ACTIONS
NICORETTE(r) patch (Nicotine Transdermal System) is a multilayered, laminated, flexible thin film containing nicotine as the active ingredient. NICORETTE(r) patch has been specifically designed to provide a 16-hour rate-controlled delivery of nicotine following its application to intact skin. It is intended to be applied during the day and removed at night prior to sleeping, thus minimizing the potential for any sleep disturbances. The NICORETTE(r) patch provides nicotine without the other ingredients in tobacco smoke (e.g. tar, carbon monoxide, hydrogen cyanide) thereby attenuating abstinence symptoms associated with nicotine withdrawal during the cessation of smoking. NICORETTE(r) patch increases the success rate of cessation in smokers who are motivated to quit.
INDICATIONS AND CLINICAL USE
NICORETTE(r) patch (Nicotine Transdermal System), applied while patients are awake, is indicated as a temporary aid to facilitate smoking cessation in smokers with a strong desire to quit and to provide partial substitution for the nicotine in cigarettes in order to lessen withdrawal symptoms of smoking cessation NICORETTE(r) patch treatment should be used as part of a comprehensive behavioural smoking-cessation program.
CONTRAINDICATIONS
The use of NICORETTE(r) patch (Nicotine Transdermal System) is contraindicated in the following:
Patients with hypersensitivity or allergy to nicotine or the components of the transdermal system. Patients with acute hypersensitivity reactions should discontinue use of the
NICORETTE(r) patch and should be advised of the possibility of acute hypersensitivity reactions to other forms of nicotine, including cigarettes; Patients with generalized skin disorders; Non-smokers or occasional smokers; Persons under 18 years of age (see WARNINGS); Pregnant women or nursing mothers (see WARNINGS); and Patients during the immediate post-myocardial infarction period, patients with life- threatening arrhythmias, patients with severe or worsening angina pectoris and patients who have had a recent cerebral vascular accident (see WARNINGS).
WARNINGS
General:
Nicotine from any source can be toxic and addictive. For any smoker, with or without concomitant disease, the risk of nicotine replacement in a smoking cessation program should be weighed against the hazard of continued smoking.
Safety Note Concerning Children and Pets:
The amounts of nicotine that are tolerated by adult smokers can cause severe poisoning and even prove fatal if the NICORETTE(r) patch (Nicotine Transdermal System) is applied or ingested by children or pets. Used NICORETTE(r) patches contain approximately 40% of their initial nicotine content. Therefore, patients should be cautioned to keep both the used and unused NICORETTE(r) patches out of the reach of children and pets.
Use in children:
NICORETTE(r) patch is not to be used by persons under 18 years of age. The use of NICORETTE(r) patch in children and adolescents who smoke has not been evaluated (see CONTRAINDICATIONS).
Pregnancy or Nursing Mothers:
Tobacco smoke (containing nicotine, hydrogen cyanide and carbon monoxide) has been shown to be harmful to the fetus. Nicotine has been shown in animal studies to cause fetal harm. There is a possibility that nicotine from NICORETTE(r) patches can cause fetal harm when administered to a pregnant woman. Women of child-bearing potential should be advised to take adequate precautions to avoid becoming pregnant while using NICORETTE(r) patches (see CONTRAINDICATIONS). Pregnant smokers should be encouraged to attempt cessation using educational and behavioural interventions before using pharmacological approaches. The safety of the NICORETTE(r) patch 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 (see CONTRAINDICATIONS).
Cardiovascular or Peripheral Vascular Disease:
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 recommended. Palpitations occurring in association with the use of NICORETTE(r) patch therapy have been reported occasionally. If serious cardiovascular symptoms occur with the use of NICORETTE(r) patch therapy, it should be discontinued.
Accelerated Hypertension:
NICORETTE(r) patch 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. Peptic Ulcer Disease: Nicotine delays healing in peptic ulcer disease; therefore, NICORETTE(r) patch 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 are considered to outweigh the risks.
PRECAUTIONS
General:
The patient should stop smoking completely when initiating NICORETTE(r) patch therapy (Nicotine Transdermal System) (see DOSAGE AND ADMINISTRATION). Patients should be informed that they should not continue to smoke while using NICORETTE(r) patches, because 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 NICORETTE(r) patch dose should be reduced or NICORETTE(r) patch treatment discontinued (see WARNINGS). The use of NICORETTE(r) patches beyond 10 weeks by patients who stop smoking should be discouraged because the chronic consumption of nicotine by any route can be harmful and addicting. If the patient continues to smoke, treatment should be discontinued.
