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NICOTROL NS (nicotine nasal spray) is indicated as an aid to smoking cessation for the relief of nicotine withdrawal symptoms. NICOTROL NS (nicotine nasal spray) 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 (nicotine nasal spray) for periods longer than 6 months have not been adequately studied and such use is not recommended.
Nicotine, the chief alkaloid in tobacco products, binds stereo-selectively to nicotinic-cholinergic receptors at the autonomic ganglia, in the adrenal medulla, at neuromuscular junctions, and in the brain. Two types of central nervous system effects are believed to be the basis of nicotine's positively reinforcing properties. A stimulating effect is exerted mainly in the cortex via the locus ceruleus and a reward effect is exerted in the limbic system. At low doses, the stimulant effects predominate while at high doses the reward effects predominate. Intermittent intravenous administration of nicotine activates neurohormonal pathways, releasing acetylcholine, norepinephrine, dopamine, serotonin, vasopressin, beta-endorphin, growth hormone, and ACTH.
The cardiovascular effects of nicotine include peripheral vasoconstriction, tachycardia, and elevated blood pressure. Acute and chronic tolerance to nicotine develops from smoking tobacco or ingesting nicotine preparations. Acute tolerance (a reduction in response for a given dose) develops rapidly (less than 1 hour), but not at the same rate for different physiologic effects (skin temperature, heart rate, subjective effects). Withdrawal symptoms such as cigarette craving can be reduced in most individuals by plasma nicotine levels lower than those from smoking.
Withdrawal from nicotine in addicted individuals can be characterized by craving, nervousness, restlessness, irritability, mood lability, anxiety, drowsiness, sleep disturbances, impaired concentration, increased appetite, minor somatic complaints (headache, myalgia, constipation, fatigue), and weight gain. Nicotine toxicity is characterized by nausea, abdominal pain, vomiting, diarrhea, diaphoresis, flushing, dizziness, disturbed hearing and vision, confusion, weakness, palpitations, altered respiration and hypotension.
Both smoking and nicotine can increase circulating cortisol and catecholamines, and tolerance does not develop to the catecholamine-releasing effects of nicotine. Changes in the response to a concomitantly administered adrenergic agonist or antagonist should be watched for when nicotine intake is altered during NICOTROL NS therapy and/or smoking cessation (See PRECAUTIONS: DRUG INTERACTIONS).
Each actuation of NICOTROL NS (nicotine nasal spray) 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 (nicotine nasal spray) 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 (nicotine nasal spray) 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 Section). 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).
Figure 1 : Mean and Range of the 95th and 5th Percentile Nicotine Concentrations After a 1 mg Dose of NICOTRO NS (n=30)
Table 1: Trough Plasma Nicotine Concentrations after 11 Hours of Dosing With 1 mg, 2 mg and 3 mg of NICOTROL NS (nicotine nasal spray) per hour (n=16).
|Dose||Mean (ng/mL) |
|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 (nicotine nasal spray) 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 (nicotine nasal spray) per hour as shown in Figure 2.
Figure 2 : Mean, 95th and 5th Percentile Trough Nicotine Plasma Concentrations in Subjects Taking NICOTRO NS for 12 Hours (n=16).
Sixteen smokers (7 males and 9 females) ranging in age from 22 to 44 years were dosed with 1 mg of NICOTROL NS (nicotine nasal spray) 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 (nicotine nasal spray) Administered Hourly for Ten Hours (Mean ± SD and Range), (n=16).
|Parameter||1 mg (2 sprays)||(Range)|
|Cavg (ng/mL)||8 ± 3||(2.5-12)|
|Cmax (ng/mL)||9 ± 3||(3.1-14)|
|Tmax (minutes)||13 ± 5||(10-20)|
|Cavg: average plasma nicotine concentration for the dosing interval of 10-11 hours |
Cmax: maximum measured plasma concentration after last dose administration
Tmax: time of maximum plasma concentration after last dose administration
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 (nicotine nasal spray) 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 (K12) = 4.84 ± 2.57 hr-1, (K21) = 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, Cmax and Clearance/kg) were observed for both genders. There were no differences between females or males in the kinetics of NICOTROL NS (nicotine nasal spray) .
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.
The efficacy of NICOTROL NS (nicotine nasal spray) therapy as an aid to smoking cessation was demonstrated in three single-center, placebo-controlled, double-blind trials with a total of 730 patients. One of the trials used NICOTROL NS (nicotine nasal spray) with individual counseling while the other two used group support. Patients with severe or symptomatic cardiovascular disease, hypertension, asthma, diabetes or severe allergy were not included in the studies. The amount of NICOTROL NS (nicotine nasal spray) used was left to the discretion of each patient, with a minimum dose of 8 mg/day and a maximum dose of 40 mg/day.
In all three studies, the recommended duration of treatment was 3 months; however in two of these trials, 241 patients were permitted to continue to use the product for up to 1 year, if they wished. Among the 64 patients abstinent from cigarettes at the end of a year, 23 (36%) were still using the spray, and probable dependence on the spray was seen in several patients (See Drug Abuse And Dependence).
Quitting was defined as total abstinence from smoking for at least 4 weeks. The “quit rates” are the percentage of all persons initially enrolled who continuously abstained after week 2 or 4.
