NICOTINE: 32,593 Adverse Event Reports & Safety Profile

DESCRIPTION NICOTROL ® NS (nicotine nasal spray) is an aqueous solution of nicotine intended for administration as a metered spray to the nasal mucosa. Nicotine is a tertiary amine composed of 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 NICOTROL NS. 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: C 10 H 14 N 2 Molecular Weight:

162.23 Ionization Constants: pKa 1 = 7.84, pKa 2 = 3.04 at 15°C Octanol-Water Partition Coefficient: 15:1 at pH 7 Each 10 mL spray bottle contains 100 mg nicotine (10 mg/mL) in an inactive vehicle containing disodium phosphate, sodium dihydrogen phosphate, citric acid, methylparaben, propylparaben, edetate disodium, sodium chloride, polysorbate 80, aroma and water. The solution is isotonic with a pH of 7. It contains no chlorofluorocarbons. After priming the delivery system for NICOTROL NS, each actuation of the unit delivers a metered dose spray containing approximately 0.5 mg of nicotine. The size of the droplets produced by the unit is in excess of 8 microns. One NICOTROL NS unit delivers approximately 200 applications.

Chemical

Structure

Use reduces withdrawal symptoms, including nicotine craving, associated with quitting smoking. Apply one new patch every 24 hours on skin that is dry, clean and hairless. Remove backing from patch and immediately press onto skin. Hold for 10 seconds. Wash hands after applying or removing patch. Save pouch to use for patch disposal. Dispose of the used patches by folding sticky ends together and putting in pouch. The used patch should be removed and a new one applied to a different skin site at the same time each day. If you have vivid dreams, you may remove the patch at bedtime and apply a new one in the morning. Do not wear more than one patch at a time. Do not cut patch in half or into smaller pieces. Do not leave patch on for more than 24 hours because it may irritate your skin and loses strength after 24 hours. To avoid possible burns, remove patch before undergoing any MRI (magnetic resonance imaging) procedures. It is important to complete treatment. If you feel you need to use the patch for a longer period to keep from smoking, talk to your healthcare provider.

DOSAGE AND ADMINISTRATION It is important that patients understand the instructions for use of NICOTROL NS, and have their questions answered. They should clearly understand the directions for using NICOTROL NS and safely disposing of the used container. They should be instructed to stop smoking completely when they begin using the product. Patients should be instructed not to sniff, swallow or inhale through the nose as the spray is being administered. They should also be advised to administer the spray with the head tilted back slightly. The dose of NICOTROL NS, should be individualized on the basis of each patient's nicotine dependence and the occurrence of symptoms of nicotine excess (See Individualization of Dosage ). Each actuation of NICOTROL NS delivers a metered 50 microliter spray containing 0.5 mg of nicotine. One dose is 1 mg of nicotine (2 sprays, one in each nostril). Patients should be started with 1 or 2 doses per hour, which may be increased up to a maximum recommended dose of 40 mg (80 sprays, somewhat less than 1/2 bottle) per day. For best results, patients should be encouraged to use at least the recommended minimum of 8 doses per day, as less is unlikely to be effective. In clinical trials, the patients who successfully quit smoking used the product heavily when nicotine withdrawal was at its peak, sometimes up to the recommended maximum of 40 doses per day ( in heavier smokers). Dosing recommendations are summarized in Table 4.

Table

4: Maximum Recommended Duration of Treatment Recommended Doses per Hour Maximum Doses per Hour Maximum Doses per Day 3 months 1–2 One dose=2 sprays (one in each nostril). One dose delivers 1 mg of nicotine to the nasal mucosa. 5 40 No tapering strategy has been shown to be optimal in clinical studies. Many patients simply stopped using the spray at their last clinic visit. Recommended strategies for discontinuation of use include suggesting that patients: use only 1/2 a dose (1 spray) at a time, use the spray less frequently, keep a tally of daily usage, try to meet a steadily reducing usage target, skip a dose by not medicating every hour, or set a planned "quit date" for stopping use of the spray. Individualization of Dosage The success or failure of smoking cessation is influenced by the quality, intensity and frequency of supportive care. Patients are more likely to quit smoking if they are seen frequently and participate in formal smoking cessation programs. The goal of NICOTROL NS therapy is complete abstinence. If a patient is unable to stop smoking by the fourth week of therapy, treatment should probably be discontinued. Patients who fail to quit on any attempt may benefit from interventions to improve their chances for success on subsequent attempts. Patients who were unsuccessful should be counseled and should then probably be given a "therapy holiday" before the next attempt. A new quit attempt should be encouraged when conditions are more favorable. Based on the clinical trials, a reasonable approach to assisting patients in their attempt to quit smoking is to begin initial treatment, using the recommended dosage (See DOSAGE AND ADMINISTRATION ). Regular use of the spray during the first week of treatment may help patients adapt to the irritant effects of the spray. Dosage can then be adjusted in those subjects with signs or symptoms of nicotine withdrawal or excess. Patients who are successfully abstinent on NICOTROL NS should be treated at the selected dosage for up to 8 weeks, following which use of the spray should be discontinued over the next 4 to 6 weeks. Some patients may not require gradual reduction of dosage and may abruptly stop treatment successfully. Treatment with NICOTROL NS for longer periods has not been shown to improve outcome, and the safety of use for periods longer than 6 months has not been established. The symptoms of nicotine withdrawal overlap those of nicotine excess (See CLINICAL PHARMACOLOGY, Pharmacodynamics and ADVERSE REACTIONS ). Since patients using NICOTROL NS may also smoke intermittently, it is sometimes difficult to determine if patients are experiencing nicotine withdrawal or nicotine excess. Controlled clinical trials of nicotine products suggest that palpitations, nausea and sweating are more often symptoms of nicotine excess, whereas anxiety, nervousness and irritability are more often symptoms of nicotine withdrawal.

