Composition, form of production and packaging
Tablets covered with a film coating of white or almost white color, capsular, biconvex, with the inscription "Pfizer" on one side and "CHX 0.5" on the other side.
varenicline tartrate 850 Ојg,
which corresponds to the content of varenicline 500 Ојg
Excipients: microcrystalline cellulose - 62.57 mg, calcium hydrophosphate - 33.33 mg, croscarmellose sodium - 2 mg, silicon dioxide colloid - 0.5 mg, magnesium stearate - 0.75 mg.
Composition of the film shell: opadray white YS-1-18202-A (hypromellose, titanium dioxide, macrogol) - 4 mg; opadray transparent YS-2-19114-A (hypromellose, triacetin) - 0.5 mg.
The tablets covered with a film shell of light blue color, capsular, biconcave, with the inscription "Pfizer" on one side and "CHX 1.0" on the other side.
varenicline tartrate 1.71 mg,
which corresponds to the content of varenicline 1 mg
Excipients: microcrystalline cellulose - 125.13 mg, calcium hydrophosphate - 66.66 mg, croscarmellose sodium - 4 mg, silicon dioxide colloid - 1 mg, magnesium stearate - 1.5 mg.
Composition of the film shell: opadray transparent YS-2-19114-A (hypromellose, triacetin) - 1 mg; opadray blue 03B90547 (hypromellose, titanium dioxide, macrogol, aluminum lacquer based on indigo carmine) - 8 mg.
11 pcs. (table 500 Ојg) in a blister of Aklar В® / PVC and aluminum foil or PVC and aluminum foil.
11 pcs. (table 500 mcg) and 14 pcs. (Tab 1 mg) in a blister of AklarВ® / PVC and aluminum foil or PVC and aluminum foil.
14 or 28 pcs. (Tab 1 mg) in a blister of AklarВ® / PVC and aluminum foil or PVC and aluminum foil.
56 pcs. (table 500 Ојg) in a can of high-density polyethylene.
56 pcs. (table 1 mg) in a can of high-density polyethylene.
11 pcs. (table 500 Ојg) in a blister and 14 pcs. (table 1 mg) in a blister - cardboard combined packaging.
Packing for maintenance therapy.
11 pcs. (table 500 mcg) and 14 pcs. (Tab 1 mg) in the blister, and 28 pcs. (table 1 mg) in a blister - cardboard combined packaging.
14 pcs. (table 1 mg) - blisters (2) - cardboard combined packaging.
28 pcs. (table 1 mg) - blisters (2) - cardboard combined packaging.
14 pcs. (table 1 mg) - blisters (1) - cardboard pack with control of the first opening.
14 pcs. (table 1 mg) - blisters (2) - cardboard pack with control of the first opening.
14 pcs. (table 1 mg) - blisters (4) - cardboard pack with control of the first opening.
14 pcs. (table 1 mg) - blisters (8) - cardboard pack with control of the first opening.
56 pcs. (table 500 Ојg) - a can (1) - a pack of cardboard.
56 pcs. (table 1 mg) - a can (1) - a pack of cardboard.
Tertiary packaging for the full course for 12 weeks.
A pack of cardboard, containing:
11 pcs. (table 500 mcg) and 14 pcs. (Tab 1 mg) in the blister, and 28 pcs. (table 1 mg) in a blister - cardboard combined packaging (1);
28 pcs. (table 1 mg) - blisters (2) - packings cardboard combined (2).
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
The drug for the treatment of nicotine addiction. Varenicline with high affinity and selectivity binds to the? 4? 2 n-cholinoreceptors 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.
Electrophysiological in vitro studies and neurobiochemical studies in vivo have shown that varenicline binds to and reacts to? 4? 2 n-cholinergic 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? 4? 2 n-cholinergic receptors and activate the mesolimbic dopamine system - the neuronal mechanism that underlies the mechanisms of the formation of nicotine addiction (getting pleasure from smoking).
