NICOTROL Inhaler Ref.[50143] Active ingredients: Nicotine

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. The NICOTROL Inhaler does not deliver hydrogen cyanide and carbon monoxide. However, nicotine has been shown in animal studies to cause fetal harm. It is therefore presumed that NICOTROL Inhaler can cause fetal harm when administered to a pregnant woman. The effect of nicotine delivery by NICOTROL Inhaler 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 Inhaler 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

This product contains nicotine and should be kept out of the reach of children and pets. The amounts of nicotine that are tolerated by adult smokers can produce signs and symptoms of poisoning and could prove fatal if the nicotine from the NICOTROL Inhaler is inhaled, ingested, or buccally absorbed by children or pets. Suspected nicotine poisoning in a child should be considered a medical emergency and treated immediately. A cartridge contains about 60% of its initial drug content when it is discarded, which is about 6 mg. Patients should be cautioned to keep both the used and unused cartridges of NICOTROL Inhaler out of the reach of children and pets.

All components of the NICOTROL Inhaler system should also be kept out of the reach of children and pets to avoid accidental swallowing and choking.

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), paresthesias, 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

Skin and subcutaneous tissue disorders: rash

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

Pharmacokinetic studies in patients with moderate to severe renal impairment or moderate to severe hepatic impairment have shown decreased nicotine clearance. The pharmacokinetics of nicotine have not been studied in the elderly. 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 with potential for increased adverse effects) are anticipated. Moderate and severe renal impairment are expected to affect the clearance of nicotine or its metabolites from the circulation (See PHARMACOKINETICS). Consider dose reduction and monitoring patients for adverse events (such as nausea or dizziness) associated with elevated levels of nicotine.

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 esophagitis, active gastric or 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.

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).

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.

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.

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.

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 Inhaler therapy has not been studied in pregnant women.

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.

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.

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.

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.

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.