Allergic Reactions:
Patients should be instructed to discontinue promptly the use of NICORETTE(r) patches and contact their physician if they experience severe or persistent local skin reactions (e.g. urticaria, hives, or generalized rash). Patients using NICORETTE(r) patch therapy concurrently with other transdermal systems may exhibit local reactions at both application sites. In such patients use of one or both systems may have to be discontinued. Serious allergic reactions may occur rarely. About 1% of patients dropped out of clinical trials due to skin reactions; none had classical contact sensitization.
Skin Disease:
NICORETTE(r) patches are usually well tolerated by patients with normal skin, but may be irritating for patients with some skin disorders (atopic or eczematous dermatitis).
Strenuous Exercise:
Preliminary evidence suggests that wearing a nicotine transdermal patch during periods of strenuous exercise may lead to nicotine toxicity as a result of increased absorption of nicotine from the depot of nicotine in the skin under the patch, due to increased skin temperature and increased cutaneous vasodilation and perfusion from exercising. Three cases illustrating this phenomenon were described in Health Canada Adverse Reaction Newsletter, Volume 6, Number 1, January 1996. Advice to remove the nicotine patch before engaging in strenuous exercise was recommended by; W. Dafoe and P. Huston, Current Trends in Cardiac Rehabilitation, Canadian Medical Association Journal, February 15, 1997; 156(4) 527-532. Until definitive studies have been undertaken to clarify this hazard, it is advisable to remove the nicotine patch prior to engaging in strenuous activity.
Use in Elderly:
Seventy-nine patients over the age of 60 participated in clinical trials of NICORETTE(r) patch therapy. NICORETTE(r) patch therapy appeared to be as effective in this age group as in younger smokers. The initial dose in elderly patients may have to be adjusted because their concomitant diseases may increase risk.
Endocrine Diseases:
NICORETTE(r) patch 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.
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.
Physicians should anticipate that the pharmacokinetics of certain concomitant medications may be altered by smoking cessation with or without nicotine replacement. Therefore the dosage of certain concomitant medications may require adjustment (see Table below).
| May Require a DECREASE in Dose at Cessation of Smoking | Possible Mechanism |
| Acetaminophen, caffeine, imipramine, oxazepam, pentazocine, propranolol, theophylline | Deinduction of hepatic enzymes on smoking cessation |
| Insulin | Increase in subcutaneous insulin absorption with smoking cessation |
| Adrenergic antagonists (e.g. prazosin, labetalol) | Decrease in circulating catecholamines with smoking cessation |
| May Require an INCREASE in Dose at Cessation of Smoking | Possible Mechanism |
| Adrenergic agonists (e.g. isoproterenol, phenylephrine) | Decrease in circulating catecholamines with smoking cessation |
NICORETTE(r) patch therapy is likely to have a low abuse potential based on differences between it and cigarettes in four characteristics commonly considered important in contributing to abuse: much slower absorption, much smaller fluctuations in blood levels, lower blood levels of nicotine, and less frequent use (i.e., once daily). Dependency on NICORETTE(r) patch has not been reported. To minimize the risk of dependence, therapy should not exceed 10 weeks (see DOSAGE AND ADMINISTRATION).
A separate Patient Instruction Leaflet is included in the package of NICORETTE(r) patches (see INFORMATION FOR THE CONSUMER). It contains important information on how to use and dispose of NICORETTE(r) patches, properly. Patients should be encouraged to ask questions to ensure they understand the instructions. Patients must be advised to keep both used and unused NICORETTE(r) patches out of the reach of children and pets.
ADVERSE REACTIONS
Assessment of adverse events in patients who participated in controlled clinical trials is complicated by the occurrence of GI and CNS effects of nicotine withdrawal as well as nicotine excess. The actual incidence of both are confounded by concurrent smoking by many of the patients. When reporting adverse events in the clinical trials, the clinical investigators did not attempt to identify the cause of the symptom. The most common adverse event associated with NICORETTE(r) patch (Nicotine Transdermal System) is a mild, short-lived erythema and/or pruritus at the application site, which was seen at least once in 47% of patients on the NICORETTE(r) patches (versus 45% of patients on placebo) in the clinical efficacy trials. These signs were not considered clinically relevant and usually disappeared within one hour. After removal of the system, local erythema was noted at least once in 7% of patients and local edema in 3% of patients. Erythema generally resolved within 24 hours. About 1% of patients dropped out of the clinical trials due to skin reactions. None of these were classified as contact sensitization reactions. In the prescription to OTC switch trials approximately 32% of reported events were skin reactions. The following table summarizes the adverse events with an incidence of greater than 1% in 2 placebo-controlled clinical trials and 2 prescription to nonprescription switch trials.
