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Antismoking AgentsNicotinic Receptor Agonists
Nicotinic acetylcholine receptor agonistOral formulation used to promote smoking cessation; intranasal formulation used for dry eye diseaseMonitor closely for emerging or worsening suicidal thoughts/behavior, depression, or other changes in mood or behavior
Chantix/Varenicline/Varenicline tartrate Oral Tab: 0.5mg, 1mg, 0.5-1mgTyrvaya Nasal Spray Met: 0.6mg, 1mL
Set a patient quit date to stop smoking. Initiate varenicline 1 week before the quit date, or, the patient can begin treatment and then quit smoking between Days 8 and 35 of varenicline treatment. Titrate the dose over a 1 week period starting with 0.5 mg PO once daily on Days 1 through 3, then 0.5 mg PO twice daily on Days 4 through 7, and finally 1 mg PO twice daily on day 8 until the end of treatment. Duration of therapy should be 12 weeks; patients who are successful after 12 weeks may be treated with an additional 12 week course to increase chances of long-term abstinence. Patients who are motivated to quit and tolerated the drug, but were unsuccessful or relapsed after treatment should be encouraged to make a second attempt once factors contributing to the failed attempt have been identified and addressed. FOR PATIENTS UNABLE OR UNWILLING TO QUIT SMOKING ABRUPTLY: Initiate varenicline treatment and have patient reduce smoking by 50% from baseline within the first 4 weeks, reduce smoking by an additional 50% in the next 4 weeks, and continue reducing with the goal of complete abstinence by 12 weeks. Continue varenicline for an additional 12 weeks, for a total of 24 weeks of treatment. Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional advice and support. Patients should be provided with appropriate supportive educational materials and counseling.
1 spray (0.03 mg) in each nostril twice daily, approximately 12 hours apart. If a dose is missed, resume regular dosing at the next scheduled dosing time.
2 mg per day PO; 0.12 mg (4 sprays) intranasally per day.
Safety and efficacy have not been established.
No dosage adjustment is necessary for patients with hepatic impairment.
CrCl 30 mL per minute or more: No dosage adjustment needed.CrCl less than 30 mL per minute: Initially, 0.5 mg PO once per day. Max: 0.5 mg PO twice daily. Intermittent hemodialysisVarenicline is removed by hemodialysis. A maximum dose of 0.5 mg PO once daily may be given if well tolerated in patients with end-stage renal disease on hemodialysis.
Administer tablets after eating with a full glass of water.
Each carton contains 2 glass nasal spray bottles. Each nasal spray bottle provides enough medication to deliver 1 spray in each nostril twice daily for 15 days. DO NOT open the second bottle until the contents of the first bottle have been exhausted.DO NOT shake the nasal spray bottles.Before the initial use, prime the pump by spraying 7 actuations into the air away from the face. If not used for more than 5 days, the pump must be re-primed with 1 spray into the air. Avoid priming the pump more than needed.To administer the spray:If needed, blow nose to clear the nostrils.Remove the cap and clip. Do not throw away the cap or clip as they will be placed back on the nasal applicator after each use.Hold the bottle upright. Place 1 finger on each side of the base of the nasal applicator and place the thumb underneath the bottle.Tilt head back slightly without lying down.Insert the nasal applicator into 1 of the nostrils. Tilt the nasal applicator to point the tip towards the top of the ear on the same side as the nostril. Leave space between the tip and the inside wall of the nose; DO NOT press the tip against the inside wall of the nose.Place the tongue on the roof of the mouth and breathe gently while pressing and releasing the nasal applicator once.Repeat this process to deliver the second spray into the other nostril.Wipe the nasal applicator with a clean tissue after each use.Replace the applicator cap and clip.Discard nasal spray bottle 30 days after opening the bottle.
Chantix:- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees FTyrvaya:- Discard opened bottle after 30 days- Do not freeze- Store between 68 to 77 degrees F
Orally administered varenicline should be avoided in patients with a known hypersensitivity to varenicline or any component of the formulation. Life-threatening hypersensitivity reactions, including angioedema, have occurred. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx). There were infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise. Rarely, serious skin reactions such as Stevens-Johnson syndrome and erythema multiforme have also been reported during postmarketing use of the drug. Patients should be instructed to discontinue the medication and seek immediate medical care if they experience a serious rash with mucosal lesions or any other signs of hypersensitivity.
