PRINCIPIOS DE FARMACOLOGIA

Nicotine Nicorette®, Habitrol®, Nicoderm®, Nicotrol®, Prostep® [ Indications/Dosage ] [ Administration ] [ Contraindications ] [ Interactions ] [ Adverse Reactions ] [ Patient Education ] [ Costs ] [ Product Info ] [ Classification ] [ Manufacturer Links ] [ Chemical Structures] Description: Nicotine is a naturally occurring alkaloid, long used by pharmacologists to investigate the autonomic nervous system. It is now used clinically as a drug to help smokers quit smoking. Nicotine by itself is not considered a health threat. The benefit of nicotine patches in helping smokers quit smoking has been demonstrated in a meta-analysis of 17 double-blind, placebo-controlled studies.[270] Commercially, nicotine is complexed with polacrilin, a cationic resin, and is marketed as a chewing gum, and also as a transdermal patch. Nicotine chewing gum was approved by the FDA in January 1984, and transdermal patches were approved in November 1991. The patent for Nicorette® gum expired in 1994. The FDA approved nonprescription sale of the gum and the patches in February 1996 and July 1996, respectively. The first inhaled dosage form of nicotine, Nicotrol NS®, designed to be used as a nasal inhaler, was launched in September 1996. On May 5, 1997, the FDA approved a prescription-only oral inhalation system (Nicotrol® Inhaler) for nicotine replacement therapy. Nicotine transdermal systems (NTS) may be combined with the use of bupropion (Zyban®) for treating the symptoms of smoking cessation, and the combined therapy received FDA approval in 1999. A less potent analog of nicotine, lobeline sulfate, is currently undergoing investigation (see Investigational section). Mechanism of Action: Nicotine's pharmacological actions are complex and include effects on both the central and peripheral nervous systems. Nicotine is classified as a stimulant of autonomic ganglia, although it possesses both stimulant and depressant actions. The end result of stimulation at what are now referred to as nicotinic receptors is a variety of cholinergic and adrenergic effects. These include: tachycardia or bradycardia mediated by either stimulation or interference with sympathetic or parasympathetic pathways, stimulation of receptors in the carotic and aortic bodies, release of epinephrine from the adrenal medulla, and stimulation of the chemoreceptor-trigger zone. At the neuromuscular junction, nicotine is an agonist, but paralysis ensues due to receptor desensitization. The effects on the GI tract are secondary to parasympathetic stimulation. Pharmacokinetics: Nicotine is delivered as a chewing gum or as a transdermal patch. Nicotine is readily absorbed through the buccal mucosa when the gum is chewed, although the absorption is slower than that from cigarette smoke. The rate and extent of absorption during 20—30 minutes of rhythmic chewing vary from 50—90% of the content of the gum. The amount absorbed depends on the time the saliva is held in the mouth as opposed to being swallowed or expectorated. Very little nicotine is absorbed from the GI tract due to extensive first-pass metabolism through the liver. While regular use of the gum provides steady-state blood levels of nicotine similar to those achieved by smokers, neither the gum nor the patch can provide peak levels as rapidly as occur after inhaling tobacco smoke. Nicotine levels reach the brain within 7 seconds after a single puff on a cigarette, but peak concentrations can require as long as 4 hours after application of a patch. Chewing gum produces peak plasma concentrations within 15—20 minutes. Peak plasma concentrations from the various transdermal preparations are as follows: Habitrol: 5—6 hours; Nicoderm: 4 hours; and ProStep: 9 hours after application. Nicotine is widely distributed in the body tissues, particularly the CNS. It crosses the placenta and is secreted in milk. The concentrations of nicotine in amniotic fluid and fetal serum exceed those in maternal serum. Detectable amounts also appear in the serum and urine of infants of smoking, nursing mothers. Plasma concentrations of nicotine decline in a biphasic manner. The initial half-life is 2—3 minutes and the terminal half-life is 30—120 minutes, with considerable variation among individuals. Three brands of patches (e.g., Habitrol, Nicoderm, ProStep) are designed to be worn for 24 hours and then removed. The Nicotrol brand is to be applied upon waking and removed at bedtime. Most of the drug is metabolized in the liver by oxidation to cotinine and nicotine-1'-oxide. Cotinine has a plasma half-life of about 10—40 hours. Nicotine and its metabolites are excreted by the kidneys; about 10—20% of nicotine is eliminated unchanged in the urine.

