Nicotrol

INDICATIONS AND USAGE NICOTROL NS is indicated as an aid to smoking cessation for the relief of nicotine withdrawal symptoms. NICOTROL NS therapy should be used as a part of a comprehensive behavioral smoking cessation program. The safety and efficacy of the continued use of NICOTROL NS for periods longer than 6 months have not been adequately studied and such use is not recommended.

DOSAGE AND ADMINISTRATION It is important that patients understand the instructions for use of NICOTROL NS, and have their questions answered. They should clearly understand the directions for using NICOTROL NS and safely disposing of the used container. They should be instructed to stop smoking completely when they begin using the product. Patients should be instructed not to sniff, swallow or inhale through the nose as the spray is being administered. They should also be advised to administer the spray with the head tilted back slightly. The dose of NICOTROL NS, should be individualized on the basis of each patient's nicotine dependence and the occurrence of symptoms of nicotine excess (See Individualization of Dosage ). Each actuation of NICOTROL NS delivers a metered 50 microliter spray containing 0.5 mg of nicotine. One dose is 1 mg of nicotine (2 sprays, one in each nostril). Patients should be started with 1 or 2 doses per hour, which may be increased up to a maximum recommended dose of 40 mg (80 sprays, somewhat less than 1/2 bottle) per day. For best results, patients should be encouraged to use at least the recommended minimum of 8 doses per day, as less is unlikely to be effective. In clinical trials, the patients who successfully quit smoking used the product heavily when nicotine withdrawal was at its peak, sometimes up to the recommended maximum of 40 doses per day ( in heavier smokers). Dosing recommendations are summarized in Table 4. Table 4: Maximum Recommended Duration of Treatment Recommended Doses per Hour Maximum Doses per Hour Maximum Doses per Day 3 months 1–2 One dose=2 sprays (one in each nostril). One dose delivers 1 mg of nicotine to the nasal mucosa. 5 40 No tapering strategy has been shown to be optimal in clinical studies. Many patients simply stopped using the spray at their last clinic visit. Recommended strategies for discontinuation of use include suggesting that patients: use only 1/2 a dose (1 spray) at a time, use the spray less frequently, keep a tally of daily usage, try to meet a steadily reducing usage target, skip a dose by not medicating every hour, or set a planned "quit date" for stopping use of the spray. Individualization of Dosage The success or failure of smoking cessation is influenced by the quality, intensity and frequency of supportive care. Patients are more likely to quit smoking if they are seen frequently and participate in formal smoking cessation programs. The goal of NICOTROL NS therapy is complete abstinence. If a patient is unable to stop smoking by the fourth week of therapy, treatment should probably be discontinued. Patients who fail to quit on any attempt may benefit from interventions to improve their chances for success on subsequent attempts. Patients who were unsuccessful should be counseled and should then probably be given a "therapy holiday" before the next attempt. A new quit attempt should be encouraged when conditions are more favorable. Based on the clinical trials, a reasonable approach to assisting patients in their attempt to quit smoking is to begin initial treatment, using the recommended dosage (See DOSAGE AND ADMINISTRATION ). Regular use of the spray during the first week of treatment may help patients adapt to the irritant effects of the spray. Dosage can then be adjusted in those subjects with signs or symptoms of nicotine withdrawal or excess. Patients who are successfully abstinent on NICOTROL NS should be treated at the selected dosage for up to 8 weeks, following which use of the spray should be discontinued over the next 4 to 6 weeks. Some patients may not require gradual reduction of dosage and may abruptly stop treatment successfully. Treatment with NICOTROL NS for longer periods has not been shown to improve outcome, and the safety of use for periods longer than 6 months has not been established. The symptoms of nicotine withdrawal overlap those of nicotine excess (See CLINICAL PHARMACOLOGY, Pharmacodynamics and ADVERSE REACTIONS ). Since patients using NICOTROL NS may also smoke intermittently, it is sometimes difficult to determine if patients are experiencing nicotine withdrawal or nicotine excess. Controlled clinical trials of nicotine products suggest that palpitations, nausea and sweating are more often symptoms of nicotine excess, whereas anxiety, nervousness and irritability are more often symptoms of nicotine withdrawal.