In Placebo-Controlled Clinical Trials and Prescription to OTC Switch Trials
| Body System/Adverse Event | Prescription Treatment Groups | Prescription to OTC Switch | |
| Nicorette Patch % (n=258) | Placebo % (n=251) | Nicorette Patch % (n=3885) | |
| CNS: | |||
| Headache | 5.4 | 4.0 | 3.3 |
| Vertigo | 3.1 | 0.8 | - |
| Digestive: | |||
| Nausea | 3.5 | 4.0 | 2.4 |
| Flatulence | 2.7 | 2.4 | - |
| Diarrhea | 1.9 | 1.6 | - |
| Taste Perversion | 1.9 | 1.6 | - |
| Mouth Ulceration | 1.6 | 0.4 | - |
| Heartburn/Indigestion | 1.2 | 2.4 | - |
| Tongue Disorder | 1.2 | 0.4 | - |
| Musculoskeletal: | |||
| Myalgia | 3.1 | 3.1 | - |
| Skin (Not Application Site): | |||
| Rash/Pruritus/Tingling/Edema | 1.9 | 1.2 | - |
| Acne | 1.2 | 0.0 | - |
| Body as a whole | |||
| Pain | - | - | 2.1 |
SYMPTOMS AND TREATMENT OF OVERDOSAGE
Symptoms:
There have been two reported cases of applying several nicotine patches simultaneously. Both people were attempting suicide and combined several nicotine patches, 21 mg, with other drugs. No serious effects resulted from either attempt. Signs and symptoms of an overdose from a NICORETTE(r) patch are 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 of nicotine produce convulsions quickly and death follows as a result of peripheral or central respiratory paralysis or, less frequently, cardiac failure. The acute, minimal, oral lethal dose of nicotine in human adults is believed to be 40 to 60 mg (<1 mg/kg). Much lower doses have been reported to be toxic in children.
Treatment:
The NICORETTE(r) patch should be removed immediately if the patient shows signs of over dosage and the patient should seek immediate medical care by contacting a physician or local poison-control centre. The skin surface should be flushed with water and dried. Soap must not be used since it may increase nicotine absorption. Nicotine will continue to be delivered into the bloodstream for several hours after removal of the system because of a depot of nicotine in the skin. Persons ingesting NICORETTE(r) patches should be referred to a health care facility for management. Due to the possibility of nicotine-induced seizures, activated charcoal should be administered. In unconscious patients with a secure airway, instill activated charcoal via a nasogastric tube. Repeated doses of activated charcoal should be administered as long as the system remains in the gastrointestinal tract since it will continue to release nicotine for many hours. A saline cathartic or sorbitol added to the first dose of activated charcoal may speed gastrointestinal passage of the system. 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.
DOSAGE AND ADMINISTRATION
Patients must desire to stop smoking and should be instructed to stop smoking immediately as they begin using NICORETTE(r) patch (Nicotine Transdermal System) therapy. If the patient is unable to avoid cigarette smoking within 2 weeks of starting treatment, NICORETTE(r) patch therapy should be stopped, since few additional patients in clinical trials were able to quit after this time. The duration of treatment should not exceed 10 weeks. The patient should be told to read the patient instruction leaflet on NICORETTE(r) patch therapy and should be encouraged to ask questions.
: One patch daily for six weeks. For patients who wish to wean themselves rather than abruptly stop, follow the regimen outlined in the table below:
| Dose | Duration |
| Nicorette Patch 15 mg/16 hours Nicorette Patch 10 mg/16 hours Nicorette Patch 5 mg/16 hours | First 6 weeks Next 2 weeks Last 2 weeks |
Smoking cessation should be accompanied by a behavioral support program.
