VARENICLINE- varenicline tartrate tablet, film coated VARENICLINE- varenicline tartrate kit

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

VARENICLINE TARTRATE (UNII: 82269ASB48) (VARENICLINE - UNII:W6HS99O8ZO)

Available from:

Par Pharmaceutical, Inc.

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Varenicline tablets are indicated for use as an aid to smoking cessation treatment. Varenicline tablets are contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to varenicline tablets. Risk Summary Available data have not suggested an increased risk for major birth defects following exposure to varenicline in pregnancy, compared with women who smoke [see Data]. Smoking during pregnancy is associated with maternal, fetal, and neonatal risks (see Clinical Considerations). In animal studies, varenicline did not result in major malformations but caused decreased fetal weights in rabbits when dosed during organogenesis at exposures equivalent to 50 times the exposure at the maximum recommended human dose (MRHD). Additionally, administration of varenicline to pregnant rats during organogenesis through lactation produced developmental toxicity in offspring at maternal exposures equivalent to 36 times human exposure at the MRHD [see Data]. The estimated background risk of oral clefts is increased by approximately 30% in infants of women who smoke during pregnancy, compared to pregnant women who do not smoke. The background risk of other major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk 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 quitting smoking with varenicline during pregnancy reduces these risks. Data Human Data A population-based observational cohort study using the national registers of Denmark and Sweden compared pregnancy and birth outcomes among women exposed to varenicline (N=335, includes 317 first trimester exposed) with women who smoked during pregnancy (N=78,412) and with non-smoking pregnant women (N=806,438). The prevalence of major malformations, the primary outcome, was similar in all groups, including between smoking and non-smoking groups. The prevalence of adverse perinatal outcomes in the varenicline-exposed cohort was not greater than in the cohort of women who smoked, and differed somewhat between the three cohorts. The prevalences of the primary and secondary outcomes are shown in Table 6. Table 6. Summary of Primary and Secondary Outcomes for Three Birth Cohorts   Outcome Varenicline Cohort (n=335) Smoking Cohort (n=78,412) Non-Smoking Cohort (n=806,438) Major congenital malformation* 12 / 334 (3.6%) 3,382 / 78,028 (4.3%) 33,950 /804,020 (4.2%) Stillbirth 1 (0.3%) 384 (0.5%) 2,418 (0.3%) Small for gestational age 42 (12.5%) 13,433 (17.1%) 73,135 (9.1%) Preterm birth 25 (7.5%) 6,173 (7.9%) 46,732 (5.8%) Premature rupture of membranes 12 (3.6%) 4,246 (5.4%) 30,641 (3.8%) Sudden infant death syndrome** 0/307 (0.0%) 51/71,720 (0.1%) 58/755,939 (<0.1%) *Included only live births in the cohorts. Prevalence among first trimester varenicline-exposed pregnancies (11/317 [3.5%]). **There was a lag in death data in Denmark, so the cohorts were smaller. The study limitations include the inability to capture malformations in pregnancies that do not result in a live birth, and possible misclassification of outcome and of exposure to varenicline or to smoking. Other small epidemiological studies of pregnant women exposed to varenicline did not identify an association with major malformations, consistent with the Danish and Swedish observational cohort study. Methodological limitations of these studies include small samples and lack of adequate controls. Overall, available studies cannot definitely establish or exclude any varenicline-associated risk during pregnancy. Animal Data Pregnant rats and rabbits received varenicline succinate during organogenesis at oral doses up to 15 and 30 mg/kg/day, respectively. While no fetal structural abnormalities occurred in either species, maternal toxicity, characterized by reduced body weight gain, and reduced fetal weights occurred in rabbits at the highest dose (exposures 50 times the human exposure at the MRHD of 1 mg twice daily based on AUC). Fetal weight reduction did not occur in rabbits at exposures 23 times the human exposure at the MRHD based on AUC. In a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate from organogenesis through lactation. Maternal toxicity, characterized by a decrease in body weight gain was observed at 15 mg/kg/day (36 times the human exposure at the MRHD based on AUC). However, decreased fertility and increased auditory startle response occurred in offspring at the highest maternal dose of 15 mg/kg/day. Risk Summary There are no data on the presence of varenicline in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies varenicline was present in milk of lactating rats [see Data]. 