ndications...Dosage For use as an aid in the treatment of nicotine withdrawal following cessation of smoking: •for use as a single agent for smoking cessation: Oral dosage (chewing gum): Adults: Chew 1 piece of gum (equivalent to 2 mg of nicotine) whenever the urge to smoke occurs. The appropriate daily dose will vary between patients, however, most patients need 20 mg/day during the first month. The maximum adult dose is 60 mg/day. In a study of 90 highly-motivated smokers, the 2 mg strength was found no better than placebo. Only the 4 mg strength produced statistically significantly higher abstinence rates over a period of 6 weeks.[1066] Continuous use for longer than 3 months is not recommended. If gum consumption is not spontaneously reduced within 6 months, a gradual withdrawal should be initiated. Children: safety and efficacy have not been established. Transdermal dosage (Habitrol® patch): Adults weighing more than 100 pounds, smoking at least 10 cigarettes/day and/or without cardiovascular disease: Initially, one 21 mg patch on intact skin once daily for 4—8 weeks. This brand of patch should be worn for 24 hours and then removed. Patients who have abstained from smoking should be reduced to one 14 mg patch/day for the next 2—4 weeks and then one 7 mg patch/day for 2—4 weeks. Adults weighing less than 100 pounds, smoking less than 10 cigarettes/day and/or with cardiovascular disease: Initially, one 14 mg patch on intact skin once daily for 4—8 weeks. This brand of patch should be worn for 24 hours and then removed. Patients who have abstained from smoking should be reduced to one 7 mg patch/day for 2—4 weeks. Transdermal dosage (Nicoderm CQ® patch): Adults weighing more than 100 pounds, smoking at least 10 cigarettes/day and/or without cardiovascular disease: Initially, one 21 mg patch on intact skin once daily for 6 weeks. This brand of patch should be worn for 24 hours and then removed. Patients who have abstained from smoking should be reduced to one 14 mg patch/day for the next 2 weeks and then one 7 mg patch/day for 2 weeks. Adults weighing less than 100 pounds, smoking less than 10 cigarettes/day and/or with cardiovascular disease: Initially, one 14 mg patch on intact skin once daily for 6 weeks. This brand of patch should be worn for 24 hours and then removed. Patients who have abstained from smoking should be reduced to one 7 mg patch/day for 2—4 weeks. Transdermal dosage (Nicotrol® patch): Adults weighing more than 100 pounds, smoking at least 10 cigarettes/day and/or without cardiovascular disease: Initially, one 15 mg patch on intact skin for 16 hrs/day (i.e., apply upon waking and remove at bedtime) for 4—12 weeks. Patients who have abstained from smoking should be reduced to one 10 mg patch for 16 hrs/day for the next 2—4 weeks and then one 5 mg patch for 16 hrs/day for 2—4 weeks. Transdermal dosage (ProStep® patch): Adults weighing more than 100 pounds, smoking at least 10 cigarettes/day and/or without cardiovascular disease: Initially, one 22 mg patch on intact skin once daily for 4—8 weeks. This brand of patch should be worn for 24 hours and then removed. Patients who have abstained from smoking should be reduced to one 11 mg patch/day for the next 2—4 weeks. Adults weighing less than 100 pounds, smoking less than 10 cigarettes/day and/or with cardiovascular disease: One 11 mg patch on intact skin once daily for 4—8 weeks. This brand of patch should be worn for 24 hours and then removed. Children: Safety and efficacy have not been established. Nasal inhalation dosage: Adults: The recommended dosage is one spray (= 0.5 mg nicotine/spray) into each nostril 1—2 times each hour as needed whenever the patient feels the need to smoke. Two sprays (one into each nostril) is considered one dose. The maximum recommended usage is 5 doses (total of 10 sprays)/hour or 40 doses (total of 80 