CONTRAINDICATIONS Use of NICOTROL NS therapy is contraindicated in patients with known hypersensitivity or allergy to nicotine or to any component of the product.

ADVERSE REACTIONS Assessment of adverse events in the 730 patients who participated in controlled clinical trials 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 the many minor complaints that smokers commonly have, by continued smoking by many patients and the local irritation from both active drug and the pepper placebo. No serious adverse events were reported during the trials.

Common

Smoker's Complaints Common complaints experienced by the smokers in the study (users of both active and placebo spray) include: chest tightness, dyspepsia, paresthesia (tingling) in limbs, constipation, and stomatitis.

Tobacco Withdrawal Symptoms

Symptoms of tobacco withdrawal were frequent in users of both active and placebo sprays. Common withdrawal symptoms seen in over 5% of patients included: anxiety, irritability, restlessness, cravings, dizziness, impaired concentration, weight increase, emotional lability, somnolence and fatigue, increased sweating, and insomnia. Less frequently seen probable withdrawal symptoms (under 5%) included: confusion, depression, apathy, tremor, increased appetite, incoordination, and increased dreaming. Anxiety, irritability, restlessness, and tobacco cravings occurred about equally in both groups, while other symptoms tended to be slightly more common on placebo spray. Effects of the Spray NICOTROL NS and the pepper-containing placebo were both associated with irritant side effects on the nasopharyngeal and ocular tissues. During the first 2 days of treatment, nasal irritation was reported by nearly all (94%) of the patients, the majority of whom rated it as either moderate or severe. Both the frequency and severity of nasal irritation declined with continued use of NICOTROL NS but was still experienced by most (81%) of the patients after 3 weeks of treatment, with most patients rating it as moderate or mild. Other common side effects for both active and placebo groups were: runny nose, throat irritation, watering eyes, sneezing, and coughing. The following local events were reported somewhat more commonly for active than for placebo spray: nasal congestion, subjective comments related to the taste or use of the dosage form, sinus irritation, transient epistaxis, eye irritation, transient changes in sense of smell, pharyngitis, paresthesia of the nose, mouth or head, numbness of the nose, or mouth, burning of the nose or eyes, earache, facial flushing, transient changes in sense of taste, hoarseness, nasal ulcer or blister. Effects of Nicotine Feelings of dependence on the spray were reported by more patients on active spray than placebo. Drug-like effects such as calming were also more frequent on active spray (See DRUG ABUSE AND DEPENDENCE ).

Other Adverse Effects

Adverse events which could not be classified and listed above and which were reported by >1% of patients on active spray are listed in the following table: Adverse Events Not Attributable to Intercurrent Illness Adverse Event Active Placebo HEADACHE 18% 15% BACK PAIN 6% 4% DYSPNEA 5% 6% NAUSEA 5% 5% ARTHRALGIA 5% 1% MENSTRUAL DISORDER 4% 4% PALPITATION 4% 4% FLATULENCE 4% 3% TOOTH DISORDER 4% 1% GUM PROBLEMS 4% 1% MYALGIA 3% 4% ABDOMINAL PAIN 3% 3% CONFUSION 3% 3% ACNE 3% 1% DYSMENORRHEA 3% 0% PRURITUS 2% 3% Adverse events reported with a frequency of <1% among active spray users are listed below: Body as a Whole: edema peripheral, pain, numbness, allergy Gastrointestinal: dry mouth, hiccup, diarrhea Hematologic: purpura Neurological: aphasia, amnesia, migraine, numbness Respiratory: bronchitis, bronchospasm, sputum increased Skin and appendages: rash, purpura Special Senses: vision abnormal Adverse reactions not listed above that have been identified during post-marketing experience with the nicotine nasal spray formulation are listed below: Gastrointestinal disorders: dysphagia General disorders and administration site conditions: chest pain Immune system disorders: anaphylactic reaction Nervous system disorders: seizure