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; however the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for varenicline and any potential adverse effects on the breastfed child from varenicline or from the underlying maternal condition. Clinical Considerations Because there are no data on the presence of varenicline in human milk and the effects on the breastfed infant, breastfeeding 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 breastfeeding infants. Data In a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate through gestation and lactation Mean serum concentrations of varenicline in the nursing pups were 5-22% of maternal serum concentrations. Varenicline is not recommended for use in pediatric patients 16 years of age or younger because its efficacy in this population was not demonstrated. Single and multiple-dose pharmacokinetics of varenicline have been investigated in pediatric patients aged 12 to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied. Steady-state systemic exposure in adolescent patients of bodyweight >55 kg, as assessed by AUC (0-24), was comparable to that noted for the same doses in the adult population. When 0.5 mg BID was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight ≤ 55 kg compared to that noted in the adult population. The efficacy and safety of varenicline was evaluated in a randomized, double-blind, placebo-controlled study of 312 patients aged 12 to 19 years, who smoked an average of at least 5 cigarettes per day during the 30 days prior to recruitment, had a score of at least 4 on the Fagerstrom Test for Nicotine Dependence scale, and at least one previous failed quit attempt. Patients were stratified by age (12 to 16 years of age, n = 216 and 17 to 19 years of age, n = 96) and by body weight (≤55 kg and >55 kg). Patients were randomized to one of two doses of varenicline, adjusted by weight to provide plasma levels in the efficacious range (based on adult studies) and placebo. Patients received treatment for 12 weeks, followed by a non-treatment period of 40 weeks, along with age-appropriate counseling throughout the study. Results from this study showed that varenicline, at either dose studied, did not improve continuous abstinence rates at weeks 9 through 12 of treatment compared with placebo in subjects 12 to 19 years of age. The varenicline safety profile in this study was consistent with that observed in adult studies. A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65 to 75 years) for 7 consecutive days was similar to that of younger subjects. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Varenicline is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.2)]. No dosage adjustment is recommended for elderly patients. Varenicline is substantially eliminated by renal glomerular filtration along with active tubular secretion. Dose reduction is not required in patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), and for patients with end-stage renal disease undergoing hemodialysis, dosage adjustment is needed [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. Varenicline is not a controlled substance. Humans Fewer than 1 out of 1,000 patients reported euphoria in clinical trials with varenicline. At higher doses (greater than 2 mg), varenicline produced more frequent reports of gastrointestinal disturbances such as nausea and vomiting. There is no evidence of dose-escalation to maintain therapeutic effects in clinical studies, which suggests that tolerance does not develop. Abrupt discontinuation of varenicline was associated with an increase in irritability and sleep disturbances in up to 3% of patients. This suggests that, in some patients, varenicline may produce mild physical dependence which is not associated with addiction. In a human laboratory abuse liability study, a single oral dose of 1 mg varenicline did not produce any significant positive or negative subjective responses in smokers. In non-smokers, 1 mg varenicline produced an increase in some positive subjective effects, but this was accompanied by an increase in negative adverse effects, especially nausea. A single oral dose of 3 mg varenicline uniformly produced unpleasant subjective responses in both smokers and non-smokers. Animals Studies in rodents have shown that varenicline produces behavioral responses similar to those produced by nicotine. In rats trained to discriminate nicotine from saline, varenicline produced full generalization to the nicotine cue. In self-administration studies, the degree to which varenicline substitutes for nicotine is dependent upon the requirement of the task. Rats trained to self-administer nicotine under easy conditions continued to self-administer varenicline to a degree comparable to that of nicotine; however in a more demanding task, rats self-administered varenicline to a lesser extent than nicotine. Varenicline pretreatment also reduced nicotine self-administration.