Patients should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness (e.g., schizophrenia, depression, bipolar disorder) during treatment with orally administered varenicline, due to serious neuropsychiatric symptoms reported during use of the drug. If neuropsychiatric symptoms develop, evaluate the patient for symptom severity and the extent to which the patient is benefiting from treatment, and consider dose reduction or discontinuation, or continued treatment with closer monitoring. In many cases, resolution of symptoms has occurred after discontinuation, although the symptoms can persist; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve Post-marketing reports have included mood or behavioral changes or a psychiatric event such as psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, anxiety, panic, mania, depression, suicidal ideation, suicide attempt, and completed suicide in patients with or without a psychiatric history. Some reported cases may have been complicated by symptoms of nicotine withdrawal, such as depressed mood, in patients who stopped smoking, although most occurred during varenicline treatment. It should be noted that depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by concomitant use of alcohol. Advise patients and caregivers that the patient should stop taking the drug and contact a healthcare provider immediately if agitation, depressed mood, suicidal ideation, suicidal behavior, or other behavioral changes that are not typical for the patient are observed. The boxed warning in the product labeling regarding serious neuropsychiatric effects was removed in December 2016 following results from the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES), which was a large, randomized, double-blind, active- and placebo-controlled smoking cessation clinical trial assessing varenicline, bupropion, and nicotine replacement therapy in patients with (n = 4003) and without (n = 3912) a history of a psychiatric disorder. In the non-psychiatric cohort, fewer patients receiving varenicline reported a serious neuropsychiatric event than patients receiving placebo (0.1% vs. 0.4%). There was a similar incidence of serious neuropsychiatric events between the psychiatric patients receiving varenicline or placebo (0.6% each). In the psychiatric cohort, there were more neuropsychiatric events reported in each treatment group than in the non-psychiatric cohort, and the incidence of events at endpoint was higher in psychiatric patients receiving each of the active treatments than placebo. Risk differences in the psychiatric cohort versus placebo were: 2.7% for varenicline, 2.2% for bupropion, and 0.4% for transdermal nicotine. More patients in the varenicline-treated psychiatric cohort had serious neuropsychiatric events involving a psychiatric hospitalization than in patients receiving placebo (0.5% vs. 0.2%).
Patients should be advised to use caution when driving or operating machinery or performing other tasks that require mental alertness until they know how varenicline will affect them. There have been reports of motor vehicle accidents, near-miss traffic incidents, and other accidental injuries during the use of orally administered varenicline. In some cases, patients have experienced drowsiness, dizziness, loss of consciousness, or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving or operating machinery. There have also been postmarketing reports of patients experiencing increased effects of ethanol intoxication while taking varenicline. Some cases have described unusual and sometimes aggressive behavior, and have often been accompanied by amnesia of the events. Patients should be advised to reduce their amount of ethanol ingestion while taking varenicline until they know whether the drug affects their tolerance for alcohol. Instruct patients to discontinue varenicline and notify their healthcare provider if they experience somnambulism or other complex sleep-related behaviors. Somnambulism (sleep-walking) has been reported in patients taking varenicline, with some cases describing harmful behavior to self, others, or property.
Seizures have been reported in patients treated with oral varenicline during clinical trials and postmarketing experience. Some patients had no history of seizures, whereas others had a history of seizure disorder that was remote or well-controlled. In most cases, the seizure occurred within the first month of therapy. Weigh this potential risk against the potential benefits before prescribing varenicline in patients with a history of seizures or other factors that can lower the seizure threshold. Tell patients to discontinue varenicline and contact a health care provider immediately if they experience a seizure while on treatment.
A comprehensive evaluation of cardiovascular risk (i.e., randomized controlled trials and meta-analysis) suggests that orally administered varenicline may be associated with a small, increased risk of certain cardiovascular events, such as myocardial infarction or stroke, in patients with cardiac disease. However, because smoking is an independent major risk factor for cardiovascular disease, the health benefits of smoking cessation must be balanced with concerns of potential drug-related cardiac risks. In one smoking cessation trial of patients with stable cardiac disease, nonfatal myocardial infarction and nonfatal stroke occurred more frequently in patients using varenicline than placebo, but the difference was not statistically significant, and all-cause and cardiovascular mortality was lower in patients treated with varenicline. A meta-analysis showed an increased hazard ratio of 1.95 for Major Adverse Cardiovascular Events (MACE) with varenicline, which was not statistically significant. A large postmarketing neuropsychiatric safety outcome trial showed few MACE events; therefore, the findings did not significantly contribute to identifying the cardiac risk of varenicline. Patients should be instructed to seek medical attention if they experience new or worsening cardiac symptoms (such as those suggestive of myocardial infarction or stroke) while receiving varenicline.