sprays)/day. Patients should be encouraged to use at least 8 doses (16 sprays)/day, the minimum effective dose. The recommended duration of treatment is 3 months. Treatment for longer periods has not been shown to improve outcome. The safety of use for periods longer than 6 months has not been established. Oral inhalation dosage: Adults > 18 years of age: The recommended initial dose is 24 to 64 mg (6 to 16 cartridges) per day for up to 12 weeks followed by a gradual reduction in dosage over a period of up to 12 weeks. Use for more than 6 months is not recommended. •for use as an aid in the treatment of nicotine withdrawal following cessation of smoking in combination with Zyban® (see Bupropion monograph): Transdermal dosage (Habitrol® patch): Adults >= 18 years of age: According to the manufacturer of Habitrol®, the combination of Habitrol® (starting dose of 21 mg/day of nicotine topically) with Zyban® (300 mg/day of bupropion PO) was associated with significantly higher 4-week abstinence rates than Habitrol® alone. However, quit rates for the combination were not significantly higher. (Habitrol® package insert) For the treatment of Tourette's syndrome† as an adjunct to haloperidol: Transdermal dosage (Nicoderm® patch): Children: Sixteen children between the ages of 9 and 15 years with Tourette's syndrome were given a single nicotine patch (Nicoderm®) that delivered 7 mg nicotine/24 hrs. The patch was applied to the deltoid area and was to be worn for 24 hours. Patients were seen within 24 hours and then at variable times thereafter. Fifteen of the 16 patients received a second patch. Although patches were removed after 24 hours, and greater than 24 hours elapsed between the two doses, no patient received more than 2 patches. The mean Yale Global Tic Severity Scale was significantly reduced (36%) from the mean baseline score with 6 patients having between 50% and 80% improvement. Other medications such as haloperidol and pimozide were continued concomitantly while nicotine patches were applied.[1368] For ulcerative colitis†: •For the treatment of active ulcerative colitis†: Transdermal dosage: Adults: Several randomized, double-blind studies have been conducted of treating active disease with transdermal application of nicotine. In one study published in 1994, 35 patients received nicotine patches and 37 received placebo. Nicotine patches that released 5 or 15 mg of nicotine over a period of 16 hours were administered daily at bedtime. If no clinical benefit was seen after 2 weeks, the dose was increased to 25 mg/day. The total duration of the study was 6 weeks. No patient reported smoking during the trial. Patients receiving nicotine patches had significant improvements in both symptoms and histology. Side effects were higher in the nicotine group. After the trial, no patient reported a craving for smoking.[743] This study was critized because no endoscopic evaluation was conducted. In another study published in 1997, 31 patients received nicotine patches and 33 received placebo. The duration of this study was 4 weeks. Treatment with nicotine patches (11 mg/day for the first 7 days, then 22 mg/day for the following 21 days) was associated with a rate of clinical improvement that was significantly higher than the rate associated with placebo. In this study, sigmoidoscopy scores improved but histologic disease activity did not. Five of 31 patients could not tolerate the 22 mg patch due to nondermatologic reactions.[1428] •For secondary prophylaxis of ulcerative colitis (i.e., ulcerative colitis prophylaxis†): Transdermal dosage: Adults: A randomized trial of transdermal nicotine 15 mg/day did not find a significant benefit of nicotine compared to placebo for maintaining remission in patients with ulcerative colitis.[1015] Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. †non-FDA-approved indication