The NICORETTE(r) patch system should be applied promptly upon its removal from the protective pouch to prevent loss of nicotine from the system. A NICORETTE(r) patch should be applied only once a day to a non-hairy, clean, and dry skin site on the upper arm or the hip. A different site of application should be chosen each day. Each day a new NICORETTE(r) patch should be applied upon waking and removed at bedtime. It should not be worn for more than 16 hours/day.
SPECIAL INSTRUCTIONS
NICORETTE(r) patches can be a dermal irritant and can cause contact sensitization. Care should be taken to avoid unnecessary contact with active systems. If you do handle active systems, wash with water alone since soap may increase nicotine absorption. Do not touch your eyes.
When the used system is removed from the skin, it should be folded over and placed in its pouch. The used system should be disposed of immediately in such a way as to prevent its access by children or pets (see patient information leaflet for further directions on handling and disposal).
PHARMACEUTICAL INFORMATION
Drug Substance: Proper Name: nicotine Chemical Names: S-3- (1-methyl-2-pyrrolidinyl)pyridine 1-methyl-2- (3-pyridyl) pyrrolidine ss- pyridyl-[? ]-N-methylpyrrolidine Structural Formula: Molecular Formula: C10H14N2 Molecular Weight: 162.23 Physical Form: Nicotine is a clear, colorless to pale yellow oily liquid with an unpleasant pungent odour; it is volatile, hygroscopic, and turns brown on exposure to air or light. Solubility: Nicotine is miscible with water below 60degC; very soluble in alcohol, chloroform, ether, petroleum ether, kerosene and oils. pKa: 3.04 and 7.84 (at 15degC) pH: 10.2 (0.05 M solution) Octanol-water partition coefficient: 15:1 at pH 7 Boiling Point: 247degC (at 745 mm Hg) with partial decomposition at 123-125degC (at 17 mm Hg).
Composition: The NICORETTE(r) patch (Nicotine Transdermal System) is a multilayered, rectangular-shaped, laminated thin film containing nicotine as the active ingredient. Proceeding from the visible surface toward the surface attached to the skin, there are 3 distinct layers:
An outer backing layer composed of a laminated polyester film.
A middle layer containing an adhesive, a structural non-woven material and nicotine. The adhesive controls the rate of delivery of nicotine to the skin.
A disposable liner that protects the systems; the liner is removed prior to use.
Stability and Storage: Store at room temperature below 30degC. Once removed from the protective pouch, NICORETTE(r) patches should be applied promptly since nicotine is volatile and the system may lose strength.
AVAILABILITY
NICORETTE(r) patches (Nicotine Transdermal System) are labelled with the average amount of nicotine absorbed by the patient over 16 hours. NICORETTE(r) patches are available in packages of 7 and 14 patches in the following 3 strengths:
| Strength (amount available) | Size | Total Amount of nicotine | Patch imprint |
| 15 mg/ 16 hours system | 30 cm 2 | 24.9 mg | Nicorette 15 mg |
| 10 mg/ 16 hours system | 20 cm 2 | 16.6 mg | Nicorette 10 mg |
| 5 mg /16 hours system | 10 cm 2 | 8.3 mg | Nicorette 5 mg |
INFORMATION FOR THE CONSUMER
The following Patient Instruction Booklet (Insert) is included in the package of NICORETTE (r) patch (Nicotine Transdermal System).
Mfr. Std.
This leaflet provides general information about nicotine and specific information about NICORETTE(r) Patch treatment. Please read all of it carefully, especially the section marked "Important Cautions", before you start using the patches. If you have any questions or want more information, be sure to ask your doctor or pharmacist or call 1-888-730-INFO.
The NICORETTE(r) patch can help you stop smoking cigarettes. Although it may be an effective aid, it is only one part of your stop smoking program. Your own chances of quitting smoking depend on how much you want to quit, how strongly you are addicted to nicotine, and how closely you follow a stop smoking program, like the ACTIVESTOP Program that is available with the NICORETTE(r) patch. For information on the ACTIVE STOP Program see www.nicorette.ca. YOUR SUCCESS IN THIS PROGRAM IS DIRECTLY RELATED TO YOUR COMMITMENT TO STOP SMOKING.
There are immediate beneficial effects on your health when you stop smoking. However, when using NICORETTE(r) patches certain precautions must be taken for their safe use.
Can you smoke or use other nicotine containing products while using the NICORETTE(r) Patch?