Oral varenicline should be used cautiously in patients with renal impairment or renal failure. Varenicline is substantially excreted by the kidneys and the risk of toxic reactions is greater in patients with impaired renal function. Dosage adjustments are necessary in patients with CrCl less than 30 mL per minute and those with end-stage renal disease receiving dialysis.
No overall differences in safety or effectiveness were observed during clinical trials in geriatric patients vs. younger adults. Clinical experience has not identified differences in responses. However, greater sensitivity of some older patients cannot be ruled out. Geriatric patients are more likely to have decreased renal function. Since varenicline is known to be substantially excreted by the kidney and the risk of toxic reactions are greater in patients with impaired renal function, care should be taken when dosing oral varenicline in the elderly; it may be useful to monitor renal function.
There are no data on the use of intranasal varenicline in pregnant patients to inform any drug associated risk. Available data from orally administered varenicline have not suggested an increased risk for major birth defects in exposed infants following maternal exposure as compared with mothers who smoke. Overall, however, available study results cannot definitively establish or exclude any varenicline-associated risk during pregnancy. In 1 population-based observational study using national registries from Denmark and Sweden where pregnancy and birth outcomes were compared among patients exposed to varenicline, patients who smoked during pregnancy, and non-smoking pregnant patients, the prevalence of major malformations was similar in all groups. The prevalence of other adverse perinatal outcomes in the varenicline-exposed cohort was not greater than in the cohort of patients who smoked. Study limitations included the inability to capture malformations from pregnancies without a live birth and misclassifications of outcomes, varenicline exposure, or smoking exposure. Other small epidemiological studies did not identify an association between varenicline use during pregnancy and major malformations. Smoking during pregnancy causes increased risks of orofacial clefts, premature rupture of membranes, placenta previa, placental abruption, ectopic pregnancy, fetal growth restriction and low birth weight, stillbirth, preterm delivery and shortened gestation, neonatal death, sudden infant death syndrome and reduction of lung function in infants. It is not known whether smoking cessation with varenicline during pregnancy reduces these risks. Non-pharmacologic smoking cessation efforts are used to help reduce the proportion of patients who continue to smoke in late pregnancy, thereby reducing adverse perinatal outcomes. Nicotine replacement treatment is used during pregnancy only if the likelihood of smoking cessation justifies the potential risk of the treatment or the risk that the patient will continue to smoke. The potential effects of varenicline on labor and delivery are not known.
There are no data on the presence of varenicline in human milk, the effects on the breast-fed infant, or the effects on human milk production. In animal studies varenicline was present in milk of lactating rats. However, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The lack of clinical data during lactation precludes a clear determination of the risk of varenicline to an infant during lactation. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for varenicline and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. If varenicline use is required, breast-feeding women should monitor their infant for seizures and excessive vomiting, which are adverse reactions that have occurred in adults that may be clinically relevant in a breast-feeding infant. The decision of whether to use a pharmacologic method for smoking cessation in a woman who is breast-feeding should be evaluated in comparison to the risks associated with passive exposure of the infant to tobacco smoke. Nicotine replacement products may be considered as an alternate smoking cessation treatments to varenicline in breast-feeding mothers if supportive cessation interventions are ineffective. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Safety and efficacy of intranasal varenicline in pediatric patients have not been established. Additionally, orally administered varenicline is not recommended for children or adolescents because its efficacy in these populations has not been demonstrated. Varenicline did not improve continuous abstinence rates at weeks 9 through 12 of treatment compared to placebo in a randomized, double-blind study of 312 patients 12 to 19 years of age, who smoked an average of at least 5 cigarettes per day, had a Fagerstrom Test for Nicotine Dependence score of at least 4, and at least 1 previous failed attempt to quit. The safety profile of varenicline was similar to that of adults.