The efficacy of varenicline as a means to treat nicotine dependence is due to its partial agonism with respect to? 4 Г— 2 n-cholinergic receptors, binding to which reduces craving for smoking and facilitates withdrawal symptoms and simultaneously reduces the sense of pleasure from smoking (antagonism in the presence of nicotine).
In two placebo-controlled double-blind clinical trials examining the efficacy of varenicline and bupropion, varenicline demonstrated a statistically significant advantage. During active treatment, cravings for smoking and manifestation of withdrawal syndrome were significantly reduced in patients randomized to the varenicline group, compared with placebo. Varenicline also significantly reduced the effects of reinforcement arising from smoking, which can strengthen the habit of smoking in patients who smoke during treatment, compared with placebo. The effect of varenicline on cravings for smoking, withdrawal syndrome, and reinforcement effects were not evaluated at follow-up when no medication was given.
A placebo-controlled blind clinical trial demonstrated the efficacy of an additional 12 weeks of varenicline therapy for abstinence from smoking compared with placebo.
Patients who do not want or are not able to set a goal to quit smoking within 1-2 weeks can be offered to start treatment, with the option of choosing their own date for quitting within 5 weeks.
Patients who had previously tried to quit smoking with varenicline and who were re-treated with varenicline had the best level of confirmed persistent abstinence compared to placebo.
In a placebo-controlled, double-blind clinical trial in patients not able or unwilling to quit for 4 weeks but wishing to gradually reduce smoking for 12 weeks before quitting, a higher level of persistent abstinence compared with placebo was confirmed.
When using the drug varenicline in patients with chronic obstructive pulmonary disease, there were no differences in the safety profile compared with healthy patients.
C max in blood plasma is usually achieved 3-4 hours after ingestion. With subsequent administration in healthy volunteers, the equilibrium state was achieved within 4 days. The drug is almost completely absorbed after ingestion and has a high systemic bioavailability, not related to eating and taking time 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.
Varenicline is distributed in tissues and penetrates through the BBB, getting into the brain. Binding to plasma proteins is low (? 20%) and does not depend on the age and function of the kidneys.
Varenicline undergoes minimal biotransformation: 92% of the dose is excreted by the kidneys unchanged and less than 10% - in the form of metabolites. Among the metabolites of varenicline in urine are found N-carbamyl glucuronide varenicline and hydroxyvarieniclin. In blood plasma, varenicline is circulated 91% unchanged.Among circulating metabolites, N-carbamylglucuronid varenicline and N-glucosylvarenicline have been found.
T 1/2 varenicline is about 24 hours. The excretion of varenicline by the kidney is carried out, mainly, by glomerular filtration in combination with active tubular secretion.
Pharmacokinetics in special clinical cases
The pharmacokinetics of varenicline are not significantly affected by age, race, sex, smoking status, or concomitant therapy.
The pharmacokinetics of varenicline did not change in patients with impaired renal function of mild degree (CK> 50 mL / min and в‰Ґ80 mL / min). In patients with moderate renal insufficiency (CK> 30 mL / min and в‰Ґ50 mL / min), the varenicline AUC increased 1.5-fold compared with that in patients with normal renal function (CK> 80 mL / min). In patients with severe renal dysfunction (CK <30 mL / min), AUC varenicline increased 2.1-fold. In patients with terminal stage of renal failure, varenicline was effectively removed during hemodialysis.
Given the absence of a pronounced metabolism of varenicline in the liver, the pharmacokinetics of varenicline should not be altered in patients with impaired hepatic function.
The pharmacokinetics of varenicline in elderly people with normal renal function (age 65 to 75 years) does not change.
- nicotine dependence in adults.
The likelihood of successful smoking cessation therapy is increased in patients who are motivated to quit smoking, who receive additional counseling and support.
Champix В® is taken internally regardless of food intake. Tablets should be swallowed whole, washed down with water.
Treatment with Champix should be started 1-2 weeks before the date chosen by the patient for stopping smoking. Either the patient can start taking the drug and stop smoking between 8 and 35 days of treatment with Champix В® .
The recommended dose is 1 mg 2 times / day with titration of the dose according to the scheme given in the table.