Administration Oral Administration •Instruct patient to chew gum slowly until a tingling sensation in the mouth occurs, then stop chewing until the sensation subsides. Repeat this process for about 30 minutes. DO NOT SWALLOW THE GUM. Transdermal System Administration Transdermal Patches: •Determine if patch is to be worn for 16 or 24 hours. Habitrol, Nicoderm, and ProStep are designed to be worn for 24 hours and then removed. The Nicotrol brand is to be applied upon waking and removed at bedtime. •Apply to any hairless site. Avoid applying to areas with cuts, callouses, scars, oil, burns, or irritation. Use firm pressure over patch for 10 seconds to ensure contact with skin, especially around the edges. If patch becomes loose or falls off, replace with another one. Do not cut or trim patch. Patches should not be affected by showering or bathing. •Wash hands with plain water after applying the patch; soaps can increase absorption. Nasal Inhalation Administration •Instruct patients on proper use of the inhaler. Patients should be instructed to stop smoking completely while using this product. •Each actuation delivers 0.5 mg of nicotine. One dose represents 1 spray in each nostril (total dose = 2 sprays).

Contraindications For any smoker, with or without concomitant disease, the risk of nicotine replacement therapy in a smoking cessation program should be weighed against the hazard of continued smoking, and the likelihood of achieving cessation of smoking without nicotine replacement. Since nicotine blood levels from patches can be additive to nicotine from tobacco smoking, patients should be warned against smoking while wearing the patches. The use of patches in a subject with preexisting cardiovascular disease does not appear to pose a greater risk than smoking itself, as long as the subject refrains from smoking while wearing the patch. Cardiovascular effects of nicotine typically include peripheral vasoconstriction, tachycardia, and blood pressure elevation. The risks of nicotine replacement therapy in patients with certain cardiovascular and peripheral vascular diseases should be weighed against the benefits of including nicotine replacement in a smoking cessation program. Transdermal nicotine has been used safely as an aid to smoking cessation in patients with cardiac disease; however, those with a recent history (within the past 2 weeks) of unstable angina, myocardial infarction, CABG surgery, or cardiac arrhythmia were excluded.[1326] In general, nicotine replacement therapy should not be used in patients with serious cardiac arrhythmias, during the immediate post-myocardial infarction period, or in patients with severe or worsening angina pectoris. Nicotine therapy should be used with caution in patients with hypertension, hyperthyroidism, pheochromocytoma, insulin-dependent diabetes mellitus, or vasospastic diseases (e.g., Buerger's disease, Prinzmetal's angina) because increases in blood pressure, heart rate, and plasma glucose can follow the effects of nicotine-induced catecholamine release. In a comparative trial, the combination of nicotine (Habitrol®) and bupropion (Zyban®) for smoking cessation had a higher incidence of treatment-emergent hypertension compared to either agent alone or to placebo. Most patients in the trial had evidence of preexisting hypertension. Monitoring for treatment-emergent hypertension is recommended in patients receiving the combination of nicotine and bupropion as well as for those receiving nicotine alone. Spontaneous abortion has been reported in pregnant women during nicotine replacement therapy. Although a causal relationship has not been established, nicotine may have been a contributing factor. The specific effects of nicotine replacement therapy on fetal development are unknown. However, the harmful effects of cigarette smoking on maternal and fetal health are clearly established. Effects include low birth weight, an increased risk of spontaneous abortion, and increased perinatal mortality. Pregnant smokers should be encouraged to stop smoking through educational and behavioral interventions before using pharmacological agents. Nicotine replacement theray should be used during pregnancy only if the likelihood of smoking cessation justifies the potential risk of nicotine replacement by the patient, who may continue to smoke. Nicotine is classified as FDA pregnancy category D for the transdermal systems and category X for the gum. Nicotine replacement therapy should be used with caution in women who are breast-feeding. Nicotine is distributed into breast milk. However, proper use of nicotine gum or transdermal or intranasal nicotine would be expected to produce lower concentrations of nicotine in milk than would cigarette smoking. Although some clearance of orally absorbed nicotine in infants will occur through first-pass metabolism in the liver, the efficiency of nicotine removal is probably lowest at birth. The safety of nicotine replacement therapy in nursing infants has not been examined. The decision of whether to use nicotine replacement therapy in a woman who is breast-feeding should be evaluated in comparison to the risks associated with exposure of the infant to nicotine and other tobacco contaminants in the breast milk as well as those of passive exposure to tobacco smoke. Nicotine may delay healing in peptic ulcer disease. Therefore, nicotine should be used with caution in patients with active peptic ulcers. Nicotine replacement in a smoking cessation program should only be used when the benefits outweigh the potential risks. The effectiveness of nicotine replacement therapy in children who smoke has not been evaluated. The amount of nicotine tolerated by adult smokers could produce toxic symptoms in children. Thus, nicotine gum or transdermal or intranasal nicotine should not be used in children. Nicotine chewing gum is relatively contraindicated in patients with dental disease and in patients with temporomandibular joint (TMJ) disorder because injury to teeth or aggravation of TMJ can result from chewing. Nicotine chewing gum is relatively contraindicated in patients with a history of esophagitis or mouth or throat inflammation because these conditions can be exacerbated. Nicotine transdermal systems may be irritating for patients with some types of skin disease such as atopic or eczematous dermatitis.