GI bleeding / Delayed / Incidence not knownGI obstruction / Delayed / Incidence not knownpancreatitis / Delayed / Incidence not knownpeptic ulcer / Delayed / Incidence not knownseizures / Delayed / Incidence not knownerythema multiforme / Delayed / Incidence not knownStevens-Johnson syndrome / Delayed / Incidence not knownlaryngeal edema / Rapid / Incidence not knownangioedema / Rapid / Incidence not knownbradycardia / Rapid / Incidence not knownpulmonary embolism / Delayed / Incidence not knownstroke / Early / Incidence not knownatrial fibrillation / Early / Incidence not knownatrial flutter / Early / Incidence not knownmyocardial infarction / Delayed / Incidence not knownthrombosis / Delayed / Incidence not knownrenal failure (unspecified) / Delayed / Incidence not knownvisual impairment / Early / Incidence not knownnight blindness / Delayed / Incidence not knownhearing loss / Delayed / Incidence not knownbronchospasm / Rapid / Incidence not knowncholecystitis / Delayed / Incidence not knownsuicidal ideation / Delayed / Incidence not known
depression / Delayed / 0-11.0constipation / Delayed / 5.0-8.0hostility / Early / 0-2.0dyspnea / Early / 1.0-2.0euphoria / Early / 0-1.0gastritis / Delayed / Incidence not knowndysphagia / Delayed / Incidence not knownesophagitis / Delayed / Incidence not knownoral ulceration / Delayed / Incidence not knownmigraine / Early / Incidence not knowncomplex sleep-related behaviors / Early / Incidence not knowndysarthria / Delayed / Incidence not knownamnesia / Delayed / Incidence not knownhallucinations / Early / Incidence not knownpsychosis / Early / Incidence not knownmania / Early / Incidence not knownethanol intoxication / Early / Incidence not knownpsoriasis / Delayed / Incidence not knownatopic dermatitis / Delayed / Incidence not knownerythema / Early / Incidence not knownhot flashes / Early / Incidence not knownperipheral edema / Delayed / Incidence not knownangina / Early / Incidence not knownsinus tachycardia / Rapid / Incidence not knownchest pain (unspecified) / Early / Incidence not knownpalpitations / Early / Incidence not knownosteoporosis / Delayed / Incidence not knownimpotence (erectile dysfunction) / Delayed / Incidence not knownnephrolithiasis / Delayed / Incidence not knownurinary retention / Early / Incidence not knownhyperglycemia / Delayed / Incidence not knowndiabetes mellitus / Delayed / Incidence not knownhypoglycemia / Early / Incidence not knownnystagmus / Delayed / Incidence not knownblurred vision / Early / Incidence not knownphotophobia / Early / Incidence not knownconjunctivitis / Delayed / Incidence not knowncataracts / Delayed / Incidence not knownsplenomegaly / Delayed / Incidence not knownthrombocytopenia / Delayed / Incidence not knownlymphadenopathy / Delayed / Incidence not knownanemia / Delayed / Incidence not knownhypokalemia / Delayed / Incidence not knownedema / Delayed / Incidence not knownhyperlipidemia / Delayed / Incidence not knownelevated hepatic enzymes / Delayed / Incidence not known
sneezing / Early / 82.0-82.0nausea / Early / 16.0-40.0headache / Early / 11.0-19.0insomnia / Early / 9.0-19.0cough / Delayed / 16.0-16.0abnormal dreams / Early / 8.0-13.0throat irritation / Early / 13.0-13.0vomiting / Early / 1.0-11.0irritability / Delayed / 0-11.0libido decrease / Delayed / 1.0-10.0emotional lability / Early / 1.0-10.0flatulence / Early / 6.0-9.0dysgeusia / Early / 5.0-8.0anxiety / Delayed / 0-8.0nasal irritation / Early / 8.0-8.0abdominal pain / Early / 5.0-7.0fatigue / Early / 4.0-7.0agitation / Early / 0-7.0xerostomia / Early / 4.0-6.0dyspepsia / Early / 5.0-5.0appetite stimulation / Delayed / 3.0-4.0drowsiness / Early / 3.0-3.0rash / Early / 1.0-3.0anorexia / Delayed / 1.0-2.0nightmares / Early / 1.0-2.0lethargy / Early / 1.0-2.0gastroesophageal reflux / Delayed / 1.0-1.0pruritus / Rapid / 0-1.0rhinorrhea / Early / 0-1.0weight gain / Delayed / Incidence not knowneructation / Early / Incidence not knowndiarrhea / Early / Incidence not knownsomnambulism / Early / Incidence not knowntremor / Early / Incidence not knownrestlessness / Early / Incidence not knowndizziness / Early / Incidence not knownrestless legs syndrome (RLS) / Delayed / Incidence not knownparosmia / Delayed / Incidence not knownpsychomotor impairment / Early / Incidence not knownparanoia / Early / Incidence not knownacne vulgaris / Delayed / Incidence not knownphotosensitivity / Delayed / Incidence not knownurticaria / Rapid / Incidence not knownhyperhidrosis / Delayed / Incidence not knownxerosis / Delayed / Incidence not knownsyncope / Early / Incidence not knownmuscle cramps / Delayed / Incidence not knownback pain / Delayed / Incidence not knownmyalgia / Early / Incidence not knownmusculoskeletal pain / Early / Incidence not knownarthralgia / Delayed / Incidence not knownmenstrual irregularity / Delayed / Incidence not knownpolyuria / Early / Incidence not knownnocturia / Early / Incidence not knownocular irritation / Rapid / Incidence not knownxerophthalmia / Early / Incidence not knownocular pain / Early / Incidence not knownvertigo / Early / Incidence not knowntinnitus / Delayed / Incidence not knownepistaxis / Delayed / Incidence not knownleukocytosis / Delayed / Incidence not knownchills / Rapid / Incidence not knownfever / Early / Incidence not known
