Varenicline

Mechanism of Action

Nicotine works through the dopamine receptor to cause drug reinforcement. The components of the midbrain that play a pivotal role in drug reinforcement, motility, and associative motor learning include the ventral tegmental area and substantia nigra pars compacta.[4] Increasing dopamine release from ventral tegmental area neurons onto their targets in the nucleus accumbens contributes to addiction. Nicotine acts on dopaminergic receptors in the ventral tegmental area, causing a burst firing of dopamine neurons leading to drug reinforcement.

According to product labeling, varenicline binds with high affinity at α4β2 nicotinic acetylcholine receptors. Therefore, the efficacy of varenicline in smoking cessation is presumed to be the result of varenicline’s activity at the α4β2 sub-type of the nicotinic receptors, where its binding produces partial agonist activity while preventing the binding of nicotine to these receptors. Varenicline binds to α4β2 nicotinic acetylcholine receptors and stimulates receptors at a lower level than nicotine. Varenicline precludes the ability of nicotine to activate α4β2 receptors and stimulate the CNS mesolimbic dopaminergic system, considered to be the neuronal mechanism underlying reinforcement and reward experienced upon addiction. Varenicline is highly selective, and it binds more potently to α4β2 receptors than other common nicotinic receptors. It decreases the craving and withdrawal syndrome that occurs with cessation attempts. Varenicline substantially lowers the stimulation of the mesolimbic dopamine system associated with nicotine addiction due to its partial agonism.[5]

Pharmacokinetics

Absorption: Maximum plasma concentrations of varenicline typically occur within 3-4 hours after oral administration. Varenicline exhibits linear pharmacokinetics over the recommended dosing range after single or repeated doses. 

Distribution: Plasma protein binding of varenicline (less than 20%) is independent of age and renal function of the person.

Metabolism: Varenicline has minimal metabolism, with 92% of the drug excreted unchanged in the urine. The elimination half-life (t1/2) of varenicline is around 24 hours.

Excretion:  varenicline is primarily eliminated via the kidney through glomerular filtration along with active tubular secretion, possibly through the organic cation transporter, OCT2.

Administration

Varenicline is prescribed only to patients 18 years or older. Varenicline is taken as a tablet and comes in 0.5 mg and 1 mg strength oral tablets. After eating, patients should take the medication with a full glass of water to decrease gastric upset.

• Starting Week: Varenicline is to be taken 0.5 mg orally once daily on days 1 to 3 and is increased to 0.5 mg twice daily on days 4 through 7. It should start one week before the target quit date.
• Continuing Weeks: 1 mg twice daily after day 8 for 11 weeks.
• Additional Therapy: Treatment duration can be up to 6 months and even longer in certain patients. Further trials are needed to determine efficacy and outcomes in those using varenicline beyond 12 months.
• Usually, start administering varenicline one week prior to the date set by the patient to quit smoking. Alternatively, the person can start varenicline administration and stop smoking between days 8 to 35 of therapy.

Special Population

Renal Impairment: In patients with renal impairment (CrCL less than 30), a maximum dose of 0.5 mg twice daily is recommended. In end-stage renal disease (ESRD) patients on hemodialysis, a maximum dose of 0.5 mg once daily is recommended.[5]

Hepatic Impairment: According to the product labeling, varenicline pharmacokinetics should be unaffected in patients with hepatic impairment due to the lack of significant hepatic metabolism.

Pregnancy Considerations: Smoking during pregnancy can cause an increased risk of orofacial clefts, premature rupture of membranes, placenta previa, placental abruption, fetal growth restriction, low birth weight, stillbirth, preterm delivery, shortened gestation, reduction of lung function in infants, neonatal death, and sudden infant death syndrome. Clinicians should screen all pregnant patients for nicotine use, and smoking cessation is recommended. The benefit of tobacco smoking cessation for pregnant patients is well established. Hence, behavioral interventions are effective and recommended. However, knowledge related to pharmacotherapy interventions in pregnancy is limited and insufficient to make specific recommendations.[6] A recent study showed that varenicline was almost three times more effective than nicotine patches in helping pregnant women to quit smoking.[7]

