Chantix

Antismoking Agents
Nicotinic Receptor Agonists

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.

GI bleeding / Delayed / Incidence not known
GI obstruction / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
peptic ulcer / Delayed / Incidence not known
seizures / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
laryngeal edema / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
bradycardia / Rapid / Incidence not known
pulmonary embolism / Delayed / Incidence not known
stroke / Early / Incidence not known
atrial fibrillation / Early / Incidence not known
atrial flutter / Early / Incidence not known
myocardial infarction / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
visual impairment / Early / Incidence not known
night blindness / Delayed / Incidence not known
hearing loss / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
cholecystitis / Delayed / Incidence not known
suicidal ideation / Delayed / Incidence not known

depression / Delayed / 0-11.0
constipation / Delayed / 5.0-8.0
hostility / Early / 0-2.0
dyspnea / Early / 1.0-2.0
euphoria / Early / 0-1.0
gastritis / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
esophagitis / Delayed / Incidence not known
oral ulceration / Delayed / Incidence not known
migraine / Early / Incidence not known
complex sleep-related behaviors / Early / Incidence not known
dysarthria / Delayed / Incidence not known
amnesia / Delayed / Incidence not known
hallucinations / Early / Incidence not known
psychosis / Early / Incidence not known
mania / Early / Incidence not known
ethanol intoxication / Early / Incidence not known
psoriasis / Delayed / Incidence not known
atopic dermatitis / Delayed / Incidence not known
erythema / Early / Incidence not known
hot flashes / Early / Incidence not known
peripheral edema / Delayed / Incidence not known
angina / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
chest pain (unspecified) / Early / Incidence not known
palpitations / Early / Incidence not known
osteoporosis / Delayed / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
nephrolithiasis / Delayed / Incidence not known
urinary retention / Early / Incidence not known
hyperglycemia / Delayed / Incidence not known
diabetes mellitus / Delayed / Incidence not known
hypoglycemia / Early / Incidence not known
nystagmus / Delayed / Incidence not known
blurred vision / Early / Incidence not known
photophobia / Early / Incidence not known
conjunctivitis / Delayed / Incidence not known
cataracts / Delayed / Incidence not known
splenomegaly / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
lymphadenopathy / Delayed / Incidence not known
anemia / Delayed / Incidence not known
hypokalemia / Delayed / Incidence not known
edema / Delayed / Incidence not known
hyperlipidemia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known

sneezing / Early / 82.0-82.0
nausea / Early / 16.0-40.0
headache / Early / 11.0-19.0
insomnia / Early / 9.0-19.0
cough / Delayed / 16.0-16.0
abnormal dreams / Early / 8.0-13.0
throat irritation / Early / 13.0-13.0
vomiting / Early / 1.0-11.0
irritability / Delayed / 0-11.0
libido decrease / Delayed / 1.0-10.0
emotional lability / Early / 1.0-10.0
flatulence / Early / 6.0-9.0
dysgeusia / Early / 5.0-8.0
anxiety / Delayed / 0-8.0
nasal irritation / Early / 8.0-8.0
abdominal pain / Early / 5.0-7.0
fatigue / Early / 4.0-7.0
agitation / Early / 0-7.0
xerostomia / Early / 4.0-6.0
dyspepsia / Early / 5.0-5.0
appetite stimulation / Delayed / 3.0-4.0
drowsiness / Early / 3.0-3.0
rash / Early / 1.0-3.0
anorexia / Delayed / 1.0-2.0
nightmares / Early / 1.0-2.0
lethargy / Early / 1.0-2.0
gastroesophageal reflux / Delayed / 1.0-1.0
pruritus / Rapid / 0-1.0
rhinorrhea / Early / 0-1.0
weight gain / Delayed / Incidence not known
eructation / Early / Incidence not known
diarrhea / Early / Incidence not known
somnambulism / Early / Incidence not known
tremor / Early / Incidence not known
restlessness / Early / Incidence not known
dizziness / Early / Incidence not known
restless legs syndrome (RLS) / Delayed / Incidence not known
parosmia / Delayed / Incidence not known
psychomotor impairment / Early / Incidence not known
paranoia / Early / Incidence not known
acne vulgaris / Delayed / Incidence not known
photosensitivity / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
hyperhidrosis / Delayed / Incidence not known
xerosis / Delayed / Incidence not known
syncope / Early / Incidence not known
muscle cramps / Delayed / Incidence not known
back pain / Delayed / Incidence not known
myalgia / Early / Incidence not known
musculoskeletal pain / Early / Incidence not known
arthralgia / Delayed / Incidence not known
menstrual irregularity / Delayed / Incidence not known
polyuria / Early / Incidence not known
nocturia / Early / Incidence not known
ocular irritation / Rapid / Incidence not known
xerophthalmia / Early / Incidence not known
ocular pain / Early / Incidence not known
vertigo / Early / Incidence not known
tinnitus / Delayed / Incidence not known
epistaxis / Delayed / Incidence not known
leukocytosis / Delayed / Incidence not known
chills / Rapid / Incidence not known
fever / Early / Incidence not known

Chantix, Tyrvaya

Rx

Nicotinic acetylcholine receptor agonist
Oral formulation used to promote smoking cessation; intranasal formulation used for dry eye disease
Monitor closely for emerging or worsening suicidal thoughts/behavior, depression, or other changes in mood or behavior

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.

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 hemodialysis
Varenicline 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.

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 avoid alcohol while taking varenicline as it may affect 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.

Chantix/Varenicline/Varenicline tartrate Oral Tab: 0.5mg, 1mg, 0.5-1mg
Tyrvaya Nasal Spray Met: 0.6mg, 1mL

2 mg per day PO; 0.12 mg (4 sprays) intranasally per day.

2 mg per day PO; 0.12 mg (4 sprays) intranasally per day.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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.[32296]
 
Affected cytochrome P450 isoenzymes and drug transporters: none
Based 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.[32296]

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.[32296]

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.

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.