Nicotine

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.

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

Pharmacokinetics Each actuation of NICOTROL NS delivers a metered 50 microliter spray containing approximately 0.5 mg of nicotine. One dose is considered 1 mg of nicotine (2 sprays, one in each nostril). Absorption Following administration of 2 sprays of NICOTROL NS approximately 53% ± 16% (Mean ± SD) enters the systemic circulation. No significant difference in rate or extent of absorption could be seen due to the deposition of nicotine on different parts of the nasal mucosa. Plasma concentrations of nicotine obtained from 1 dose (1 mg nicotine) of NICOTROL NS rise rapidly, reaching maximum venous concentrations of 2–12 ng/mL in 4–15 minutes. The apparent absorption half-life of nicotine is approximately 3 minutes. There is wide variation among subjects in their plasma nicotine concentrations from the spray. As a result, after a 1 mg dose of spray approximately 20% of the subjects reached peak nicotine concentrations similar to those seen after smoking one cigarette (7–17 ng/mL) (See DRUG ABUSE AND DEPENDENCE ). Figure 1 below plots the mean and 5th and 95th percentile nicotine concentrations after a 1 mg single dose of the nasal spray (n=30). Table 1: Trough Plasma Nicotine Concentrations after 11 Hours of Dosing With 1 mg, 2 mg and 3 mg of NICOTROL NS per hour (n=16). Dose Mean (ng/mL) ± SD (Range) 1 mg every 60 minutes (1 mg/hr) 6 ± 3 (1.7–12) 1 mg every 30 minutes (2 mg/hr) 14 ± 6 (1.5–24) 1 mg every 20 minutes (3 mg/hr) 18 ± 10 (1.2–35) The data from Table 1 is derived from a three-way cross-over study of repeated applications of NICOTROL NS in sixteen smokers (8 male, 8 female) ranging in age from 18 to 48 years. There is a slight deviation from dose-concentration proportionality from one dose to three doses of NICOTROL NS per hour as shown in Figure 2. Sixteen smokers (7 males and 9 females) ranging in age from 22 to 44 years were dosed with 1 mg of NICOTROL NS every hour for 10 hours. The pharmacokinetic parameters that were obtained are presented in Table 2. Table 2: Nicotine Pharmacokinetic Parameters at Steady-State for 1 mg/hour of NICOTROL NS Administered Hourly for Ten Hours (Mean ± SD and Range), (n=16). Parameter 1 mg (2 sprays) (Range) C avg : average plasma nicotine concentration for the dosing interval of 10–11 hours C max : maximum measured plasma concentration after last dose administration T max : time of maximum plasma concentration after last dose administration C avg (ng/mL) 8 ± 3 (2.5–12) C max (ng/mL) 9 ± 3 (3.1–14) T max (minutes) 13 ± 5 (10–20) Figure 1 Figure 2 Distribution The volume of distribution following IV administration of nicotine is approximately 2 to 3 L/kg. Plasma protein binding of nicotine is <5%. Therefore, changes in nicotine binding from use of concomitant drugs or alterations of plasma proteins by disease states would not be expected to have significant effects on nicotine kinetics. Metabolism More than 20 metabolites of nicotine have been identified, all of which are less active than the parent compound. The primary urinary metabolites are cotinine (15% of the dose) and trans-3-hydroxycotinine (45% of the dose). Cotinine has a half-life of 15 to 20 hours and concentrations that exceed nicotine by 10-fold. The major site for the metabolism of nicotine is the liver. The kidney and lung are also sites of nicotine metabolism. Elimination About 10% of the nicotine absorbed is excreted unchanged in the urine. This may be increased to up to 30% with high urine flow rates and urinary acidification below pH 5. The average plasma clearance is about 1.2 L/min in a healthy adult smoker. The apparent elimination half-life of nicotine from NICOTROL NS is 1 to 2 hours. Pharmacokinetic Model The data were well described by a two-compartment model with first-order input. Based on individual fits (N=18) the following parameters were derived after the administration of a 1 mg dose: Absorption rate constant (Ka) = 14.4 ± 7.3 hr -1 (Mean ± SD), Elimination rate constant (Ke) = 0.60 ± 0.53 hr -1 , Distribution rate constants (K 12 ) = 4.84 ± 2.57 hr -1 , (K 21 ) = 4.35 ± 2.30 hr -1 , Volume of distribution over fraction absorbed (V/F) = 2.73 ± 0.82 L/kg in 8 female and 10 male adults weighing 76 ± 15 kg. Gender Differences Intersubject variability (50% coefficient of variation) among the pharmacokinetic parameters (AUC, C max and Clearance/kg) were observed for both genders. There were no differences between females or males in the kinetics of NICOTROL NS. Renal Impairment Progressive severity of renal impairment is associated with decreased total clearance of nicotine. Nicotine clearance was decreased by 30% on average in subjects with moderate renal impairment and 50% on average in subjects with severe renal impairment. Hepatic Impairment In smokers with liver cirrhosis but only mild impairment of hepatic function (Child-Pugh score 5), the pharmacokinetics of nicotine is unaffected. However, in smokers with moderately impaired liver function (Child-Pugh score 7), total clearance has been reported to be reduced on average by 40-50%. There are no data about the pharmacokinetics of nicotine in smokers with a Child-Pugh score exceeding 7, but these subjects are expected to show similar or greater effects on clearance of nicotine as patients with moderately impaired liver function. Drug/Drug Interactions The extent of absorption is slightly reduced (approximately 10%) in patients with the common cold/rhinitis. In patients with rhinitis the peak plasma concentration is reduced by approximately 20% (concentrations are lower by 1.5 ng/mL on average) and the time to peak concentration prolonged by approximately 30% (delayed by 7 minutes on average). The use of a nasal vasoconstrictor such as xylometazoline in patients with rhinitis will further prolong the time to peak by approximately 40% (delayed by 15 minutes on average), but the peak plasma concentration remains on average the same as those with rhinitis.