Product summary:

Varenicline tablets are supplied for oral administration in two strengths: a 0.5 mg circular, biconvex, white to off-white film-coated tablets, debossed with “P” on one side and “155” on other side and a 1 mg circular, biconvex, light blue film-coated tablets, debossed with “P” on one side and “156” on other side. Varenicline tablets are supplied in the following package configurations: Description NDC Packs Starting 4-week card: 0.5 mg x 11 tablets and 1 mg x 42 tablets NDC 49884-944-99 Starting Month Box: 0.5 mg x 11 tablets and 1 mg x 42 tablets NDC 49884-944-99 Continuing 4-week card: 1 mg x 56 tablets NDC 49884-156-52 Continuing Month Box: 1 mg x 56 tablets NDC 49884-156-52 Bottles 0.5 mg - bottle of 56 NDC 49884-155-76 1 mg - bottle of 56 NDC 49884-156-76 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Authorization status:

Abbreviated New Drug Application

Patient Information leaflet

VARENICLINE- VARENICLINE TARTRATE TABLET, FILM COATED
VARENICLINE- VARENICLINE TARTRATE
Par Pharmaceutical, Inc.
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MEDICATION GUIDE
Varenicline Tablets
(var EN i kleen)
What is the most important information I should know about varenicline
tablets?
When you try to quit smoking, with or without varenicline tablets, you
may have symptoms that may be
due to nicotine withdrawal, including:
•
urge to smoke
•
depressed mood
•
trouble sleeping
•
irritability
•
frustration
•
anger
•
feeling anxious
•
difficulty concentrating
•
restlessness
•
decreased heart rate
•
increased appetite
•
weight gain
Some people have even experienced suicidal thoughts when trying to
quit smoking without medication.
Sometimes quitting smoking can lead to worsening of mental health
problems that you already have, such
as depression.
Some people have had serious side effects while taking varenicline
tablets to help them quit smoking,
including:
New or worse mental health problems, such as changes in behavior or
thinking, aggression, hostility,
agitation, depressed mood, or suicidal thoughts or actions. Some
people had these symptoms when they
began taking varenicline tablets, and others developed them after
several weeks of treatment, or after
stopping varenicline tablets. These symptoms happened more often in
people who had a history of mental
health problems before taking varenicline tablets, than in people
without a history of mental health
problems.
Stop taking varenicline tablets and call your healthcare provider
right away if you, your family, or
caregiver notice any of these symptoms. Work with your healthcare
provider to decide whether you
should continue to take varenicline tablets. In many people, these
symptoms went away after stopping
varenicline tablets, but in some people symptoms continued after
stopping varenicline tablets. It is
important for you to follow-up with your healthcare provider until
your symptoms go away.
Before taking varenicline tablets, tell your healthcare provider if
you have ev

Summary of Product characteristics

VARENICLINE- VARENICLINE TARTRATE TABLET, FILM COATED
VARENICLINE- VARENICLINE TARTRATE
PAR PHARMACEUTICAL, INC.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
VARENICLINE
TABLETS SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
VARENICLINE TABLETS.
VARENICLINE TABLETS, FOR ORAL USE
INITIAL U.S. APPROVAL: 2006
INDICATIONS AND USAGE
Varenicline is a nicotinic receptor partial agonist indicated for use
as an aid to smoking cessation
treatment. (1 and 2.1)
DOSAGE AND ADMINISTRATION
Begin varenicline tablets dosing one week before the date set by the
patient to stop smoking.
Alternatively, the patient can begin varenicline tablets dosing and
then quit smoking between days 8
and 35 of treatment. (2.1)
Starting Week: 0.5 mg once daily on days 1 to 3 and 0.5 mg twice daily
on days 4 to 7. (2.1)
Continuing Weeks: 1 mg twice daily for a total of 12 weeks. (2.1)
An additional 12 weeks of treatment is recommended for successful
quitters to increase likelihood of
long-term abstinence. (2.1)
Consider a gradual approach to quitting smoking with varenicline
tablets for patients who are sure that
they are not able or willing to quit abruptly. Patients should begin
varenicline tablets dosing and reduce
smoking by 50% from baseline within the first four weeks, by an
additional 50% in the next four weeks,
and continue reducing with the goal of reaching complete abstinence by
12 weeks. Continue treatment
for an additional 12 weeks, for a total of 24 weeks. (2.1)
Severe Renal Impairment (estimated creatinine clearance less than 30
mL/min): Begin with 0.5 mg
once daily and titrate to 0.5 mg twice daily. For patients with
end-stage renal disease undergoing
hemodialysis, a maximum of 0.5 mg daily may be given if tolerated.
(2.2)
Consider dose reduction for patients who cannot tolerate adverse
effects. (2.1)
Another attempt at treatment is recommended for those who fail to stop
smoking or relapse when
factors contributing to the failed attempt have been addre