Get your patient on Nicotrol - Nicotine inhalant (Nicotine)
Nicotrol - Nicotine inhalant prescribing information
INDICATIONS AND USAGE
NICOTROL Inhaler is indicated as an aid to smoking cessation for the relief of nicotine withdrawal symptoms. NICOTROL Inhaler therapy is recommended for use as part of a comprehensive behavioral smoking cessation program.
DOSAGE AND ADMINISTRATION
Patients must desire to stop smoking and should be instructed to stop smoking completely as they begin using NICOTROL Inhaler. It is important that patients understand the instructions, and have their questions answered. They should clearly understand the directions for using the NICOTROL Inhaler and safely disposing of the used cartridges.
The initial dosage of NICOTROL Inhaler is individualized. Patients may self titrate to the level of nicotine they require. Most successful patients in the clinical trials used between 6 and 16 cartridges a day. Best effect was achieved by frequent continuous puffing (20 minutes). The recommended duration of treatment is 3 months, after which patients may be weaned from the NICOTROL Inhaler by gradual reduction of the daily dose over the following 6 to 12 weeks. The safety and efficacy of the continued use of NICOTROL Inhaler for periods longer than 6 months have not been studied and such use is not recommended.
Dosing recommendations are summarized in the table below.
RECOMMENDED DOSING
| Duration | Recommended Cartridges/day | |
|---|---|---|
INITIAL TREATMENT | Up to 12 Weeks | 6 – 16 |
Gradual Reduction (if needed) | 6–12 Weeks | No tapering strategy has been shown to be superior to any other in clinical studies. |
Initial Treatment (Up to 12 Weeks)
For best results, patients should be encouraged to use at least 6 cartridges per day at least for the first 3 to 6 weeks of treatment. In clinical trials, the average daily dose was >6 (range 3 to 18) cartridges for patients who successfully quit smoking. Additional doses may be needed to control the urge to smoke with a maximum of 16 cartridges daily for up to 12 weeks. Regular use of NICOTROL Inhaler during the first week of treatment may help patients adapt to the irritant effects of the product. Some patients may exhibit signs or symptoms of nicotine withdrawal or excess which will require an adjustment of the dosage (See Individualization of Dosage ).
Gradual Reduction of Dose (Up to 12 Weeks)
Most patients will need to gradually discontinue the use of NICOTROL Inhaler after the initial treatment period. Gradual reduction of dose may begin after twelve weeks of initial treatment and may last for up to twelve weeks. Recommended strategies for discontinuing use include suggesting to patients that they use the product less frequently, keep a tally of daily usage, try to meet a steadily reducing target or set a planned quit date for stopping use of the product.
Individualization of Dosage
The NICOTROL Inhaler provides the smoker with adequate amounts of nicotine to reduce the urge to smoke, and may provide some degree of comfort by providing a hand-to-mouth ritual similar to smoking, although the importance of such an effect in smoking cessation is, as yet, unknown.
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 Inhaler 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 therapeutic 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 ). Dosage can then be adjusted in those patients with signs or symptoms of nicotine withdrawal or excess. Patients who are successfully abstinent on NICOTROL Inhaler should be treated at the selected dosage for up to 12 weeks, after which use of the Inhaler should be gradually reduced over the next 6 to 12 weeks. Some patients may not require gradual reduction of dosage and may abruptly stop treatment successfully. The safe use of this product for 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 Inhaler may also smoke intermittently, it is sometimes difficult to determine if they 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 Inhaler therapy is contraindicated in patients with known hypersensitivity or allergy to nicotine or to menthol.
ADVERSE REACTIONS
Assessment of adverse events in the 1,439 patients (730 on active drug) who participated in controlled clinical trials (including three dose finding studies) 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: (1) the many minor complaints that smokers commonly have, (2) continued smoking by many patients and (3) the local irritation from both the active drug and the placebo.
