Nicotrol Inhalant

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: 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

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.

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.

General

The patient should be urged to stop smoking completely when initiating NICOTROL Inhaler therapy (See DOSAGE AND ADMINISTRATION). Patients should be informed that if they continue to smoke while using the product, they may experience adverse effects due to peak nicotine levels higher than those experienced from smoking alone. If there is a clinically significant increase in cardiovascular or other effects attributable to nicotine, the treatment should be discontinued (See WARNINGS). Physicians should anticipate that concomitant medications may need dosage adjustment (See Drug Interactions). Sustained use (beyond 6 months) of NICOTROL Inhaler by patients who stop smoking has not been studied and is not recommended. (See DRUG ABUSE AND DEPENDENCE).

Bronchospastic Disease

NICOTROL Inhaler has not been specifically studied in asthma or chronic pulmonary disease. Nicotine is an airway irritant and might cause bronchospasm. NICOTROL Inhaler should be used with caution in patients with bronchospastic disease. Other forms of nicotine replacement might be preferable in patients with severe bronchospastic airway disease.

Cardiovascular or Peripheral Vascular Diseases

The risks of nicotine replacement in patients with cardiovascular and peripheral vascular diseases should be weighed against the benefits of including nicotine replacement in a smoking cessation program for them. Specifically, patients with coronary heart disease (history of myocardial infarction and/or angina pectoris), serious cardiac arrhythmias, or vasospastic diseases (Buerger's disease, Prinzmetal's variant angina and Raynaud's phenomena) should be evaluated carefully before nicotine replacement is prescribed.

Tachycardia and palpitations have been reported occasionally with the use of NICOTROL Inhaler as well as with other nicotine replacement therapies. No serious cardiovascular events were reported in clinical studies with NICOTROL Inhaler, but if such symptoms occur, its use should be discontinued.

NICOTROL Inhaler generally should not be used in patients during the immediate post-myocardial infarction period, nor in patients with serious arrhythmias, or with severe or worsening angina.

Renal or Hepatic Insufficiency

The pharmacokinetics of nicotine have not been studied in the elderly or in patients with renal or hepatic impairment. However, given that nicotine is extensively metabolized and that its total system clearance is dependent on liver blood flow, some influence of hepatic impairment on drug kinetics (reduced clearance) should be anticipated. Only severe renal impairment would be expected to affect the clearance of nicotine or its metabolites from the circulation (See PHARMACOKINETICS).

Endocrine Diseases

NICOTROL Inhaler therapy should be used with caution in patients with hyperthyroidism, pheochromocytoma or insulin-dependent diabetes, since nicotine causes the release of catecholamines by the adrenal medulla.

Peptic Ulcer Disease

Nicotine delays healing in peptic ulcer disease; therefore, NICOTROL Inhaler therapy should be used with caution in patients with active peptic ulcers and only when the benefits of including nicotine replacement in a smoking cessation program outweigh the risks.

Accelerated Hypertension

Nicotine therapy constitutes a risk factor for development of malignant hypertension in patients with accelerated hypertension; therefore, NICOTROL Inhaler therapy should be used with caution in these patients and only when the benefits of including nicotine replacement in a smoking cessation program outweigh the risks.

Information for Patient

A patient information sheet is included in the package of NICOTROL Inhaler cartridges dispensed to the patient. Patients should be encouraged to read the information sheet carefully and to ask their physician and pharmacist about the proper use of the product (See DOSAGE AND ADMINISTRATION). Patients must be advised to keep both used and unused cartridges out of the reach of children and pets.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Nicotine itself does not appear to be a carcinogen in laboratory animals. However, nicotine and its metabolites increased the incidences of tumors in the cheek pouches of hamsters and forestomach of F344 rats, respectively when given in combination with tumor-initiators. One study, which could not be replicated, suggested that cotinine, the primary metabolite of nicotine, may cause lymphoreticular sarcoma in the large intestine of rats. Neither nicotine nor cotinine was mutagenic in the Ames salmonella test. Nicotine induced reparable DNA damage in an E. coli test system. Nicotine was shown to be genotoxic in a test system using Chinese hamster ovary cells. In rats and rabbits, implantation can be delayed or inhibited by a reduction in DNA synthesis that appears to be caused by nicotine. Studies have shown a decrease in litter size in rats treated with nicotine during gestation.

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 Inhaler therapy 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 Inhaler therapy 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.

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.

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 Inhaler therapy has not been studied in pregnant women.

Labor and Delivery

NICOTROL Inhaler is not recommended for use during labor and delivery. The effect of nicotine on a mother or the fetus during labor is unknown.

