CONTRAINDICATIONS
Use of nicotine inhalation system therapy is contraindicated in patients with known hypersensitivity
or allergy to nicotine or to menthol.
WARNINGS
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.
Use in Pregnancy: Tobacco smoke, which has been shown to be harmful to the fetus, contains
nicotine, hydrogen cyanide, and carbon monoxide. The nicotine inhalation system 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 the nicotine inhalation system can cause fetal harm
when administered to a pregnant woman. The effect of nicotine delivery by the nicotine inhalation
system 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 the nicotine inhalation system 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 symptoms of poisoning and could prove fatal if the nicotine from the nicotine inhalation
system is inhaled, ingested, or buccally absorbed by children or pets. 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 the nicotine inhalation system out of the
reach of children and pets. All components of the nicotine inhalation system system should also be
kept out of the reach of children and pets to avoid accidental swallowing and choking.
PRECAUTIONS
General
The patient should be urged to stop smoking completely when initiating nicotine inhalation system
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 the
nicotine inhalation system by patients who stop smoking has not been studied and is not
recommended. (See DRUG ABUSE AND DEPENDENCE.)
Bronchospastic Disease
The nicotine inhalation system has not been specifically studied in asthma or chronic pulmonary
disease. Nicotine is an airway irritant and might cause bronchospasm. The nicotine inhalation
system 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 the nicotine inhalation
system as well as with other nicotine replacement therapies. No serious cardiovascular events were
reported in clinical studies with the nicotine inhalation system, but if such symptoms occur, its use
should be discontinued.
The nicotine inhalation system 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 CLINICAL
PHARMACOLOGY, Pharmacokinetics).
Endocrine Diseases
Nicotine inhalation system 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, nicotine inhalation system 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, nicotine inhalation system 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 the Patient
A patient information sheet is included in the package of nicotine inhalation system 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.
Carcinogenesis, Mutagenesis, and 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 Category D
(See WARNINGS.) 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 nicotine inhalation system 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.
Nicotine inhalation system 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 ug/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.
Nicotine inhalation system therapy has not been studied in pregnant women.
Labor and Delivery
Nicotine inhalation system is not recommended for use during labor and delivery. The effect of
nicotine on a mother or the fetus during labor is unknown.
Nursing Mothers
Caution should be exercised when the nicotine inhalation system is administered to nursing mothers.
The safety of nicotine inhalation system 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 nicotine inhalation system 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 nicotine inhalation system 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 nicotine inhalation system 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. Nicotine inhalation system should be used for the
treatment of tobacco dependence in the older adolescent only if the potential benefit justifies the
potential risk.
Geriatric Use
One hundred and thirty-two patients aged 60 or more participated in clinical trials of nicotine
inhalation system. The nicotine inhalation system appeared to be as effective in this age group as in
younger smokers. Because medical conditions that are precautions to nicotine use are more
common in the elderly, physicians should use care in prescribing this product to these patients.