Warnings If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider. Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known. Ask a doctor before use if you have

• a sodium-restricted diet
• heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate.
• high blood pressure not controlled with medication. Nicotine can increase your blood pressure.
• stomach ulcer or diabetes
• history of seizures Ask a doctor or pharmacist before use if you are
• using a non-nicotine stop smoking drug
• taking prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. Stop use and ask a doctor if
• mouth problems occur
• persistent indigestion or severe sore throat occurs
• irregular heartbeat or palpitations occur
• you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat
• you have symptoms of an allergic reaction (such as difficulty breathing or rash) Keep out of reach of children and pets. Nicotine lozenges may have enough nicotine to make children and pets sick. If you need to remove the lozenge, wrap it in paper and throw away in the trash. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Directions
• if you are under 18 years of age, ask a doctor before use. No studies have been done to show if this product will work for you.
• before using this product, read the enclosed User’s Guide for complete directions and other important information
• begin using the lozenge on your quit day
• if you smoke your first cigarette more than 30 minutes after waking up, use 2 mg nicotine lozenge
• if you smoke your first cigarette within 30 minutes of waking up, use 4 mg nicotine lozenge according to the following 12 week schedule: Weeks 1 to 6 Weeks 7 to 9 Weeks 10 to 12 1 lozenge every 1 to 2 hours 1 lozenge every 2 to 4 hours 1 lozenge every 4 to 8 hours
• nicotine lozenge is a medicine and must be used a certain way to get the best results
• place the lozenge in your mouth and allow the lozenge to slowly dissolve (about 20-30 minutes). Minimize swallowing. Do not chew or swallow lozenge.
• you may feel a warm or tingling sensation
• occasionally move the lozenge from one side of your mouth to the other until completely dissolved (about 20-30 minutes)
• do not eat or drink 15 minutes before using or while the lozenge is in your mouth
• to improve your chances of quitting, use at least 9 lozenges per day for the first 6 weeks
• do not use more than one lozenge at a time or continuously use one lozenge after another since this may cause you hiccups, heartburn, nausea or other side effects
• do not use more than 5 lozenges in 6 hours. Do not use more than 20 lozenges per day. it is important to complete treatment. If you feel you need to use the lozenge for a longer period to keep from smoking, talk to your health care provider.

PRECAUTIONS General The patient should be urged to stop smoking completely when initiating NICOTROL NS 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 NS by patients who stop smoking is not recommended and should be discouraged (See DRUG ABUSE AND DEPENDENCE ). Care should be taken not to spray the eyes while administering NICOTROL NS. Asthma, Bronchospasm and Reactive Airway Disease Exacerbation of bronchospasm in patients with pre-existing asthma has been reported. Use of NICOTROL NS in patients with severe reactive airway disease is not recommended. In a small clinical study of 33 subjects, use of NICOTROL NS by smokers with chronic rhinitis and sinusitis was associated with irritant effects with no significant impairment in nasal condition. Effect of NICOTROL NS on the Nasal Mucosa Topical application of either nicotine or tobacco products is irritating to the nasal mucosa and physicians should consider both the risks and benefits to the patient before initiating or continuing NICOTROL NS therapy. The effect of NICOTROL NS on the nasal mucosa was studied in 39 cigarette smokers who used NICOTROL NS for 1 month. When compared to baseline, random biopsies taken after four weeks of treatment revealed 1 patient with persistence of pre-existing dysplasia and 1 patient with a newly found dysplasia. In both, dysplasia was not seen after a recovery period of eight weeks. Forty-two patients who used NICOTROL NS for more than 6 months underwent follow-up ear, nose and throat examinations 1 to 3 months after discontinuing the use of the spray. Many reported local irritant effects of the spray during spray use, but none showed persistent mucosal injury that the examining physician could attribute to use of the product. The clinical significance of these findings is not known, but extended use of the product beyond six months is not recommended. 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 occurring in association with nicotine replacement therapy has been reported. No serious cardiovascular events were reported in clinical studies with NICOTROL NS, but if symptoms occur, its use should be discontinued. NICOTROL NS 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 would be 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 NS 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 NS 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 NS 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 To

Patient A patient instruction sheet is included in the package of NICOTROL NS dispensed to the patient. Patients should be encouraged to read the instruction sheet carefully and to ask their physician and pharmacist about the proper use of the product (See DOSAGE AND ADMINISTRATION ). It should be explained to patients that they are likely to experience nasal irritation, which may become less bothersome with continued use. Patients must be advised to keep both used and unused containers out of the reach of children and pets.