Local Irritation
NICOTROL Inhaler and the placebo were both associated with local irritant side effects. Local irritation in mouth and throat was reported by 40% of patients on active drug as compared to 18% of patients on placebo. Irritant effects were higher in the two pivotal trials with higher doses being 66% on active drug and 42% on placebo. Coughing (32% active versus 12% placebo) and rhinitis (23% active versus 16% placebo) were also higher on active drug. The majority of patients rated these symptoms as mild. The frequency of cough, and mouth and throat irritation declined with continued use of NICOTROL Inhaler. Other adverse events that occurred in over 3% of patients on active drug in placebo-controlled pivotal trials considered possibly related to the local irritant effects of the NICOTROL Inhaler are taste comments, pain in jaw and neck, tooth disorders and sinusitis.
Withdrawal
Symptoms of withdrawal were common in both active and placebo groups. Common withdrawal symptoms seen in over 3% of patients on active drug included: dizziness, anxiety, sleep disorder, depression, withdrawal syndrome, drug dependence, fatigue and myalgia.
Nicotine-Related Adverse Events
The most common nicotine-related adverse event was dyspepsia. This was present in 18% of patients in the active group compared to 9% of patients in the placebo group. Other nicotine related events present in greater than 3% of patients on active drug include nausea, diarrhea, and hiccup.
Smoking Related Adverse Events
Smoking related adverse events present in greater than 3% of patients on active drug include chest discomfort, bronchitis, and hypertension.
Other Adverse Events
Adverse events of unknown relationship to nicotine occurring in greater than 3% of patients on active drug include headache (26% of patients on active and 15% of patients on placebo), influenza-like symptoms, pain, back-pain, allergy), paresthesia, flatulence and fever.
Adverse reactions not listed above that have been identified during post-marketing experience with the nicotine inhaler are listed below:
Gastrointestinal disorders: dysphagia
General disorders and administration site conditions: chest pain
Immune system disorders: anaphylactic reaction
Nervous system disorders: seizure
Skin and subcutaneous tissue disorders: rash
Drug Interactions
Physiological changes resulting from smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants and theophylline. Doses of these and perhaps other medications may need to be adjusted in patients who successfully quit smoking.
DESCRIPTION
NICOTROL ® Inhaler (nicotine inhalation system) consists of a mouthpiece and a plastic cartridge delivering 4 mg of nicotine from a porous plug containing 10 mg nicotine. The cartridge is inserted into the mouthpiece prior to use. Nicotine is a tertiary amine composed of a 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 the NICOTROL Inhaler. 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: C 10 H 14 N 2
Molecular Weight: 162.23
Ionization Constants: pKa 1 = 7.84, pKa 2 = 3.04 at 15°C
Octanol-Water Partition Coefficient: 15:1 at pH 7
Nicotine is the active ingredient; inactive components of the product are menthol and a porous plug which are pharmacologically inactive. Nicotine is released when air is inhaled through the inhaler.
CLINICAL PHARMACOLOGY
Pharmacologic Action
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.
Pharmacodynamics
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 Inhaler therapy and/or smoking cessation (See PRECAUTIONS, Drug Interactions ).
Pharmacokinetics
Absorption
Most of the nicotine released from the NICOTROL Inhaler is deposited in the mouth. Only a fraction of the dose released, less than 5%, reaches the lower respiratory tract. An intensive inhalation regimen (80 deep inhalations over 20 minutes) releases on the average 4 mg of the nicotine content of each cartridge of which about 2 mg is systemically absorbed. Peak plasma concentrations are typically reached within 15 minutes of the end of inhalation.
Absorption of nicotine through the buccal mucosa is relatively slow and the high and rapid rise followed by the decline in nicotine arterial plasma concentrations seen with cigarette smoking are not achieved with the inhaler. After use of the single inhaler the arterial nicotine concentrations rise slowly to an average of 6 ng/mL in contrast to those of a cigarette, which increase rapidly and reach a mean C max of approximately 49 ng/mL within 5 minutes.