CONTRAINDICATIONS Use of NICOTROL NS therapy is contraindicated in patients with known hypersensitivity or allergy to nicotine or to any component of the product.

WARNINGS Nicotine from any source can be toxic and addictive. Smoking causes lung disease, cancer, and heart disease and may adversely affect pregnant women or the fetus. For any smoker, with or without concomitant disease or pregnancy, the risk of nicotine replacement 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. Pregnancy, Warning Tobacco smoke, which has been shown to be harmful to the fetus, contains nicotine, hydrogen cyanide, and carbon monoxide. Nicotine has been shown in animal studies to cause fetal harm. It is therefore presumed that NICOTROL NS can cause fetal harm when administered to a pregnant woman. The effect of nicotine delivery by NICOTROL NS has not been examined in pregnancy (See PRECAUTIONS, Pregnancy ). Therefore, pregnant smokers should be encouraged to attempt cessation using educational and behavioral interventions before using pharmacological approaches. If NICOTROL NS is used during pregnancy, or if the patient becomes pregnant while using it, the patient should be apprised of the potential hazard to the fetus. Safety Note Concerning Children The amounts of nicotine that are tolerated by adult smokers can produce signs and symptoms of poisoning and could prove fatal if NICOTROL NS is used or ingested by children or pets. Suspected nicotine poisoning in a child should be considered a medical emergency and treated immediately. A full bottle of NICOTROL NS contains 100 mg of nicotine, some of which will still be in the bottle when it is discarded. Therefore, patients should be cautioned to keep both used and unused containers of NICOTROL NS out of the reach of children and pets.

Drug Interactions The extent of absorption and peak plasma concentration is slightly reduced in patients with the common cold/rhinitis. In addition, the time to peak concentration is prolonged. The use of a nasal vasoconstrictor such as xylometazoline in patients with rhinitis will further prolong the time to peak (See PHARMACOKINETICS ). Smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications. May Require a Decrease in Dose at Cessation of Smoking Possible Mechanism Acetaminophen, caffeine, imipramine, oxazepam, pentazocine, propranolol, or other beta-blockers, theophylline Deinduction of hepatic enzymes on smoking cessation. Insulin Increase of subcutaneous insulin absorption with smoking cessation. Adrenergic antagonists (e.g. prazosin, labetalol) Decrease in circulating catecholamines with smoking cessation. May Require an Increase in Dose at Cessation of Smoking Possible Mechanism Adrenergic agonists (e.g. isoproterenol, phenylephrine) Decrease in circulating catecholamines with smoking cessation.