Interactions Smoking cessation and therapy with a nicotine preparation can increase the effect of insulin. Insulin dose reduction may be necessary if an insulin-dependent patient suddenly stops smoking. Smoking cessation can increase the therapeutic effects of propoxyphene, propranolol (and possibly other beta-adrenergic blockers), theophylline, warfarin, and other drugs that are metabolized by the hepatic P-450 enzyme system. Substances in tobacco smoke can induce these hepatic enzymes. Smoking cessation may allow for a correction in the activity of these enzymes, necessitating a dose reduction of drugs metabolized via this pathway. Nicotine transdermal systems (NTS) have been used concurrently with bupropion for smoking cessation therapy. However, when used together, the combination may induce clinically significant blood pressure elevations in some patients. Close monitoring of blood pressure is recommended if this combination is prescribed.

Adverse Reactions Concern has been expressed regarding the potential cardiovascular toxicity of nicotine patches in subjects with cardiovascular disease. To assess this, Joseph et al. evaluated VA subjects, 45 years or older, with documented cardiac disease and found that, while study end points including both serious and minor events were slightly more frequent in the group receiving and using nicotine patches compared to the placebo group, this difference was not statistically significant.[1326] Since nicotine patches generally produce lower nicotine blood concentrations than tobacco smoking and since the nicotine dose-response curve from patches is much flatter than for smoking, it should not be expected that use of nicotine patches would pose a greater cardiovascular risk than smoking itself. Pharmacologically, the effects of nicotine on the cardiovascular system mimick those of sympathetic stimulation; agonism of nicotinic receptors on adrenal medullary cells causes the release of epinephrine and norepinephrine. Nicotine raises systolic and diastolic blood pressure and can increase the inotropic and chronotropic actions of the heart. The degree to which these reactions occur is a function of the nicotine blood concentration. Hypertension has been reported with nicotine patches. New onset or worsening of existing hypertension occurs in a higher percentage of patients (i.e., 6.1%) taking bupropion concurrently with nicotine trandermal systems (NTS) for smoking cessation. However, the product literature for nicotine patches does not describe other cardiovascular reactions such as atrial fibrillation, ventricular tachycardia, premature ventricular contractions (PVCs), myocardial ischemia, or myocardial infarction as adverse reactions. The absence of these findings is consistent with the kinetics of nicotine patches and the Joseph study. Since nicotine blood levels from patches can be additive to nicotine from tobacco smoking, patients should be warned against smoking while wearing the patches. The use of patches in a subject with preexisting cardiovascular disease does not appear to pose a greater risk than smoking itself, as long as the subject refrains from smoking while wearing the patch. Nicotine patches may cause localized erythema, pruritus, rash, or urticaria. Symptoms of nicotine overdose include nausea/vomiting, severe abdominal pain, diarrhea, severe headache, and/or severe weakness. More severe symptoms of overdose include fainting or syncope, hypotension, weak pulse, and seizures. Minor side effects that occur during use of nicotine products include mild headache, appetite stimulation, constipation, diarrhea, dizziness, dysmenorrhea, flushing, insomnia, and irritability. Other reported side effects include hiccups, jaw ache, and sore throat. Nicotine chewing gum is stickier and heavier than regular gum and can affect artificial teeth or other dental work.

270. Fiore MC et al. The effectiveness of the nicotine patch for smoking cessation: a meta-analysis. JAMA 1994;271:1940—7.

1066. Sachs DPL. Effectiveness of the 4-mg dose of nicotine polacrilex for the initial treatment of high-dependent smokers. Arch Intern Med 1995;155:1973—80.

1368. Silver AA, Shytle RD, Philipp MK et al. Case study: long-term potentiation of neuroleptics with transdermal nicotine in Tourette's syndrome. J Am Acad Child Adolesc Psych 1996;35:1631—6.

743. Pullan RD, Rhodes J, Ganesh S et al. Transdermal nicotine for active ulcerative colitis. N Engl J Med 1994;330:811—5.

1428. Sandborn WJ, Tremaine WJ, Offord KP et al. Transdermal nicotine for mildly to moderately active ulcerative colitis. Ann Intern Med 1997;126:364—71.

1015. Thomas GAO, Rhodes J, Mani V et al. Transdermal nicotine as maintenance therapy for ulcerative colitis. N Engl J Med 1995;332:988—92.

1326. Joseph AM, Norman SM, Ferry LH et al. The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med 1996;335:1792—8.