Use in Nursing Mothers

Caution should be exercised when the NICOTROL Inhaler is administered to nursing mothers. The safety of NICOTROL Inhaler therapy in nursing infants has not been examined. Nicotine passes freely into breast milk; the milk to plasma ratio averages 2.9. Nicotine is absorbed orally. An infant has the ability to clear nicotine by hepatic first-pass clearance; however, the efficiency of removal is probably lowest at birth. Nicotine concentrations in milk can be expected to be lower with NICOTROL Inhaler when used as recommended than with cigarette smoking, as maternal plasma nicotine concentrations are generally reduced with nicotine replacement. The risk of exposure of the infant to nicotine from NICOTROL Inhaler therapy should be weighed against the risks associated with the infant's exposure to nicotine from continued smoking by the mother (passive smoke exposure and contamination of breast milk with other components of tobacco smoke) and from the NICOTROL Inhaler alone, or in combination with continued smoking.

Pediatric Use

Safety and effectiveness in pediatric and adolescent patients below the age of 18 years have not been established for any nicotine replacement product. However, no specific medical risk is known or expected in nicotine dependent adolescents. NICOTROL Inhaler should be used for the treatment of tobacco dependence in the older adolescent only if the potential benefit justifies the potential risk.

Geriatric Use

Clinical studies of NICOTROL Inhaler did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reports on clinical experience have not identified differences between older and younger patients. In general, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosage range reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease.

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.

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.

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 present in greater than 3% of patients on active drug include chest discomfort, bronchitis, and hypertension.

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, paresthesias, flatulence and fever.

NICOTROL Inhaler is likely to have a low abuse potential based on differences between the product and cigarettes in three characteristics commonly considered important in contributing to abuse: slower absorption, smaller fluctuations in blood levels and lower blood levels of nicotine. NICOTROL Inhaler, like many other nicotine-based smoking cessation therapies, does not produce arterial concentrations similar to cigarettes. However, nicotine withdrawal symptoms were noted in clinical trials at the time of NICOTROL Inhaler tapering and after NICOTROL Inhaler discontinuation.

Dependence might occur from transference of tobacco-related nicotine dependence to the NICOTROL Inhaler. The use of the inhaler beyond 6 months has not been evaluated in clinical trials and is not recommended. To minimize the risk of dependence, patients should be encouraged to withdraw gradually from NICOTROL Inhaler therapy after 3 months of usage (See DOSAGE AND ADMINISTRATION). If necessary, dose reduction can be achieved by gradual reduction of the dose over a 6 to 12 week period.

Signs and Symptoms of Nicotine Toxicity

Signs and symptoms of an overdose of the NICOTROL Inhaler would be expected to be the same as those of acute nicotine poisoning including: pallor, cold sweat, nausea, salivation, vomiting, abdominal pain, diarrhea, headache, dizziness, disturbed hearing and vision, tremor, mental confusion, and weakness. Prostration, hypotension, and respiratory failure may ensue with large overdoses. Lethal doses produce convulsions quickly and death follows as a result of peripheral or central respiratory paralysis or, less frequently, cardiac failure.

Overdose from Inhalation

The oral LD50 for nicotine is >5 mg/kg in dogs and >24 mg/kg in rodents. Death is due to respiratory paralysis. The oral minimum acute lethal dose for nicotine in adult humans is reported to be 40 to 60 mg (<1 mg/kg). The effects of using several cartridges in rapid succession are unknown (See WARNINGS, Safety Note Concerning Children).

One cartridge of NICOTROL Inhaler contains 10 mg nicotine, of which, approximately 4 mg is delivered nicotine. It is unlikely that an excessive nicotine overdose will occur via inhalation. Should such an overdose occur, however, with signs of nicotine poisoning, the patient should be instructed to contact his/her physician immediately. For additional emergency information, call your regional poison center or call the National Capital Poison Center toll free (1-800-222-1222).

Overdose from Ingestion

Persons ingesting NICOTROL Inhaler cartridges should be referred to a health care facility for management. In unconscious patients with a secure airway, instill activated charcoal via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal. Repeated doses of activated charcoal should be administered as long as the cartridge remains in the gastrointestinal tract since it will continue to release nicotine for many hours. The NICOTROL Inhaler cartridges can be identified with a radiogram.

Management of Nicotine Poisoning

Other supportive measures include diazepam or barbiturates for seizures, atropine for excessive bronchial secretions or diarrhea, respiratory support for respiratory failure, and vigorous fluid support for hypotension and cardiovascular collapse.