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Pharmacological properties

Pharmacodynamics

Mechanism of action

Varenicline with high affinity and selectivity binds to α4β2-neuronal nicotinic acetylcholine receptors, where it acts as a partial agonist - a compound with two types of agonistic activity - lower internal activity compared to nicotine, and as an antagonist in the presence of nicotine.

In vitro electrophysiological studies and in vivo neurochemical studies have shown that varenicline binds to neuronal nicotinic acetylcholine receptors α4β2 and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Nicotine competes for the same α binding site4β2 human nAChR to which varenicline has a higher affinity. Therefore, varenicline can effectively block the ability of nicotine to fully activate α receptors4β2 and the mesolimbic dopamine system (the neuronal mechanism underlying the fixation of the reflex and pleasure that a person experiences after smoking). Varenicline is a highly selective substance that binds more strongly to the α receptor subtype4β2 (Ki = 0.15 nM) than with other common nicotinic receptors (α3β4 Ki = 84 nM, α7 Ki = 620 nM, α1βγδ Ki = 3,400 nM), or with non-nicotinic receptors and transporters (Ki1 mcM, except for 5-HT receptors3: Ki = 350 nM).

Pharmacodynamic effects. The efficacy of Champix is ​​the result of a partial agonistic activity of varenicline on the nicotinic receptor α4β2. The agonistic effect of varenicline is to bind to the nicotinic receptor α4β2, which provides an effect sufficient to alleviate the symptoms of cravings for smoking and to stop smoking. The antagonistic effect of varenicline is to prevent the binding of nicotine to the nicotinic receptor α4β2, which, in turn, leads to a decrease in the pleasure and supporting effect of smoking.

Clinical Efficiency and Safety

The efficacy of Champix to get rid of tobacco dependence was demonstrated in three clinical trials involving chronic smokers (≥10 cigarettes per day).

In two clinical trials, the efficacy of Champix was prospectively compared with the efficacy of sustained-release bupropion and placebo when used to get rid of tobacco dependence. Confirmed carbon monoxide (CO) level of abstinence from smoking for 4 weeks for the drug Champix had a statistical advantage compared with bupropion and placebo.

After a period of no treatment for 40 weeks, the level of prolonged abstinence from smoking for 52 weeks was determined as the ratio of all patients who did not smoke (and did not even inhale smoke from cigarettes) and whose level of expiratory CO was not higher than 10 ‰ from the 9th on the 52nd week, had an advantage when using the Champix drug and amounted to 22.1 and 23% compared with the use of bupropion (16.4 and 15%) and placebo (8.4 and 10, 3%).

In these studies, active treatment reported a significant reduction in effects such as craving for smoking and smoking cessation syndrome in selectively selected patients who received Champix compared to patients who received placebo. Champix also significantly reduced the reinforced effect of smoking, which could maintain the smoking habit in patients who smoked during treatment, compared with placebo. The effect of varenicline on smoking cravings, withdrawal symptoms and the strengthened smoking effect have not been investigated for a long period without treatment.

The benefit of additional therapy with Champix to maintain abstinence from smoking was evaluated for 12 weeks during the 3rd study. This study demonstrated the benefits of supplementation with Champix to maintain abstinence compared to placebo.The likelihood of supporting abstinence from smoking at week 24 following the follow-up treatment with Champix for 12 weeks was 2.47 compared with placebo. The advantage over placebo in the level of abstinence from smoking was achieved within 52 weeks.

To date, there is no clinical experience with the use of Champix to determine its effectiveness for African American patients.

Establishment of a cessation date between week 1 and week 5

The safety and efficacy of Champix was studied in patients who were able to set a date for stopping smoking between the 1st and 5th week of treatment. The results of the study demonstrated that patients who are unwilling or unable to set a date for quitting smoking within 1-2 weeks can be offered to start treatment, and to choose a date for stopping smoking later, within 5 weeks.

Patients with cardiovascular disease

The efficacy and safety of varenicline were evaluated in smokers with cardiovascular disorders and were similar to those observed in smokers without cardiovascular disorders. During treatment, a low level of cardiovascular disease was detected in the placebo group and in the varenicline group.

Patients with moderate to moderate COPD

The efficacy and safety of Champix for eliminating tobacco dependence in patients with moderate or moderate COPD were demonstrated in a randomized, double-blind, placebo-controlled clinical trial. The safety profile of varenicline is comparable to that reported from other studies in the general population, including pulmonary safety.

Results for a 4-week confirmed abstinence rate of carbon monoxide (CO) are 42.3% for Champix and 8.8% for placebo. The level of long-term abstinence from smoking (9–52 weeks) is 18.5% for the Champix drug and 5.6% for the placebo.