Cimetidine: (Minor) Inhibitors of OCT2 (e.g., cimeditine) may increase the exposure of varenicline but these changes may not necessitate a dose adjustment of varenicline as the increase in systemic exposure is not expected to be clinically meaningful. Administration cimetidine (300 mg four times daily), with varenicline (2 mg single dose) to 12 smokers increased the systemic exposure of varenicline by 29% due to a reduction in varenicline renal clearance. In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter OCT2. Another H2 antagonist may be preferable to cimetidine in patients taking varenicline. Ethanol: (Major) Patients should be advised to reduce the amount of alcohol they ingest while taking varenicline until they know whether the drug affects their tolerance for alcohol. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by a patient's concomitant use of alcohol. There have been postmarketing reports of patients experiencing increased alcohol intoxication while taking varenicline. Some cases described unusual and sometimes aggressive behavior, and were often accompanied by amnesia for the events. (Major) Patients should be advised to reduce the amount of alcohol they ingest while taking varenicline until they know whether the drug affects their tolerance for ethanol. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by a patient's concomitant use of alcohol. There have been postmarketing reports of patients experiencing increased ethanol intoxication while taking varenicline. Some cases described unusual and sometimes aggressive behavior, and were often accompanied by amnesia for the events.
Varenicline is a partial agonist of nicotinic acetylcholine (nACh) receptors alpha4-beta2, alpha4alpha6-beta2, alpha3-beta4, alpha3alpha5-beta4, and full alpha7. These receptors are believed to be the site whereby nicotine exerts its effects. Similar to most abused substances, nicotine increases dopamine release in the nucleus accumbens and prefrontal cortex. Cravings for nicotine are stimulated by low levels of mesolimbic dopamine during periods of abstinence. Varenicline is effective because it partially stimulates alpha4-beta2 receptors to produce a modest level of mesolimbic dopamine thereby diminishing nicotine cravings and withdrawal symptoms. This mesolimbic dopamine level is lower than that produced by nicotine. Varenicline also has the added benefit of blocking the effects of nicotine by occupying receptor sites. By blocking receptors, varenicline reduces the pharmacologic reward of nicotine in cases where a patient relapses and uses tobacco. Varenicline binds with high affinity and selectivity to these nACh receptors. Varenicline also binds with moderate affinity to 5-HT3 (serotonin) receptors. The exact mechanism by with varenicline treats the symptoms of dry eye disease is unknown; however, it is believed to occur through binding to the heteromeric sub-type(s) of nACh receptors. By binding to these receptors, varenicline activates the trigeminal parasympathetic pathway resulting in increased production of basal tear film.
Varenicline is administered orally and intranasally. Twenty percent or less of varenicline is plasma protein bound and is independent of both age and renal function. Metabolism is minimal. Approximately 92% of an administered dose is excreted unchanged in the urine. Elimination via the kidneys is primarily through glomerular filtration along with active tubular secretion by the human organic cation transporter, OCT2. The elimination half-life is about 24 hours for the oral formulation and 19 hours +/- 10 hours for the intranasal formulation. Affected cytochrome P450 isoenzymes and drug transporters: noneBased on in vitro studies, varenicline does not inhibit cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. It does not induce CYP1A2 or CYP3A4.
Varenicline is almost completely absorbed, and systemic availability is high with oral administration. The maximum plasma concentration (Cmax) occurs within 3 to 4 hours and steady-state is reached in about 4 days after multiple doses. Food or time-of-day do not affect varenicline oral bioavailability.
Following nasal administration of 0.12 mg (i.e., 0.06 mg spray in each nare), varenicline was detected in the plasma within 5 minutes and achieved peak concentration within 2 hours. The mean Cmax and systemic exposure (AUC) were 0.34 ng/mL and 7.46 ng x hour/mL, respectively. The AUC following the 0.12 mg intranasal dose was approximately 7.5% of the exposure observed following a 1 mg oral dose.