You must not smoke, chew nicotine gum or tobacco, or use snuff while using a NICORETTE(r) patch because you may overdose on nicotine. Signs of a nicotine overdose include bad headaches, dizziness, upset stomach, drooling, vomiting, diarrhea, cold sweat, blurred vision, difficulty with hearing, mental confusion, weakness and fainting. If you experience any of these symptoms, consult your doctor, or local poison control center, immediately.
In certain medical conditions, the NICORETTE(r) patch should not be used. Be sure to tell your doctor or pharmacist before trying the NICORETTE(r) patch if you have had any of the following:
a heart attack (myocardial infarction) or stroke
irregular heart beat (arrhythmia)
severe or worsening heart pain (angina)
heart disease
stomach problems or ulcers
allergies to drugs
allergic reaction from adhesive tape or bandages
skin diseases
high blood pressure
overactive thyroid
diabetes requiring insulin
kidney or liver disease
treatment for poor circulation
treatment of circulation disorders of the brain
Smoking may alter the effects of some medicines. Once you have quit, it may be necessary for your doctor to adjust the doses of medicines you may be using. Therefore, it is important to tell your doctor or pharmacist about ALL medicines you are taking and consult them before you use the NICORETTE(r) patch.
Nicotine in any form may cause harm to your unborn baby if you use nicotine while you are pregnant. Do not use NICORETTE(r) patches if you are pregnant or nursing. Be careful not to become pregnant while using NICORETTE(r) patches. If you think you might be pregnant, do not use NICORETTE(r) patches until you have talked to your doctor.
The NICORETTE(r) patch is a skin patch containing nicotine designed to help you quit smoking cigarettes. When you put a NICORETTE(r) patch on your skin, nicotine passes from the patch through the skin and into your blood. It is the nicotine in cigarettes that causes addiction to smoking, and helps to relieve symptoms of nicotine withdrawal such as irritability, frustration, anger, anxiety, difficulty in concentration and restlessness. A NICORETTE(r) patch is applied when you wake up each day and worn during your waking hours for 16 hours. The patch is removed at bedtime, thus allowing a patch-free period while you sleep.
There are 3 steps in the NICORETTE(r) patch Program. Step 1: Establish your quit date and stop smoking completely before you begin using the NICORETTE(r) patch. You will begin treatment with the 15 mg NICORETTE(r) patch. Use one patch daily for 6 weeks. After that you may stop or, if you prefer you can slowly reduce the amount of NICORETTE(r) patch you use until you stop using the patches completely. Step 2: Begin your weaning phase by using the 10 mg patch for 2 weeks. Step 3: Complete your weaning phase by using the 5 mg patch for 2 weeks.
| Step 1 (15 mg) | ||
| Treatment begins Weeks 1 to 6 | Step 2 (10 mg) | |
| Step 3 (5 mg) | ||
| Phase out Period | ||
| Weeks 7 to 8 | Weeks 9 to 10 | |
Do not use the NICORETTE(r) patch for more than ten consecutive weeks without consulting a doctor.
?
When you wake up each day, select a location for application of the NICORETTE(r) patch on a healthy non-hairy, clean, dry area of the upper part of your arm or on the hip. Do not shave the area, as this may be irritating to the skin, when the patch is applied. Do not put the NICORETTE(r) patch on skin that is very oily, inflamed, swollen, red, burned, broken out, cut, or irritated in any way, since these conditions may alter the amount of drug absorbed.
Do not remove the NICORETTE(r) patch from its sealed protective pouch until you are ready to use it because it will lose strength if stored out of the pouch. Using scissors, cut along the dotted line to open the pouch. Save the pouch, because you will use it when throwing away the NICORETTE(r) patch at bedtime (see 6).
A clear protective release liner covers the sticky side of the NICORETTE(r) patch - the side that will be put on your skin. The liner has a partial cut in it to help you remove it from the patch. With the sticky side facing you, pull the liner away from the NICORETTE(r) patch. Try not to touch the adhesive surface with your hands.