Day of taking the drug
1-3 day 500 mcg 1 time / day
4-7 day 500 mcg 2 times / day
from the 8th day - until the end of treatment 1 mg 2 times / day
If the side effects of Champix В® are poorly tolerated, the dose can be reduced temporarily or permanently.
The course of treatment is 12 weeks. Patients who successfully quit smoking by the end of the 12th week are advised to maintain an additional course of treatment with a drug at a dose of 1 mg 2 times / day for 12 weeks.
For patients who are unable or unwilling to abstain from smoking, a gradual approach with varenicline therapy may be considered. In this case, smoking should be reduced within 12 weeks of therapy and quit smoking by the end of this period. After this, patients should take varenicline for another 12 weeks, so that the total treatment period is 24 weeks.
Patients who have the appropriate motivation but who have not managed to stop smoking during the previous course of treatment with varenicline, or who have a relapse after treatment, recommend another attempt, provided that the reasons for the failure of the first attempt were established and measures were taken for their elimination.
Data on the efficacy of an additional 12-week course of therapy in patients who did not manage to quit smoking after the initial course of therapy or with a relapse of smoking are not available. The risk of recurrence of smoking is increased in people who have recently completed therapy to stop smoking. In patients with a high risk of recurrence, a gradual dose reduction is possible.
For patients with mild renal insufficiency (CK> 50 ml / min and? 80 ml / min) and moderate severity (CK> 30 ml / min and? 50 ml / min), dose adjustment is not required. In patients with moderate renal insufficiency that do not tolerate adverse reactions to Ciampix В® , the daily dose may be reduced to 1 mg 1 time / day.For patients with severe renal insufficiency (CC <30 ml / min), the recommended dose of Champix В® is 1 mg 1 time / day. Treatment begins with a dose of 500 Ојg 1 time / day, which after 3 days increase to 1 mg 1 time / day. Due to a lack of clinical data on the use of Champix В® in patients with terminal stage of renal failure , the drug is not recommended for such patients.
Patients with a dysfunction of the liver dosage adjustment is not required.
For elderly patients, dose adjustment is not required. In this category of patients, the probability of renal impairment is higher, so it is advisable to evaluate it before starting treatment.
Champix В® should not be administered to children and adolescents under 18 years of age , as information on the safety of the drug in this age group is not enough.
Smoking-related reactions (nicotine withdrawal syndrome), with or without therapy with ChampixВ®: mood reduction and dysphoria, insomnia, irritability, feelings of displeasure and anger, anxiety, impaired concentration, motor anxiety, decreased heart rate, increased appetite, or an increase in body weight, possibly exacerbation of concomitant mental disorders.
Neither during the development of clinical trials of Champix В® , nor during the analysis of their results, attempts were made to distinguish between undesirable phenomena associated with the use of the study drug and undesirable reactions possibly associated with the nicotine withdrawal syndrome itself.
According to the results of clinical studies, adverse reactions usually appeared within the first week after initiation of treatment, were usually mild or moderate and their frequency was independent of the patient's age, race or sex.
In patients who received Champix В® at the recommended dose of 1 mg 2 times / day after the titration period, the most frequent of the reported adverse reactions was nausea (28.6%). In most cases, nausea occurred during the early stages of therapy, was mild or moderate, and it was rarely necessary to stop taking the medication.
The incidence of interruption of therapy due to adverse events was 11.4% in the group receiving varenicline and 9.7% for the placebo group. The frequency of discontinuation of therapy due to major adverse reactions in the group receiving varenicline and in the placebo group, respectively: nausea - 2.7% and 0.6%; headache - 0.6% and 1.0%; insomnia - 1.3% and 1.2%; unusual dreams - 0.2% and 0.2%.
Determination of the frequency of adverse reactions: very often (? 10%); often (from? 1% to <10%); infrequently (from? 0.1% to <1%); rarely (from> 0.01% to <0.1%); very rarely (<0.01%); frequency is unknown (can not be determined from available data).
Infections: very often - nasopharyngitis; often - bronchitis, sinusitis; infrequently - fungal infections, viral infections.