ADVERSE REACTIONS Assessment of adverse events in the 730 patients who participated in controlled clinical trials is complicated by the occurrence of signs and symptoms of nicotine withdrawal in some patients and nicotine excess in others. The incidence of adverse events is confounded by the many minor complaints that smokers commonly have, by continued smoking by many patients and the local irritation from both active drug and the pepper placebo. No serious adverse events were reported during the trials. Common Smoker's Complaints Common complaints experienced by the smokers in the study (users of both active and placebo spray) include: chest tightness, dyspepsia, paresthesia (tingling) in limbs, constipation, and stomatitis. Tobacco Withdrawal Symptoms Symptoms of tobacco withdrawal were frequent in users of both active and placebo sprays. Common withdrawal symptoms seen in over 5% of patients included: anxiety, irritability, restlessness, cravings, dizziness, impaired concentration, weight increase, emotional lability, somnolence and fatigue, increased sweating, and insomnia. Less frequently seen probable withdrawal symptoms (under 5%) included: confusion, depression, apathy, tremor, increased appetite, incoordination, and increased dreaming. Anxiety, irritability, restlessness, and tobacco cravings occurred about equally in both groups, while other symptoms tended to be slightly more common on placebo spray. Effects of the Spray NICOTROL NS and the pepper-containing placebo were both associated with irritant side effects on the nasopharyngeal and ocular tissues. During the first 2 days of treatment, nasal irritation was reported by nearly all (94%) of the patients, the majority of whom rated it as either moderate or severe. Both the frequency and severity of nasal irritation declined with continued use of NICOTROL NS but was still experienced by most (81%) of the patients after 3 weeks of treatment, with most patients rating it as moderate or mild. Other common side effects for both active and placebo groups were: runny nose, throat irritation, watering eyes, sneezing, and coughing. The following local events were reported somewhat more commonly for active than for placebo spray: nasal congestion, subjective comments related to the taste or use of the dosage form, sinus irritation, transient epistaxis, eye irritation, transient changes in sense of smell, pharyngitis, paresthesia of the nose, mouth or head, numbness of the nose, or mouth, burning of the nose or eyes, earache, facial flushing, transient changes in sense of taste, hoarseness, nasal ulcer or blister. Effects of Nicotine Feelings of dependence on the spray were reported by more patients on active spray than placebo. Drug-like effects such as calming were also more frequent on active spray (See DRUG ABUSE AND DEPENDENCE ). Other Adverse Effects Adverse events which could not be classified and listed above and which were reported by >1% of patients on active spray are listed in the following table: Adverse Events Not Attributable to Intercurrent Illness Adverse Event Active Placebo HEADACHE 18% 15% BACK PAIN 6% 4% DYSPNEA 5% 6% NAUSEA 5% 5% ARTHRALGIA 5% 1% MENSTRUAL DISORDER 4% 4% PALPITATION 4% 4% FLATULENCE 4% 3% TOOTH DISORDER 4% 1% GUM PROBLEMS 4% 1% MYALGIA 3% 4% ABDOMINAL PAIN 3% 3% CONFUSION 3% 3% ACNE 3% 1% DYSMENORRHEA 3% 0% PRURITUS 2% 3% Adverse events reported with a frequency of <1% among active spray users are listed below: Body as a Whole: edema peripheral, pain, numbness, allergy Gastrointestinal: dry mouth, hiccup, diarrhea Hematologic: purpura Neurological: aphasia, amnesia, migraine, numbness Respiratory: bronchitis, bronchospasm, sputum increased Skin and appendages: rash, purpura Special Senses: vision abnormal Adverse reactions not listed above that have been identified during post-marketing experience with the nicotine nasal spray formulation are listed below: Gastrointestinal disorders: dysphagia General disorders and administration site conditions: chest pain Immune system disorders: anaphylactic reaction Nervous system disorders: seizure

Pregnancy The harmful effects of cigarette smoking on maternal and fetal health are clearly established. These include low birth weight, an increased risk of spontaneous abortion, and increased perinatal mortality. The specific effects of NICOTROL NS on fetal development are unknown. Therefore pregnant smokers should be encouraged to attempt cessation using educational and behavioral interventions before using pharmacological approaches. Spontaneous abortion during nicotine replacement therapy has been reported; as with smoking, nicotine as a contributing factor cannot be excluded. NICOTROL NS should be used during pregnancy only if the likelihood of smoking cessation justifies the potential risk of using it by the pregnant patient, who might continue to smoke. Teratogenicity Animal Studies Nicotine was shown to produce skeletal abnormalities in the offspring of mice when toxic doses were given to the dams (25 mg/kg IP or SC). Human Studies Nicotine teratogenicity has not been studied in humans except as a component of cigarette smoke (each cigarette smoked delivers about 1 mg of nicotine). It has not been possible to conclude whether cigarette smoking is teratogenic to humans. Other Effects Animal Studies A nicotine bolus (up to 2 mg/kg) to pregnant rhesus monkeys caused acidosis, hypercarbia, and hypotension (fetal and maternal concentrations were about 20 times those achieved after smoking one cigarette in 5 minutes). Fetal breathing movements were reduced in the fetal lamb after intravenous injection of 0.25 mg/kg nicotine to the ewe (equivalent to smoking 1 cigarette every 20 seconds for 5 minutes). Uterine blood flow was reduced about 30% after infusion of 0.1 µg/kg/min nicotine to pregnant rhesus monkeys (equivalent to smoking about six cigarettes every minute for 20 minutes). Human Experience Cigarette smoking during pregnancy is associated with an increased risk of spontaneous abortion, low birth weight infants and perinatal mortality. Nicotine and carbon monoxide are considered the most likely mediators of these outcomes. The effects of cigarette smoking on fetal cardiovascular parameters have been studied near term. Cigarettes increased fetal aortic blood flow and heart rate and decreased uterine blood flow and fetal breathing movements. NICOTROL NS has not been studied in pregnant women.