In all three studies, NICOTROL NS (nicotine nasal spray) was more effective than placebo at 6 weeks, 3 months, 6 months, and 1 year. The two studies where NICOTROL NS (nicotine nasal spray) could be used for more than 6 months did not have a better outcome at 1 year than the study in which NICOTROL NS (nicotine nasal spray) was discontinued at 6 months.
Table 3: Quit Rates by Treatment (N=730 smokers in 3 Studies)
|Group||Size (n)||At 6 Weeks||At 3 Months||At 6 Months||At 1 Year|
Patients treated with NICOTROL NS (nicotine nasal spray) had more relief of the urge to smoke and withdrawal symptoms compared with placebo-treated patients.
NICOTROL NS allows the patient to vary the dose of nicotine on a short-term basis. As with other variable dose smoking cessation products, NICOTROL NS (nicotine nasal spray) may be useful in the management of highly dependent smokers.
|All Trimesters||D||Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.|
Other Medical Problems
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
- Angina (severe chest pain) or
- Asthma or
- Breathing problems or
- Buerger disease (circulation problem) or
- Diabetes (insulin-dependent) or
- Heart rhythm problems (eg, arrhythmia) or
- Hypertension (high blood pressure) or
- Hyperthyroidism (overactive thyroid) or
- Pheochromocytoma (adrenal problem) or
- Raynaud disease (circulation problem) or
- Stomach ulcer or
- Tachycardia (fast heart rate)—Use with caution. May make these conditions worse.
- Heart attack, history of or
- Heart or blood vessel disease—Use with caution. May cause side effects to become worse.
- Kidney disease, severe or
- Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.
- Nasal allergies, chronic or
- Nasal polyps or
- Rhinitis (runny nose), chronic or
- Sinusitis, chronic—Use is not recommended due to potential for nasal irritation.
Precautions While Using Nicotrol NS
Do not smoke or use any tobacco products with the nasal spray. If you continue to smoke or chew tobacco, you may have serious unwanted effects from nicotine. Call your doctor right away if you have dizziness, headaches, an upset stomach, drooling, vomiting, diarrhea, cold sweats, blurred vision, trouble hearing, confusion, fainting, or weakness.
Do not use any other nicotine products with the nasal spray. This includes nicotine patches, lozenges, or gum. You may have serious unwanted effects if you use more than one nicotine product.
Pregnant women should only use this medicine as directed by a doctor. Cigarette smoke can seriously harm your child. Try to stop smoking without using medicine. The risks to your child from this medicine are not fully known.
Nicotine products must be kept out of the reach of children and pets. Small amounts of nicotine can cause serious unwanted effects in children, and a used bottle may contain enough nicotine to cause problems. If the spray bottle is touched by a child, contact your doctor or poison control center at once.
During the first week, you may have a hot, peppery feeling in your throat or nose, coughing, a runny nose, sneezing, or watery eyes. Do not stop using the medicine. If you continue to use the nasal spray, you should adjust to these effects. If these effects do not lessen after several weeks, check with your doctor.
Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.
Nicotrol NS Description
Nicotrol® NS (nicotine nasal spray) is an aqueous solution of nicotine intended for administration as a metered spray to the nasal mucosa.
Nicotine is a tertiary amine composed of pyridine and a pyrrolidine ring. It is a colorless to pale yellow, freely water-soluble, strongly alkaline, oily, volatile, hygroscopic liquid obtained from the tobacco plant. Nicotine has a characteristic pungent odor and turns brown on exposure to air or light. Of its two stereoisomers, S(-)nicotine is the more active. It is the prevalent form in tobacco, and is the form in Nicotrol NS. The free alkaloid is absorbed rapidly through skin, mucous membranes, and the respiratory tract.
Chemical Name: S-3-(1-methyl-2-pyrrolidinyl) pyridine
Molecular Formula: C10H14N2
Molecular Weight: 162.23
Ionization Constants: pKa1 = 7.84, pKa2 = 3.04 at 15°C
Octanol-Water Partition Coefficient: 15:1 at pH 7
Each 10 mL spray bottle contains 100 mg nicotine (10 mg/mL) in an inactive vehicle containing disodium phosphate, sodium dihydrogen phosphate, citric acid, methylparaben, propylparaben, edetate disodium, sodium chloride, polysorbate 80, aroma and water. The solution is isotonic with a pH of 7. It contains no chlorofluorocarbons.
After priming the delivery system for Nicotrol NS, each actuation of the unit delivers a metered dose spray containing approximately 0.5 mg of nicotine. The size of the droplets produced by the unit is in excess of 8 microns. One Nicotrol NS unit delivers approximately 200 applications.
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.
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). 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 symptoms of poisoning and could prove fatal if Nicotrol NS is used or ingested by children or pets. 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.
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, paraesthesia (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, paraethesias 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 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
Neurological: aphasia, amnesia, migraine, numbness
Respiratory: bronchitis, bronchospasm, sputum increased
Skin and appendages: rash, purpura
Special Senses: vision abnormal
Common side effects of Nicotrol NS include: nasal mucosa irritation. Other side effects include: arthralgia. See below for a comprehensive list of adverse effects.