (NRT). With simultaneous use of varenicline in smokers and patches containing nicotine for 12 days it showed a statistically significant decrease in the average garden (by 2.6 mm Hg. Art.) On the last day of the study. The frequency of nausea, headache, vomiting, dizziness, and dyspepsia, fatigue combination therapy were higher than the background of one of NRT.
The safety and efficacy of varenicline in combination with other anti-smoking have not been studied.
Dosage and administration:
Inside, swallowing a whole, drinking water, regardless of the meal.
The probability of a successful drug therapy for smoking cessation is increased in patients who are motivated to stop smoking, which provided additional advice and support.
Treatment with varenicline should be started 1 week before the selected date of the patient quitting smoking. The recommended dose is 1 mg twice a day with a dose titration as follows:
| Day dosing | Dose |
| Day 1-3 | 0.5 mg 1 time per day |
| Day 4-7 | 0.5 mg 2 time per day |
| 8 days prior to the end of treatment | 1 mg 2 time per day |
If a patient can not tolerate the side effects of varenicline, the dose can be temporarily or permanently reduced.
The course of treatment - 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of drug treatment may be conducted at a dose of 1 mg 2 times a day for 12 weeks.
Patients who are unable to quit smoking during the initial 12-week course of treatment, or who relapse after treatment begins, should be encouraged to make another attempt, assuming that were established cause of the failure of the first attempt, and took measures to correct them.
Impaired renal function. Changing the dose of varenicline in patients with mild renal impairment (Cl creatinine> 50 ml / min and & le80 ml / min) and moderate renal insufficiency (Cl creatinine> 30 ml / min and & le50 mL / min) is not required.
In patients with severe renal impairment (Cl creatinine <30 ml / min) the recommended dose of CHAMPIX is 1 mg 1 time per day. Treatment started with a dose of 0.5 mg once a day 1 which increased 3 days later 1 mg 1 time per day.
Due to the lack of clinical data on the use of varenicline in patients with end-stage renal disease the drug is not recommended in these patients (see. "Contraindications").
Abnormal liver function. Correction Champiksa® dose in patients with impaired its function is not required.
Elderly patients. Correction dose of varenicline in elderly patients is not required. Older people more likely to decrease in renal function, so it is advisable to evaluate before beginning the treatment.
Children. CHAMPIX is not recommended for children and adolescents under 18 years of age, as data on its safety and efficacy in this age group are not sufficient (see. "Contraindications").
Overdose:
Cases of varenicline overdose has been reported.
Treatment: symptomatic.
Varenicline appear in hemodialysis patients with severe renal impairment, however no experience with hemodialysis in overdose.
Special instructions:
Physiological changes that occur after quitting during therapy with or without her varenicline may affect the pharmacokinetics or pharmacodynamics of some drugs, which may require dose adjustment of (eg theophylline, warfarin and insulin).
Completion of treatment of varenicline in 3% of patients accompanied by increased irritability, cravings, depression and / or insomnia.
During post-marketing use of the drug, there were reports of the appearance of neuropsychiatric symptoms, including behavioral disorders, agitation, depressed mood, suicidal thoughts and suicidal behavior in patients attempting to quit smoking with varenicline (see. "Side Effects" section). The physician should explain to patients, samples quit smoking using varenicline, the possibility of neuropsychiatric symptoms and consider the possibility of gradually reducing the dose. Patients, their family members or caregivers should be advised of the need to stop taking varenicline and immediate treatment to the doctor with the appearance of behavioral disorders, agitation or depressive mood, which had previously not been characterized to the patient, as well as in case of suicidal thoughts or behavior. Prior to treatment patients should be advised to report any mental disorders that they had before.
Effects on ability to drive and use machinery. Given that varenicline may cause dizziness and somnolence, patients are not recommended to drive a car, use sophisticated technology or to perform other potentially dangerous tasks until they appreciate your response to the drug.