Pharmacokinetics

Suction

WITHmax plasma varenicline is usually achieved 3-4 hours after ingestion. After prolonged oral administration in healthy volunteers, a stable state was reached within 4 days. In fact, after oral administration, absorption is complete, and systemic availability is high. Food or time of taking varenicline does not affect its oral bioavailability.

Distribution

Varenicline is distributed in tissues, including brain tissue. In a stable state, the apparent distribution volume averages 415 L (% CV = 50). The binding of varenicline to plasma proteins is low (≤20%) and does not depend on the patients age and renal function.

Metabolism

Varenicline undergoes minimal metabolism - 92% of varenicline is excreted unchanged in the urine, and less than 10% in the form of metabolites. Minor metabolites in the urine include varenicline N-carbamyl glucuronide and hydroxyvarenicline. 91% of varenicline circulating in the blood is in a bound state. Minor metabolites include varenicline N-carbamyl glucuronide and N-glucosyl varenicline.

In vitro studies have shown that varenicline does not inhibit cytochrome P450 enzymes (IC50 6.400 ng / ml). The following cytochrome P450 enzymes were studied: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 / 5. Also, when studying human hepatocytes in vitro, it was shown that varenicline does not induce the activity of cytochrome P450 enzymes such as 1A2 and 3A4. Therefore, it is unlikely that varenicline can affect the pharmacokinetics of compounds metabolized by cytochrome P450 enzymes.

Breeding

T½ varenicline - about 24 hours. Renal excretion of varenicline occurs mainly through glomerular filtration in the kidneys, along with active tubular secretion using an organic cation transporter, OCT2.

Linearity / nonlinearity

Varenicline exhibits linear kinetics if it is taken in a single dose (0.1–3 mg) or in multiple doses (1-3 mg / day).

Pharmacokinetics in special patient groups

There are no clinically significant differences in the pharmacokinetics of varenicline depending on age, race, gender, smokers status or the use of concomitant drugs, as has been demonstrated in special studies of pharmacokinetics and in pharmacokinetics analyzes of different groups of patients.

Patients with liver failure

The pharmacokinetics of varenicline does not change in patients with liver failure.

Patients with kidney failure

The pharmacokinetics of varenicline did not change in patients with mild renal failure (expected creatinine clearance of 50 ml / min and ≤80 ml / min). In patients with moderate renal failure (expected creatinine clearance ≥30 ml / min and ≤50 ml / min), the concentration of varenicline increased 1.5 times compared with patients with normal renal function (expected creatinine clearance 80 ml / min). In patients with severe renal failure (expected creatinine clearance of 30 ml / min), the concentration of varenicline increased 2.1 times. In patients with end-stage renal failure, varenicline was effectively eliminated by hemodialysis.

Elderly patients

The pharmacokinetics of varenicline in elderly patients with normal renal function (aged 65–75 years) is similar to that in patients of a younger age. In patients with severe renal failure, the dose is recommended to be selected individually.

Use in children

In a study of 22 sick children aged 12 to 17 years (inclusive) who received single doses of varenicline 0.5 mg and 1 mg, its pharmacokinetics was approximately proportional to doses in the range of 0.5–1 mg. AUC Assessment System Exposure(0-inf) and renal clearance of varenicline were comparable to those in adults.

Indications

To get rid of nicotine addiction.

Application

The use of the drug to eliminate nicotine addiction will be more successful in patients who themselves want to quit smoking, and who are provided with additional advice and support.

Champix tablets should be swallowed whole with water. Champix can be taken without regard to food.

Champix is ​​taken orally. The recommended dose of varenicline is 1 mg 2 times a day after application in low doses for 1 week in this way:

Days 1-3 0.5 mg once daily
Days 4–7 0.5 mg 2 times a day
Day 8 – until the end of treatment 1 mg 2 times a day

The patient should determine the date of cessation of smoking. Usually, the use of Champix should be started 1-2 weeks before this date.

Patients who cannot tolerate the side effects of Champix can reduce the dose to 0.5 mg 2 times a day temporarily or for the entire course of treatment.

Treatment with Champix should be carried out for 12 weeks.

For patients who successfully quit smoking at the end of the 12th week, the possibility of prescribing an additional 12-week course of treatment with Champix at a dose of 1 mg 2 times a day may be considered.

There is no data on the effectiveness of the additional 12-week therapy in patients who did not succeed in getting rid of nicotine addiction during the initial course of therapy, or who recur after treatment.

When using drugs to get rid of nicotine addiction, the risk of a return to smoking increases in the period immediately after the end of therapy. In patients with a high risk of relapse, the feasibility of gradually reducing the dose at the end of treatment should be considered.

Patients with kidney failure

Patients with renal failure of mild (creatinine clearance 50 and ≤80 ml / min) and moderate (creatinine clearance ≥30 and ≤50 ml / min) dose adjustment is not required.

Renal patients