From the side of metabolism: often - decreased appetite, increased appetite; infrequently - anorexia, polydipsia; frequency unknown - hyperglycemia, diabetes mellitus.
Mental disorders: very often - unusual dreams, insomnia; infrequently - panic reaction, bradyphrenia, disturbance of thinking, mood swings; frequency is unknown - somnambulism.
From the nervous system: very often - headache; often - drowsiness, dizziness, changes in taste, incl. decreased taste sensations; infrequently - tremor, coordination disorder, lethargy, dysarthria, hypertonus, motor anxiety, dysphoria, hypoesthesia, apathy, increased libido, decreased libido; rarely - cerebrovascular accident.
From the cardiovascular system: infrequently - atrial fibrillation, palpitations, angina, tachycardia; frequency unknown - myocardial infarction.
From the side of the organ of vision: infrequently - scotoma, scleral discoloration, pain in the eyeball, pupil dilated, photophobia, myopia, increased lacrimation, conjunctivitis.
From the side of the hearing organ and the vestibular apparatus: infrequently, noise in the ears.
On the part of the respiratory system: often - shortness of breath, cough; infrequently - infections of the upper respiratory tract, hoarseness of the voice, pain in the pharynx and larynx, irritation of the pharynx, congestion in the airways, congestion in the paranasal sinuses, exudation in the nasopharynx, rhinorrhea, snoring, dysphonia, allergic rhinitis.
From the side of the digestive system: very often - nausea; often - vomiting, constipation, diarrhea, bloating, stomach discomfort, dyspepsia, flatulence, dryness of the oral mucosa, gastroesophageal reflux disease, abdominal pain, toothache; infrequently - vomiting with blood, an admixture of blood in the stool, gastritis, intestinal disturbances, stool breaking, belching, aphthous stomatitis, tenderness of the gums, and lined tongue.
From the skin and subcutaneous tissues: often - rash, itchy skin; infrequently - generalized rash, erythema, acne, hyperhidrosis, increased sweating at night.
From the musculoskeletal system: often - arthralgia, myalgia, back pain; infrequent - stiffness of joints, muscle spasms, bone chondrite.
From the urinary system: infrequently - Glucosuria, nocturia, polyuria, pollakiuria.
From the side of the reproductive system: infrequently - menorrhagia, vaginal discharge, sexual dysfunction.
General and local reactions: often - chest pains, fatigue; infrequently - discomfort in the chest, fever, sensation of cold, asthenia, disturbance of the circadian rhythm of sleep, malaise, cyst, flu-like syndrome.
Research results: often - weight gain; infrequent increase of blood pressure, depression of the ST segment on the ECG, a decrease in the amplitude of the T wave on the ECG, an increase in heart rate, a "flush" of the blood to the skin of the face, a decrease in the number of platelets, a change in liver function parameters, a change in sperm, an increase in the C-reactive protein concentration, calcium in the blood.
Cessation of smoking with or without therapy is accompanied by the development of the syndrome of "withdrawal" of nicotine and exacerbation of concomitant mental disorders.
In the course of post-marketing research , cases of depressed mood, agitation, behavioral or thinking disorders, anxiety, psychosis, hallucinations, mood swings, aggressive behavior, suicidal tendencies and suicidal attempts were recorded in patients trying to quit smoking with Champix В® . Since these phenomena are fixed according to the results of voluntary communication by a population of undetermined size, it is not always possible to establish precisely their frequency or cause-and-effect relationship with 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. Role of varenicline В® in the development of the reactions described in these messages is not known. Also registered cases of allergic reactions - angioedema and rare but severe cases of skin reactions, including Stevens-Johnson syndrome, erythema multiforme.
hypersensitivity to any component of the drug;
- end-stage kidney failure;
- child and adolescence to 18 years (not enough clinical data on efficacy and safety in this age group);
lactation period (breastfeeding).
PREGNANCY AND LACTATION
Adequate and well-controlled studies on the safety of varenicline in pregnancy has not been finished, so the drug is contraindicated.