The temperature dependency of nicotine release from the NICOTROL Inhaler was studied between 68°F and 104°F in eighteen patients. Average achievable steady-state plasma levels after 20 minutes of an intensive inhalation regimen each hour at ambient room temperature are on the order of 23 ng/mL. The corresponding nicotine plasma levels achievable at 86°F and 104°F are on the order of 30 and 34 ng/mL. Nicotine peak plasma concentration (C max ) at steady-state, after 20 minutes of an intensive inhalation regimen per hour, for 10 hours.
| C max (ng/mL) | |||
|---|---|---|---|
| 20°C/68°F | 30°C/86°F | 40°C/104°F | |
| N=18 | N=18 | N=18 | |
Mean | 22.5 | 29.7 | 34.0 |
S.D. | 7.7 | 8.3 | 6.9 |
Min | 11.1 | 17.6 | 24.1 |
Max | 40.4 | 47.2 | 48.6 |
Ad libitum use of the NICOTROL Inhaler typically produces nicotine plasma levels of 6–8 ng/mL, corresponding to about 1/3 of those achieved with cigarette smoking.
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 is 1 to 2 hours.
Gender Differences
Intersubject variability coefficients of variation (C.V.) for the pharmacokinetic parameters (AUC and C max ) were approximately 40% and 30% respectively, for males and females. There were no medically significant differences between females and males in the kinetics of NICOTROL Inhaler.
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.
CLINICAL TRIALS
The efficacy of NICOTROL Inhaler therapy as an aid to smoking cessation was demonstrated in two single-center, placebo-controlled, double-blind trials with a total of 445 healthy patients. The number of NICOTROL Inhaler cartridges used was a minimum dose of 4 cartridges/day and a maximum dose of 20 cartridges/day. In both studies, the recommended duration of treatment was 3 months; however, the patients were permitted to continue to use the product for up to 6 months, if they wished. The quit rates are the percentage of all persons initially enrolled who continuously abstained after week 2. NICOTROL Inhaler was more effective than placebo at 6 weeks, 3 months and 6 months. The efficacy is shown in the following table.
| Quit Rates by Treatment (N= 445 Patients in 2 Studies) | |||||
|---|---|---|---|---|---|
| Group | Number of Patients | At 6 Weeks | At 3 Months | At 6 Months | At 12 Months Follow-up, patients not on treatment. |
NICOTROL Inhaler | 223 | 44–45% | 31–32% | 20–21% | 11–13% |
Placebo | 222 | 14–23% | 8–15% | 6–11% | 5–10% |
Patients who used NICOTROL Inhaler had a significant reduction in the "urge to smoke", a major nicotine withdrawal symptom, compared with placebo-treated patients throughout the first week (See Figure 1).
CLINICAL TRIALS
The efficacy of NICOTROL Inhaler therapy as an aid to smoking cessation was demonstrated in two single-center, placebo-controlled, double-blind trials with a total of 445 healthy patients. The number of NICOTROL Inhaler cartridges used was a minimum dose of 4 cartridges/day and a maximum dose of 20 cartridges/day. In both studies, the recommended duration of treatment was 3 months; however, the patients were permitted to continue to use the product for up to 6 months, if they wished. The quit rates are the percentage of all persons initially enrolled who continuously abstained after week 2. NICOTROL Inhaler was more effective than placebo at 6 weeks, 3 months and 6 months. The efficacy is shown in the following table.
| Quit Rates by Treatment (N= 445 Patients in 2 Studies) | |||||
|---|---|---|---|---|---|
| Group | Number of Patients | At 6 Weeks | At 3 Months | At 6 Months | At 12 Months Follow-up, patients not on treatment. |
NICOTROL Inhaler | 223 | 44–45% | 31–32% | 20–21% | 11–13% |
Placebo | 222 | 14–23% | 8–15% | 6–11% | 5–10% |
Patients who used NICOTROL Inhaler had a significant reduction in the "urge to smoke", a major nicotine withdrawal symptom, compared with placebo-treated patients throughout the first week (See Figure 1).
How Supplied
NICOTROL INHALER (nicotine inhalation system) is supplied as 168 cartridges each containing 10 mg (4 mg is delivered) nicotine (NDC 0009-5400-01). Each unit consists of 5 mouthpieces, 28 storage trays each containing 6 cartridges and 1 plastic storage case. A patient information leaflet is enclosed with the package.
Store at room temperature not to exceed 77°F (25°C).
Protect cartridges from light.
Pharmacologic Action
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.