Breastfeeding Considerations: Varenicline is a partial nicotine agonist used to assist smoking cessation. However,  based on animal data on nicotine, varenicline may interfere with infant lung development; hence use is not recommended in nursing mothers. As no facts are available on using varenicline during breastfeeding, other smoking cessation modalities may be preferred. If a mother chooses to breastfeed while using varenicline, clinicians should monitor her infant for seizures and excessive vomiting.[4]

Adverse Effects

• The most common adverse effects experienced with varenicline are nausea, insomnia, abnormal vivid dreams, and headaches. The adverse effect of nausea can be mitigated by starting at lower doses and up-titrating the dose as tolerated. Patients also complain of disturbed sleep, sleepwalking, agitation, drowsiness, and constipation.[5] 
• Varenicline has also been implicated in specific skin syndromes such as Stevens-Johnson syndrome, erythema multiforme,  and photosensitivity. 
• Renal function also must be monitored as varenicline can cause renal failure and kidney stones.
• Varenicline may also increase the risk of pancreatitis, and patients taking varenicline should be monitored for abdominal symptoms of pancreatitis.[8]

Contraindications

• There is an FDA-mandated warning for severe psychiatric symptoms, including suicidal ideation, as there are reports of such adverse outcomes with varenicline. Patients taking varenicline should have closer therapeutic supervision to monitor these behavioral symptoms. It is not a contraindication to use varenicline in patients with underlying psychiatric illnesses; however, clinicians should monitor symptoms for further deterioration. Patients exhibiting worsening psychiatric behaviors or suicidal ideation should promptly stop varenicline therapy.[8]
• Serious hypersensitivity reactions or skin reactions to varenicline may occur, and patients exhibiting Stevens-Johnson syndrome or erythema multiforme should be advised not to take varenicline.
• Take caution and monitor closely if the patient has a history of renal impairment, psychiatric disorder, or seizure disorder.

Monitoring

• Varenicline excretion is via the renal route, and thus it is crucial to monitor renal function. Before initiating a patient on varenicline, the clinician should obtain a baseline creatinine.[9] 
• Patients on varenicline require close monitoring for signs or symptoms of depression, agitation, behavior changes, skin reactions, or suicidal ideation.
• Smoking during pregnancy is widespread and poses a significant public health issue. Varenicline and other newer pharmacologic agents have not been studied well and generally are not used to promote cessation during pregnancy. Because varenicline is a relatively new drug on the market, few studies have shown strong evidence for either major positive or negative outcomes associated with the gestational use of varenicline. Currently, controlled studies have shown no evidence of an increased risk of spontaneous abortion, major congenital malformation, or intrauterine death. Due to limited efficacy and pregnancy safety data, varenicline is not a standard recommendation as a smoking cessation aid for pregnant women. Further studies are necessary for this topic. If a patient has been exposed to varenicline inadvertently during the first trimester, the recommendation is to perform a detailed fetal anomaly scan.[10]

Toxicity

There are currently no antidotes to varenicline. If there are serious adverse effects, including psychiatric conditions or skin hypersensitivity reaction, discontinue varenicline immediately. Varenicline therapy may stop abruptly with no side effects, and there is no need for a taper. Evaluation of prolonged exposure to varenicline in adults has not revealed any alteration of hematological, biochemical, and anatomicopathological parameters. Varenicline is removed by dialysis in patients with end-stage renal disease; however, there is no experience in dialysis following an overdose.[10]

Enhancing Healthcare Team Outcomes

Therapy with varenicline requires an interprofessional healthcare team approach to optimize the chance of success and minimize the adverse effect profile. This interprofessional team includes clinicians, nurses, and pharmacists, all collaborating their efforts and exercising open communication so that every team member operates from the same information. Since smoking cessation will improve almost all aspects of health, the team needs to create an environment for the greatest patient success.

Smoking remains a significant public health problem, and despite decades of research, there is no definitive solution to help people quit this social habit. Many drugs are on the market to help people quit smoking, but none works consistently, and relapse rates are high. Because smokers can present with various medical disorders, the onus is on healthcare workers to educate them on the dangers of smoking. Varenicline is a relatively new drug on the market, and data indicates that it can help people quit smoking in the short term; however, the patient also has to be provided with psychosocial support at the same time.[11][12]