It is unknown whether varenicline is excreted in breast milk in humans. If you need to use the drug during lactation, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
For patients with mild (estimated QA> 50 ml / min? 80 mL / min) and moderate (calculated QC? 30 mL / min? 50 mL / min) renal dysfunction dose adjustment is required. In case of severe adverse reactions in patients with moderate renal impairment the dose may be reduced to 1 mg 1 time / day.
For patients with severe renal impairment (estimated creatinine clearance <30 mL / min), the recommended dose is 1 mg varenicline 1 time / day. Treatment started with a dose of 500 mg 1 time / day, which after 3 days was increased to 1 mg 1 time / day. Experience of varenicline in patients with renal disease in the terminal stage is insufficient, and the drug is not recommended in these cases.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Patients with impaired liver function correction dose is not required.
APPLICATION FOR CHILDREN
Contraindications: age 18 years (insufficient clinical data on the efficacy and safety of the drug in this age group).
APPLICATION IN ELDERLY PATIENTS
Elderly patients correction dose is not required. It should be borne in mind that in these patients the likelihood of impaired renal function above, so it is advisable to carry out its assessment before starting treatment.
The effect of smoking cessation on the organism
physiological changes that occur after smoking cessation in background or without treatment with varenicline В® , can alter the pharmacokinetics or pharmacodynamics of certain drugs, which may require dosage adjustment (for example, theophylline, warfarin and insulin). Because smoking induce isozymes CYP1A2, smoking cessation may result in increased concentrations of substrates of this isoenzyme in blood plasma.
analysis of clinical trials data showed no increased risk of serious neuropsychiatric disorders in the application of varenicline compared with placebo. In addition, the results of independent observational studies do not confirm an increased risk of serious neuropsychiatric disorders in the application of varenicline compared with nicotine replacement therapy or bupropion therapy.
During post-marketing use of the drug, there were reports of the appearance of neuropsychiatric disorders, including conduct disorder, or thinking, anxiety, psychosis, mood swings, aggressive behavior, agitation, depressed mood, suicidal thoughts and suicidal behavior in patients attempting to quit smoking with varenicline. Not all patients have stopped smoking at the time of occurrence of these symptoms and not all patients had previously observed mental impairment.
The physician should explain to patients receiving the drug for the purpose of smoking cessation, the possibility of the development of neuropsychiatric symptoms and the need to gradually reduce the dose. Patients, their families or caregivers should be advised of the need to stop taking vareniclineВ® and immediate treatment to the appearance of the doctor or behavioral disturbances of thinking, agitation or depressive mood, and also in the event of suicidal behavior, or that had not previously been characterized to the patient. In many cases, after the drug was observed the disappearance of these symptoms, but sometimes the symptoms persisted. In this context it recommended further monitoring of patients as long as symptoms persist. Prior to initiation of treatment should be to find out whether the patient has previously had any mental disorders.
It should also be borne in mind that depressed mood, in rare cases, in conjunction with suicidal thoughts or attempts, can accompany smoking cessation. In addition, the process of quitting, together with or without pharmacotherapy it is usually associated with exacerbations of existing psychiatric disorders (eg, depression).
Conducted clinical studies of varenicline in patients with major depressive disorder without psychotic phenomena, receiving regular antidepressant therapy and / or in patients who have had a major depressive episode in the past 2 years and the therapy has been successful. According to the state of patients for psychiatric evaluation scales there were no differences between groups of patients receiving placebo and varenicline. Also, there were no worsening of depression during therapy varenicline in both groups of patients. In the application of varenicline in patients with a history of mental illness should be careful.
A meta-analysis of 15 clinical trials with a duration of treatment? 12 weeks involving 7002 patients (4190 patients taking varenicline, 2812 patients were taking placebo) was conducted to systematically assess the cardiovascular safety of varenicline.
In the application of varenicline В®in patients with cardiovascular disease was a slight increase in the frequency of complications of these diseases. Such complications are more likely to occur in patients with pre-existing diseases of the cardiovascular system. The overall mortality and mortality due to cardiovascular disease was lower in patients treated with varenicline. Patients taking varenicline should inform your doctor about new symptoms of cardiovascular disease or aggravation of existing ones. Patients should immediately seek medical help in case of symptoms characteristic of myocardial infarction or stroke.
