CONTRAINDICATIONS
Use of nicotine inhalation system therapy is contraindicated in patients with known hypersensitivity
or allergy to nicotine or to menthol.
Use of nicotine transdermal systems is contraindicated in patients with hypersensitivity or allergy to
nicotine or to any of the components of the therapeutic system.
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.
.
The patient should be urged to stop smoking completely when initiating nicotine transdermal therapy
(see DOSAGE AND ADMINISTRATION). Patients should be informed that if they continue to
smoke while using nicotine transdermal systems, 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 nicotine transdermal system
dose should be reduced or nicotine transdermal system treatment discontinued (see WARNINGS).
Physicians should anticipate that concomitant medications may need dosage adjustment, see DRUG
INTERACTIONS.
The use of nicotine transdermal systems beyond 3 months by patients who stop smoking should be
discouraged, because the chronic consumption of nicotine by any route can be harmful and
addicting.
Allergic Reactions
In a 6-week, open-label, dermal irritation and sensitization study of nicotine transdermal systems, 7
of 230 patients exhibited definite erythema at 24 hours after application. Upon rechallenge, 4
patients exhibited mild to moderate contact allergy. Patients with contact sensitization should be
cautioned that a serious reaction could occur from exposure to other nicotine-containing products or
smoking. In the efficacy trials, erythema following system removal was typically seen in about 14%
of patients, some edema in 3%, and dropouts due to skin reactions occurred in 2% of patients.
Patients should be instructed to promptly discontinue the use of nicotine transdermal systems and
contact their physicians, if they experience severe or persistent local skin reactions (e.g., severe
erythema, pruritus, or edema) at the site of application or a generalized skin reaction (e.g., urticaria,
hives, or generalized rash).
Patients using nicotine transdermal therapy concurrently with other transdermal products may
exhibit local reactions at both application sites. Reactions were seen in two of seven patients using
concomitant Estraderm (estradiol transdermal system) in clinical trials. In such patients, use of one
or both systems may have to be discontinued.
Skin Disease
Nicotine transdermal systems are usually well tolerated by patients with normal skin, but may be
irritating for patients with some skin disorders (atopic or eczematous dermatitis).
Cardiovascular or Peripheral Vascular Diseases
The risks of nicotine replacement in patients with certain 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) should be carefully screened and evaluated before
nicotine replacement is prescribed.
Tachycardia occurring in association with the use of nicotine transdermal therapy was reported
occasionally. If serious cardiovascular symptoms occur with the use of nicotine transdermal
therapy, it should be discontinued.
Nicotine transdermal therapy was as well tolerated as placebo in a controlled trial in patients with
coronary artery disease (see CLINICAL STUDIES). One patient on Nicoderm 21 mg/day, two on
Nicoderm 14 mg/day, and eight on placebo discontinued treatment due to adverse events.
Nicotine transdermal therapy did not affect angina frequency or the appearance of arrhythmias on
Holter monitoring in these patients.
Nicotine transdermal therapy generally should not be used in patients during the immediate
post-myocardial infarction period, patients with serious arrhythmias, and patients with severe or
worsening angina pectoris.
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 (seeCLINICAL
PHARMACOLOGY, Pharmacokinetics).
Endocrine Diseases
Nicotine transdermal 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 transdermal 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 transdermal 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 instruction sheet is included in the package of nicotine transdermal systems dispensed to
the patient. The instruction sheet contains important information and instructions on how to properly
use and dispose of nicotine transdermal systems. Patients should be encouraged to ask questions of
the physician and pharmacist.
Patients must be advised to keep both used and unused systems 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 in rats.
Nicotine and cotinine were not mutagenic in the Ames Salmonella test. Nicotine induced repairable
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, increased risk of spontaneous abortion, and increased perinatal mortality.
The specific effects of nicotine transdermal 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 transdermal therapy should be used during pregnancy only if the likelihood of smoking
cessation justifies the potential risk of use of nicotine replacement by the patient who may continue
to smoke.
Teratogenicity
Animal Studies: Nicotine was shown to produce skeletal abnormalities in the offspring of mice
when given doses toxic 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 1 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 mg/kg/min nicotine for 20 minutes to pregnant rhesus monkeys (equivalent to
smoking about 6 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 effect of cigarette
smoking on fetal cardiovascular parameters has been studied near term. Cigarettes increased fetal
aortic blood flow and heart rate and decreased uterine blood flow and fetal breathing movements.
Nicotine transdermal therapy has not been studied in pregnant humans.
Labor and Delivery
The nicotine transdermal system is not recommended to be left on during labor and delivery. The
effects of nicotine on a mother or the fetus during labor are unknown.
Nursing Mothers
Caution should be exercised when nicotine transdermal therapy is administered to nursing women.
The safety of nicotine transdermal 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. The nicotine concentrations in milk can be expected to be lower
with nicotine transdermal therapy, when used as directed, 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 transdermal 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 nicotine transdermal therapy alone or in combination with continued smoking.
Pediatric Use
Nicotine transdermal therapy is not recommended for use in children, because the safety and
effectiveness of nicotine transdermal therapy in children and adolescents who smoke have not been
evaluated.
Geriatric Use
Fifty-six patients over the age of 60 participated in clinical trials of nicotine transdermal therapy.
Nicotine transdermal therapy appeared to be as effective in this age group as in younger smokers.
However, asthenia, various body aches, and dizziness occurred slightly more often in patients over
60 years of age.