Immediately apply the sticky side of the NICORETTE(r) patch to your skin on a clean, dry, non-hairy portion of your upper arm or hip. Firmly press down on the patch and rub it with your palm for 10-20 seconds to ensure that the patch sticks well especially around the edges. Note that adhesion may be impacted by many factors such as skin type or weather
conditions. Should the patch become loose, re-apply with a bandage or adhesive dressing tape. Rinse your hands with water (DO NOT USE SOAP, soap increases the absorption of nicotine) when you have finished applying the NICORETTE(r) patch. Nicotine on your hands could get into your eyes and nose and could cause stinging, redness, or more serious problems. Remove the patch before you go to bed, thus allowing for a patch-free period during sleep. Fold the used patch in half with the sticky side together. Place it in its pouch (kept from the morning application) or place it in a piece of aluminum foil. Dispose of the used patch out of the reach of children and pets. Choose a different place on your skin to apply a new NICORETTE(r) patch the next day and repeat 1-6. The same area should not be used again for at least one week.
You should put on a new NICORETTE (r) patch each day at about the same time after you wake up so that you don't forget. The patch should be removed at bedtime to provide a patch-free (nicotine- free) period. Do not wear it for more than 16 hours each day. The patch should be removed 2 hours before engaging in prolonged strenuous exercise. Fold the used patch in half with the sticky side together. Place it in its pouch or in a piece of aluminum foil. Dispose of the used patch out of the reach of children and pets. Reapply a new patch after exercising.
The NICORETTE(r) patch adheres very firmly to the skin. You may keep it on while using a hot tub, bathing, or taking a shower.
If the NICORETTE(r) patch falls off, put a new one on a different skin area that is clean and dry. Remove the new patch, as usual, at bedtime.
When you first put on a NICORETTE(r) patch, mild itching, burning, or tingling is common and should go away within an hour. After you remove the patch, the skin under the patch might be somewhat red, but it should not stay red for more than a day. If you get a skin rash after using a NICORETTE(r) patch or if the skin under the patch becomes swollen or very red, remove the patch and call your doctor. Do not put on a new patch. It is possible you may be allergic to one of the components of the patch. If you do become allergic to NICORETTE(r) patches, you could get sick from using cigarettes or other nicotine-containing products.
Keep each NICORETTE(r) patch in its protective pouch until you are ready to use it because the patch will lose nicotine into the air if it is stored outside the pouch. Store at room temperature below 30degC because the patches are sensitive to heat. Remember, the inside of your car can reach temperatures much higher than this in the summer.
NICORETTE(r) PATCHES CAN BE POISONOUS AND EXTREMELY DANGEROUS TO CHILDREN OR PETS IF APPLIED TO THE SKIN OR SWALLOWED. KEEP NEW OR USED NICORETTE PATCHES OUT OF THE REACH OF CHILDREN AND PETS. DO NOT SMOKE EVEN WHEN YOU ARE NOT WEARING THE PATCH. THE NICOTINE IN YOUR SKIN WILL STILL BE ENTERING YOUR BLOODSTREAM FOR SEVERAL HOURS AFTER YOU TAKE THE PATCH OFF. REMOVE THE NICOTINE PATCH AND CONSULT YOUR DOCTOR IF YOU EXPERIENCE IRREGULAR HEART BEAT, CHEST PAIN, PALPITATIONS OR LEG PAIN OR IF SEVERE STOMACH UPSET (INDIGESTION, HEARTBURN) DEVELOPS.
The average amount of nicotine delivered to the patient from each NICORETTE(r) patch (31 mg/cm2/hr) is approximately proportional to the surface area of each system and results in systemic absorption of 5, 10 and 15 mg/day, respectively from each of the 3 systems over a 16-hour period. The dose of nicotine absorbed from the NICORETTE(r) patches represents approximately 95% of the amount released in 16 hours. The remainder is lost via evaporation from the edge. About 40% of the total amount of nicotine remains in the system 16 hours after application. The composition of the 3 dosages of NICORETTE(r) patches are as follows:
| Nicorette Dose | Dose Absorbed (mg/16 hours) | System Surface Area (cm 2 ) | Total Nicotine Content (mg) |
| Treatment Dose | 15 | 30 | 24.9 |
| First Weaning Dose | 10 | 20 | 16.6 |
| Second Weaning Dose | 5 | 10 | 8.3 |
Nicotine, the chief alkaloid in tobacco products, stereo-selectively binds to acetylcholine 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 responsible for nicotine's positively reinforcing properties. A stimulating effect, exerted mainly in the cortex via the locus ceruleus, produces increased alertness and cognitive performance. A "reward" effect via the "pleasure system" in the brain 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. 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 one hour), but at distinct rates 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 for smoking. Withdrawal from nicotine in addicted individuals is 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 dose-related and 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.
