Varenicline
When ATH:
N07BA03
Pharmacological action
Reducing nicotine dependence.
Pharmacokinetics
Варениклин связывается с a4v2 нейронными никотиновыми ацетилхолиновыми рецепторами мозга, in regard to which it is a partial agonist, ie. at the same time shows agonism (but less, than nicotine) and antagonism in the presence of nicotine.
Electrophysiological studies in vitro and in vivo studies neyrobiohimicheskie shown, that varenicline binds to the α4β2 neuronal nicotinic acetylcholine receptors and stimulates, but to a much lesser extent, than nicotine. Nicotine interacts with the same receptor, varenicline which has a higher affinity. In this regard, full activation varenicline blocks α4β2 receptors by nicotine, which is the basis of the effect of the pleasure of smoking with the subsequent formation of dependence. Varenicline has high selectivity and binds to α4β2 receptors more active (Ki = 0.15 nM), than with other nicotinic receptors (a3v4 Ki = 84 nM, a7 Ki = 620 nM, a1vgd Ki = 3,400 nM) or other receptors and transporters (Ki > 1 M, except to the 5-HT3 receptor: Ki = 350 nM).
The efficacy of varenicline in the treatment of nicotine dependence is associated with partial agonist varenicline against α4β2 nicotinic receptor. The binding of the drug to these receptors reduces cravings to smoke and withdrawal (agonist activity) and at the same time reduces the effect of pleasure from smoking, followed by the formation of dependence by blocking the interaction of α4β2 with nicotine receptors (antagonistic activity).
Testimony
Nicotine dependence in adults.
Dosage regimen
Varenicline is used inside. The recommended dose of varenicline 1 mg twice a day. Its titrated during the first week as follows:
1 - 3 days – 0,5 mg once daily 4 - 7 days – 0,5 mg twice a day 8 day - the end of treatment – 1 mg twice a day
The patient must choose the date of smoking cessation. Treatment should be initiated for varenicline 1-2 a week before that date.
If the patient can not tolerate adverse effects of varenicline, the dose may be temporarily or permanently reduced to 0,5 mg twice a day.
Varenicline tablets should be swallowed whole and washed down with water. Varenicline can be taken with or without food.
Treatment continued for varenicline 12 weeks.
Patients, Stop smoking for 12 weeks, possible additional 12-week course of treatment at a dose of varenicline 1 mg twice a day.
Additional information on the effectiveness of the 12-week course of treatment for patients, who failed to quit smoking during the first year, and patients, who resumed smoking after completion of therapy, no.
When using anti-tobacco smoking increased the risk of renewed immediately after the completion of treatment. If the risk is high, possibly the gradual reduction of the dose.
Side effect
Reaction, associated with smoking cessation (Nicotine withdrawal), in the background, or without therapy, varenicline: depressed mood and dysphoria, insomnia, irritability, feeling of displeasure and anger, alarm, impaired concentration, restlessness, a decrease in heart rate, increased appetite or weight gain, possible worsening of psychiatric comorbidity.
Neither the development schemes of clinical trials of varenicline, nor in the analysis of their results no attempt to distinguish between adverse events, related to study medication, and adverse reactions, perhaps, associated itself with nicotine withdrawal symptoms.
According to the results of clinical studies adverse reactions usually occur within the first week of treatment, We were, usually, mild or moderate and their frequency does not depend on the age, race or sex of the patient. Patients, treated at the recommended dose of varenicline 1 mg 2 times / day after a period of titration, the most frequent of the reported adverse reactions were nausea (28.6%). In the majority of cases nausea occurred early in therapy, It expressed mild to moderate, discontinuation of the drug is rarely needed.
The frequency of discontinuation due to adverse events was 11.4% in Group, poluchavshey and varenicline 9.7% to placebo. The frequency of discontinuation due to adverse reactions in the main group, receiving varenicline and placebo, 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: Often (≥ 1/10); often (≥ 1/100 but < 1/10); rarely (≥ 1/1000, but < 1/100).
Infection: rarely – bronchitis, nazofaringit, sinusitis, fungal infections, viral infections.
Metabolism: often – increased appetite; rarely – anorexia, decreased appetite, polydipsia, weight gain, lowering blood calcium.
From the central and peripheral nervous system: Often – unusual dreams, insomnia, headache; often – drowsiness, dizziness, disgevziya; rarely – panic reaction, bradyphrenia, aphronia, mood swings, tremor, incoordination, dysarthria, restlessness, disforija, gipesteziya, apathy.
Cardio-vascular system: rarely – increased blood pressure, ST-segment depression on ECG, decrease in the amplitude of the T wave on the ECG, increase in heart rate, Atrial fibrillation, heartbeat.
From the senses: rarely – scotoma, discoloration of sclera, pain in the eyeball, mydriasis, photophobia, myopia, increased lacrimation, noise in ears, decrease in sense of taste.
The respiratory system: rarely – breathlessness, cough, hoarseness, pain in the throat and larynx, throat irritation, congestion in the airways, stagnation in the paranasal sinuses, exudation in the nasopharynx, rhinorrhea, snoring.