Drug Interactions

The extent of absorption and peak plasma concentration is slightly reduced in patients with the common cold/rhinitis. In addition, the time to peak concentration is prolonged. The use of a nasal vasoconstrictor such as xylometazoline in patients with rhinitis will further prolong the time to peak (See PHARMACOKINETICS ). Smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications.

May

Require a Decrease in Dose at Cessation of Smoking Possible Mechanism Acetaminophen, caffeine, imipramine, oxazepam, pentazocine, propranolol, or other beta-blockers, theophylline Deinduction of hepatic enzymes on smoking cessation.

Insulin

Increase of 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. 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 were 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

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 NS 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 NS 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 NS has not been studied in pregnant women. Labor and Delivery NICOTROL NS 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 NICOTROL NS is administered to nursing mothers. The safety of NICOTROL NS 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 NS 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 NS 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 NICOTROL NS alone, or in combination with continued smoking.

Pediatric

Use NICOTROL NS therapy is not recommended for use in the pediatric population because its safety and effectiveness in children and adolescents who smoke have not been evaluated.

Geriatric Use

Clinical studies of NICOTROL NS 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.

Drug Interactions The extent of absorption and peak plasma concentration is slightly reduced in patients with the common cold/rhinitis. In addition, the time to peak concentration is prolonged. The use of a nasal vasoconstrictor such as xylometazoline in patients with rhinitis will further prolong the time to peak (See PHARMACOKINETICS ). Smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications.

May

Require a Decrease in Dose at Cessation of Smoking Possible Mechanism Acetaminophen, caffeine, imipramine, oxazepam, pentazocine, propranolol, or other beta-blockers, theophylline Deinduction of hepatic enzymes on smoking cessation.

Insulin

Increase of 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.

Active ingredient Step One (in each patch) Nicotine, 21 mg delivered over 24 hours

Active ingredient Step Two (in each patch) Nicotine, 14 mg delivered over 24 hours

Active ingredient Step Three (in each patch) Nicotine, 7 mg delivered over 24 hours

Inactive ingredients (White Ice Mint) each 2 mg piece contains: acesulfame potassium, carnauba wax, edible ink, flavor, gum base, hypromellose, magnesium oxide, menthol, peppermint oil, polysorbate 80, sodium bicarbonate, sodium carbonate, starch, sucralose, titanium dioxide, xylitol each 4 mg piece contains: acesulfame potassium, carnauba wax, D&C yellow #10 Al. lake, edible ink, flavor, gum base, hypromellose, magnesium oxide, menthol, peppermint oil, polysorbate 80, sodium carbonate, starch, sucralose, titanium dioxide, xylitol

Inactive ingredients (Original) each 2 mg piece contains: flavors, glycerin, gum base, sodium bicarbonate, sodium carbonate, sorbitol each 4 mg piece contains: D&C yellow #10, flavors, glycerin, gum base, sodium carbonate, sorbitol

Inactive ingredients (Cinnamon Surge) each 2 mg piece contains: acacia, acesulfame potassium, carnauba wax, edible ink, gum base, hypromellose, magnesium oxide, menthol, natural and artificial cinnamon flavors, peppermint oil, polysorbate 80, sodium bicarbonate, sodium carbonate, sucralose, titanium dioxide, xylitol each 4 mg piece contains: acacia, acesulfame potassium, carnauba wax, D&C yellow #10 Al. lake, edible ink, gum base, hypromellose, magnesium oxide, menthol, natural and artificial cinnamon flavors, peppermint oil, polysorbate 80, sodium carbonate, sucralose, titanium dioxide, xylitol

Inactive ingredients (Mint) each 2 mg piece contains: acesulfame potassium, gum base, magnesium oxide, menthol, peppermint oil, sodium bicarbonate, sodium carbonate, xylitol each 4 mg piece contains: acesulfame potassium, D&C yellow #10 Al. lake, gum base, magnesium oxide, menthol, peppermint oil, sodium carbonate, xylitol

Inactive ingredients (Spearmint Burst) each 2 mg piece contains: acacia, acesulfame potassium, carnauba wax, edible ink, flavors, gum base, hypromellose, magnesium oxide, menthol, peppermint oil, polysorbate 80, sodium bicarbonate, sodium carbonate, sucralose, titanium dioxide, xylitol each 4 mg piece contains: acacia, acesulfame potassium, carnauba wax, D&C yellow #10 Al. lake, edible ink, flavors, gum base, hypromellose, magnesium oxide, menthol, peppermint oil, polysorbate 80, sodium carbonate, sucralose, titanium dioxide, xylitol