Following the first application of a NICORETTE(r) patch, plasma nicotine concentrations gradually increase to reach peak levels within 5-10 hours and then slowly decline until the system is removed, after which the terminal elimination half-life of nicotine is about 4 hours. The mean peak plasma level of nicotine achieved with the 15 mg/day system is 9-15 ng/mL. After repeated application of the NICORETTE(r) patch, plasma nicotine concentrations were not significantly higher than those after a single application, indicating no accumulation (see Table and Figure below).
| Day (15 mg/16 hour System) | AUC (ng.h/mL) | AUC Inf (ng.h/mL) | C MAX (ng/mL) | t g (h) | T MAX (h) |
| 1 | 12.2 | 13.0 | 13.0 | 3.7 | 8.0 |
| 6 | 12.2 | 12.9 | 14.2 | 3.4 | 6.0 |
Plasma nicotine concentrations show a slight deviation from dose proportionality for the three NICORETTE(r) patch doses: with increasing system size the increase in concentration is somewhat less than expected. Nicotine kinetics are similar following application of the patch on the arm and hip. Following removal of the NICORETTE(r) patch after 16 hours of wear, plasma nicotine concentrations decline in an apparently exponential fashion. The half-life after removal was about twice that observed after intravenous infusion, suggesting continued absorption from the skin depot. Patients had non-detectable nicotine concentrations within 10 to 12 hours after removing the system. The average plasma nicotine level is about 20 to 36 ng/mL in moderate to heavy smokers. In comparison, the average plasma nicotine concentration in subjects delivered from the NICORETTE(r) patch 15 mg/16 hours is about 9 ng/mL.
Steady State Nicotine Pharmacokinetic Parameters for Nicorette(r) Patches
Applied for 16 Hours (N = 12)
| Range of Delivery Rate (mg/day) | |||
| 15 * Mean +- SD | 10 Mean +- SD | 5 Mean +- SD | |
| C m ax (ng/mL) | 13.0 +- 3.1 (7.8 - 17.9) | 6.9 +- 2.0 (4.8 - 10.0) | 3.5 +- 0.7 (2.7 - 4.7) |
| C avg 16 (ng/mL) | 9.4 +- 2.4 (5.3 - 13.3) | 4.9 +- 1.2 (3.0 - 6.8) | 2.7 +- 0.5 (2.0 - 3.6) |
| C avg 24 (ng/mL) | 8.7 +- 2.1 (5.2 - 11.8) | 4.8 +- 1.0 (3.3 - 6.3) | 2.7 +- 0.4 (2.1 - 3.3) |
| C m in (ng/mL) | 2.5 +- 0.8 (1.2 - 4.1) | 1.4 +- 0.5 (0.5 - 2.4) | 0.8 +- 0.3 (0.3 - 1.2) |
| T m ax (hrs) | 8 +- 3 (4 - 16) | 9 +- 4 (6 - 16) | 9 +- 4 (3 - 16) |
Cmax : maximum observed plasma concentration
Cavg 16: estimated average plasma concentration during the 0 to 16 hour period, calculated as AUC (0-16)/16 Cavg 24: average plasma concentration calculated over 24 hrs
Cmin: minimum observed plasma concentration Tmax: time of maximum plasma concentration
* Data for 15 mg system are derived from a different study than the 5 and 10 mg systems.
There are no differences in nicotine kinetics between men and women using NICORETTE(r) patches. Linear regression of both AUC and Cmax versus total body weight shows the expected inverse relationship. Men and women having low body weight are expected to have higher AUC and Cmax values. The volume of distribution following i.v. administration of nicotine is approximately 2 to 3 L/kg and the half-life ranges from 1 to 2 hours. The major elimination organ is the liver, and average plasma clearance is about 1.2 L/min; the kidney and lung also metabolize nicotine. There is no significant skin metabolism of nicotine. More than 20 metabolites of nicotine have been identified, all of which are believed to be less active than the parent compound. The primary metabolite of nicotine in plasma, cotinine, has a half-life of 15 to 20 hours and concentrations that exceed nicotine by 10-fold. 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. The primary urinary metabolites are cotinine (15% of the dose) and trans-3-hydroxycotinine (45% of the dose). Usually about 10% of nicotine is excreted unchanged in the urine. As much as 30% may be excreted unchanged in the urine with high urine flow rates and acidification below pH 5.