From the digestive system: very often - nausea; often – vomiting, constipation, diarrhea, abdominal distention, stomach discomfort, dyspepsia, flatulence, dry mouth; rarely – vomiting blood, blood in the stool, gastritis, gastroesophageal reflux disease, stomach ache, intestinal disorders, violation of the chair, belching, thrush, sore gums, coated tongue, changes in liver function tests.
Dermatological reactions: rarely – generalized rash, эritema, prurit, acne, hyperhidrosis, increased sweating at night.
On the part of the musculoskeletal system: rarely – joint stiffness, muscle spasms, pain in the chest wall, costochondritis.
From the urinary system: rarely – glycosuria, nocturia, polyuria.
Reproductive system: rarely – menorragija, vaginal discharge, sexual dysfunction, increased libido, decreased libido, changes in sperm.
Other: often – fatigue; rarely – chest discomfort, chest pain, fever, rhigosis, asthenia, circadian rhythm sleep, malaise, cyst, decrease in the number of platelets, elevated levels of C-reactive protein.
Smoking cessation 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 give up smoking with the help of varenicline, recorded cases of depressed mood, ažitacii, behavioral disturbances, suicidal thoughts and suicide attempts. Since these events are recorded on the results of voluntary reporting population of uncertain size, not always possible to accurately set their frequency or a causal relationship to drug action. Not all patients, described in these reports, had a history of mental illness and not all of them have stopped smoking. The role of varenicline in the development of reactions, described in these reports, unknown. Also recorded cases of allergic reactions – angioneurotic edema and swelling of the face.
Contraindications
end stage renal disease;
Age to 18 years (insufficient clinical data on the efficacy and safety of the drug in this age group);
pregnancy;
lactation (breast-feeding);
hypersensitivity to the drug.
Pregnancy and lactation
There are no adequate and well-controlled studies on the safety of varenicline during pregnancy was conducted, therefore, use of the drug is contraindicated.
Unknown, whether varenicline is allocated with breast milk in humans. If necessary, use during lactation should stop breastfeeding.
Cautions
Physiological changes, that occur after smoking cessation on the background or without treatment with varenicline, may alter the pharmacokinetics or pharmacodynamics of some drugs, which may require dose adjustment (eg, theophylline, warfarin and insulin).
Completion of treatment of varenicline in 3% patients accompanied by increased irritability, cravings, depression and / or insomnia.
During post-marketing use of the drug were reported occurrence of neuropsychiatric disorders, including breach of conduct, ažitaciû, depressed mood, suicidal thoughts and suicidal behavior in patients, varenicline treated for the purpose of giving up smoking. The physician should explain to patients, receiving the drug, the possibility of neuropsychiatric symptoms and the need for a gradual reduction of the dose. Patients, their families or caregivers should be advised of the need to stop taking varenicline and immediate treatment to the doctor if you have behavioral disorders, agitation or depressive mood, who previously were not specific to the patient, as well as in the event of suicidal thoughts or behavior. Prior to treatment you should find out, whether the patient had any previous psychiatric disorders.
Effects on ability to drive vehicles and management mechanisms
Varenicline can cause dizziness and drowsiness, so patients are not recommended to drive, use of sophisticated technology or perform other potentially dangerous tasks to assess individual response to the drug.
Overdose
No cases of overdose varenicline registered.
Treatment: the holding of symptomatic and supportive therapy. Varenicline appear in hemodialysis patients with severe renal impairment, However, experience with dialysis in overdose is not.
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, that varenicline does not change the pharmacokinetics of drugs, are metabolized by the action of cytochrome P450 isozymes. Since varenicline clearance less than 10% at the expense of metabolism, unlikely, that substance, affecting the activity of the enzyme system, may affect the pharmacokinetics of varenicline, therefore the dose adjustment of varenicline is not required.
Varenicline at therapeutic concentrations does not inhibit renal transport proteins in humans. Hence, Varenicline should not affect the pharmacokinetics of medicinal products, which are derived by renal secretion (in particular, metformin).
In an application does not require dose adjustment of the drug varenicline and the following drugs.
Metformin. Varenicline affecting farmakokinetiku metformin. Metformin does not cause changes in the pharmacokinetics of varenicline.
Cimetidine. Cimetidine causes an increase in the AUC of varenicline 29% by reducing its renal clearance.
Digoxin. Varenicline did not cause changes in the pharmacokinetics of digoxin at steady state.
Warfarin. Varenicline did not alter the pharmacokinetics of warfarin had no effect on prothrombin time (MHO). Smoking cessation itself may result in changes in the pharmacokinetics of warfarin.
Use in combination with other anti-smoking
Bupropion. Varenicline did not cause changes in the pharmacokinetics of bupropion in the equilibrium state.
Nikotinzamestitelynaya therapy (NZT). With simultaneous use of varenicline and plasters, nicotine containing, during 12 days in smokers was statistically significant decrease in average systolic blood pressure (on 2.6 mm Hg. Art.) the last day of the study. The frequency of nausea, headache, vomiting, dizziness, dyspepsia and fatigue on the combined therapy were higher, than on the background of one of NRT.
Safety and efficacy of varenicline in combination with other anti-smoking have not been studied.