The 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. In the application of varenicline in patients with a history of mental illness should be careful.
There is no data on the use of varenicline В® in patients with epilepsy. Against the background of varenicline В® developed seizures (absence seizures history). If there is a history of seizures or other conditions that reduce the seizure threshold, care must be taken in the application of varenicline В® . A causal relationship between the use of varenicline and the development of seizures has not been established.
Completion of therapy
Completion of treatment of varenicline 3% of patients accompanied by increased irritability, craving to smoke, depression and / or insomnia. Patients should be warned of such complications and discuss the possibility of reducing the dose.
Angioedema and hypersensitivity reactions
There are about the development of hypersensitivity reactions posts, including angioedema in patients treated with varenicline. Clinical symptoms of the complications include swelling of the face, mouth (tongue, lips, gums), neck (throat and larynx) and extremities. In addition, there are rare reports of life-threatening angioedema, for the treatment of which may require urgent medical attention due to the risk of impairment of respiratory function. Patients should stop taking varenicline and contact your physician if any symptoms develop hypersensitivity reactions.
Severe skin reaction
There are rare reports of severe life-threatening skin reactions, including Stevens-Johnson syndrome and erythema multiforme in patients taking varenicline. Becausethese reactions can be life-threatening, it is necessary to stop the use of varenicline В® at the first signs of rash or skin reactions and immediately inform the attending physician.
Impact on the ability to drive vehicles and manage mechanisms
Varenicline В® can cause drowsiness and dizziness, so patients do not recommended to drive, or to use complex equipment to carry out other potentially hazardous tasks to assess individual responses to the drug.
Varenicline overdose cases have been reported.
Treatment: symptomatic therapy. Varenicline is output during hemodialysis in patients with severe renal impairment, but no experience with hemodialysis in overdose.
Clinically significant interactions with other drugs varenicline is not revealed. Correction dose of varenicline or the following preparations, while the application is required.
In in vitro studies have shown that active secretion by the kidneys is mediated varenicline organic cation transporter Human (OST2). While the use of inhibitors OST2 not required dose correction varenicline, as It is not expected to significantly increase the systemic exposure of varenicline tartrate.
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% metabolism at the expense, it is unlikely that a substance influencing on the activity of the enzyme system, may affect the pharmacokinetics of varenicline, and therefore the correction of the dose of varenicline В® not required.
Varenicline at therapeutic concentrations does not inhibit renal transport proteins in humans. Therefore, varenicline should not affect the pharmacokinetics of drugs which are output due to renal secretion (particularly metformin).
Varenicline did not affect the pharmacokinetics of metformin. Metformin does not cause the change in the pharmacokinetics of varenicline.
Cimetidine causes an increase in AUC of varenicline 29% by reducing its renal clearance. In patients with normal renal function or mild renal impairment or moderate dose adjustment is required. In patients with severe renal insufficiency should avoid the simultaneous application of cimetidine and varenicline.
Varenicline did not affect the pharmacokinetics of digoxin at steady state.
Varenicline did not alter the pharmacokinetics of warfarin, and does not affect the prothrombin time (MHO). Smoking cessation itself may result in changes in the pharmacokinetics of warfarin.
Data on concomitant use of alcohol and varenicline are limited. During post-marketing use of varenicline reported cases enhance the toxic effect of alcohol. A causal relationship between these cases and the use of varenicline has not been established.
Use in combination with other anti-smoking
Varenicline did not affect the pharmacokinetics of bupropion in the equilibrium state.
Nicotine replacement therapy (NRT)
With simultaneous application of varenicline and plasters containing nicotine for 12 days in smokers showed a statistically significant decrease in average systolic blood pressure (2.6 mm Hg) for the last day of the study. In this case, the incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue in the combination therapy was higher than that on the background of one of NRT.
The safety and efficacy of varenicline in combination with other anti-smoking have not been studied.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in reach of children at a temperature from 15 В° to 30 В° C. Shelf life - 3 years.