The efficacy of NICORETTE(r) patch therapy as an aid to smoking cessation was demonstrated in two single-center, placebo-controlled, double-blind trials in smokers, smoking >=10 cigarettes per day (N=509), who were healthy or had diseases in their past medical history such as chronic obstructive pulmonary disease, hypertension, or myocardial infarction. In both clinical studies, NICORETTE(r) patches were applied on awakening and removed at bedtime each day. They were used with only limited behavioural support. Patients in both clinics were treated for 12 weeks followed by a 4 to 6 week weaning period. The subjects were followed for 18 to 24 months. In both studies, NICORETTE(r) patch therapy was more effective than placebo at 6 weeks, 6 months, 1 year, and 1.5 to 2 years. Quit rate data from both studies are reported in the following table.
| Study Site | Treatment | Number of | Quit Rates (%) |
| Group | Patients | Duration | ||||
| 6 Weeks | 6 Months | 1 Year | 18 Months */ 2 Years * * | |||
| Danish (a) | Nicorette | (n=145) | 53% | 24% | 17% | 12% * * |
| Study | Placebo | (n=144) | 17% | 5% | 4% | 3% * * |
| U S (b) | Nicorette | (n=113) | 61% | 34% | 25% | 24% * |
| Study | Placebo | (n=107) | 35% | 12% | 9% | 8% * |
Quit rates reported based on sustained abstinence definition (see Tonnesen et al, New Engl J Med 1991; 325:311-5).
Quit rates reported based on complete abstinence after week 2.
Patients who used NICORETTE(r) patches had a significant reduction in craving for cigarettes, a major nicotine withdrawal symptom, compared with placebo-treated patients. The effect on withdrawal symptoms, as with quit rate, is quite variable and is presumed to be due to inherent differences in patient populations, e.g., patient motivation, concomitant illness, number of cigarettes smoked per day, number of years smoking, exposure to other smokers, socioeconomic status, etc., as well as differences between the clinics themselves (one Danish, one U.S.). Patients using NICORETTE(r) patches withdrew from the trials less frequently than did patients receiving placebo. Quit rates for the 79 patients over age 60 were comparable to the quit rates for the 430 patients aged 60 and under. In addition, 2 OTC studies of healthy and high-risk smokers showed that when the NICORETTE(r) patch is used for 6 weeks as part of an OTC intervention package, it is as effective as when it is prescribed by a physician. The incidence of ADEs reported in the OTC studies did not differ from previous clinical trials or from common spontaneous reporting databases.
Only dermal irritation studies were performed with NICORETTE(r) patches, since the toxic effects of nicotine in animals have been well-documented in the literature.
Acute Toxicity: The acute toxicity of nicotine reported in the literature is summarized in the table below:
| Species | Route | Dose (mg/kg) | Response |
| Mouse | Oral | 24 | LD 50 |
| s.c. | 16 | LD 50 | |
| i.v. | 7.1 | LD 50 | |
| i.p. | 63.5 | LD 50 | |
| Rat | oral | 50-60 | Approx. LD 50 , convulsions, paralysis |
| i.v. | 9.4 | LD 50 | |
| Rabbit | dermal | 50 | Estimated LD 50 |
| Dog | i.v. | 5 | LD 50 |
| Cat | i.v. | 2 | LD 50 |
The oral LD50 for nicotine in rodents varies with species, but is in excess of 24 mg/kg. Death is due to respiratory paralysis.
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 fore-stomach 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. 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. Nicotine has been shown to produce skeletal abnormalities in the offspring of mice when given doses toxic to the dams (25 mg/kg subcutaneously or intraperitoneally). This is approximately 100 times the daily human dose of the NICORETTE(r) patch 15 mg/day. Studies in rats and monkeys have not demonstrated a teratogenic effect of nicotine at doses, which occur during cigarette smoking. 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.
Dermal irritation studies were conducted with NICORETTE(r) patches (0.83 mg nicotine/cm2) and matching placebos in rabbits (2 kg) and guinea pigs (0.25 kg). A primary skin irritation in rabbits revealed signs of erythema at the test sites of NICORETTE(r) patch treated and placebo-treated animals following a 24-hour application period. All signs of erythema cleared by 72 hours post-application. A dermal sensitization study in guinea pigs revealed no evidence of delayed contact sensitivity potential.
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