Nicorette Plus (Nicotine Polacrilex)

NICORETTE® PLUS

Hoechst Marion Roussel

Nicotine Polacrilex

Smoking Cessation Aid

Action And Clinical Pharmacology: The active component of Nicorette Plus is nicotine in the form of a natural extract from the tobacco plant.

In small doses, nicotine stimulates autonomic ganglia. Larger doses of the drug result in a blockage of the ganglia. The effects on autonomic ganglia vary according to the degree of tolerance to nicotine. The major cardiovascular effects of nicotine are vasoconstriction, tachycardia and elevated blood pressure resulting from stimulation of sympathetic ganglia and the adrenal medulla as well as from the activation of chemoreceptors of aortic and carotid bodies.

The pharmacokinetics of nicotine favour buccal (rather than gastrointestinal) absorption. Absorption from the mouth is more rapid than from the stomach and the absorbed nicotine avoids immediate and rapid inactivation by the liver (first pass effect).

Nicorette Plus is formulated to provide blood nicotine levels via buccal absorption that will approximate those produced by the inhalation of tobacco smoke. The nicotine in Nicorette Plus is bound to an ion exchange resin and is released only during chewing. The rate of release of nicotine and, as a consequence, nicotine blood levels, are related to the rate and vigor with which the gum is chewed. The chewing of a Nicorette Plus piece over a 30-minute period on a one-time-only basis produces peak blood nicotine levels of 10 ng/mL. This peak is reached by about the 25th minute and compares with a peak of 16 to 35 ng/mL reached within 5 minutes from smoking a cigarette of mild to moderate nicotine content. Blood nicotine levels increase and stabilize at 50 ng/mL, following repeated administration of Nicorette Plus at half-hourly intervals. Thus, with Nicorette Plus, it is possible to produce nicotine blood levels of the same order as those produced by smoking cigarettes.

The elimination half-life of nicotine in plasma is 120 minutes. Both nicotine and its metabolites are rapidly eliminated by the kidney. The rate of urinary excretion is dependent on the pH of the urine; excretion diminishes when the urine is alkaline.

Indications And Clinical Uses: Nicorette Plus is designed to provide partial substitution for the nicotine in cigarette smoke and is intended as a temporary aid in cushioning the patient against the psychopharmacological effects of the withdrawal symptoms of smoking cessation.

Before initiating treatment with Nicorette Plus, the physician or pharmacist should determine the patient’s level of nicotine dependence.

Contra-Indications: In patients during the immediate postmyocardial infarction period, patients with life-threatening arrhythmias, and in patients with severe or worsening angina pectoris; in patients with active temporomandibular joint disease; in pregnant women (see Warnings); in breast-feeding mothers, as nicotine is excreted in breast milk (see Warnings), and in nonsmokers and children under 18 years of age (see Warnings).

Manufacturers’ Warnings In Clinical States: The amounts of nicotine that are tolerated by adult smokers can produce symptoms of poisoning and could prove fatal if ingested by children or pets. Patients should be warned to keep Nicorette Plus out of the reach of children and pets.

Simultaneous smoking and chewing of Nicorette Plus should be avoided.

In patients with certain cardiovascular and endocrine diseases, the risks of using nicotine should be carefully weighed against the benefits of including Nicorette Plus in a smoking cessation program. 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 Nicorette Plus is used. Occasional reports of tachyarrhythmias occurring in association with the use of Nicorette Plus have been reported; therefore, if an increase in cardiovascular symptoms occurs with the use of Nicorette Plus it should be discontinued.

As the action of nicotine on the adrenal medulla (release of catecholamines) does not appear to be affected by tolerance, Nicorette Plus should be used with caution in patients with hyperthyroidism, pheochromocytoma or insulin-dependent diabetes.

Cigarette smoking is felt to play a perpetuating role in hypertension and peptic ulcer disease. Therefore, Nicorette Plus should be used in patients with systemic hypertension or peptic ulcer (active or inactive) only when the benefits of including Nicorette Plus in a smoking cessation program outweigh the risks.

Pregnancy: Women of childbearing age should be advised to take adequate precautions to avoid becoming pregnant while using Nicorette Plus. Nicorette Plus therapy should be discontinued if pregnancy is suspected (see Contraindications).

Lactation: Nicotine passes freely into the breast milk. Because of the potential for adverse reactions in nursing infants from nicotine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see Contraindications).

Children: Safety and effectiveness in children and adolescents who smoke has not been evaluated. The use of Nicorette Plus is not recommended in smokers under 18 years of age (see Contraindications).

Precautions: General: Nicorette Plus should be used with caution in patients with oral or pharyngeal inflammation and in patients with a history of esophagitis or peptic ulcer.

The Nicorette Plus dosage form dictates that it be used with caution in patients whose dental problems might be exacerbated by chewing gum. In such patients, prior dental evaluation may be advisable.

Nicorette Plus is sugar-free and has been formulated to minimize stickiness. As with other gums, however, the degree to which Nicorette Plus may stick to dentures, dental caps or partial dentures may depend on the materials from which they are made and other factors such as amount of saliva produced, possible interaction with denture adhesives, denture cleaning compounds, dryness of mouth due to other causes and salivary constituents. Should an excessive degree of adherence to dental work occur, there is the possibility that, as with other gums, Nicorette Plus may damage dental work. If this should occur, the patient should discontinue its use and consult a physician or dentist.

The sustained use of Nicorette Plus by former smokers is not to be encouraged because the chronic consumption of nicotine is addicting. The relative risks of a possible return to smoking should be weighed against the long-term use of Nicorette Plus.

Nicotine was not mutagenic in the Ames Salmonella test. Literature reports indicate that nicotine is neither an initiator nor a tumor-promoter in mice. There is inconclusive evidence to suggest that cotinine, an oxidized metabolite of nicotine, may be carcinogenic in rats. Cotinine was not mutagenic in the Ames Salmonella test.

Studies have shown a decrease of litter size in rats treated with nicotine during the time of fertilization.

Drug Interactions: 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.

Other reported effects of smoking, which do not involve enzyme induction, include reduced diuretic effects of furosemide and decreased cardiac output, and reduced effect on blood pressure with propranolol, which may also relate to the hormonal effects of nicotine. Smoking cessation may reverse these actions.

Weight Gain: Weight gain is commonly associated with abstention from smoking. The mechanism for this is believed to be a combination of the abstention from the oral habit of cigarette smoking and its replacement by increased intake of food and reduced gastrointestinal motility due to the absence of the stimulant nicotine. Patients who quit smoking should always be monitored for weight gain.

Liquid Consumption: Patients should be advised not to consume liquids while chewing Nicorette Plus, as the pH of the oral cavity may be reduced and interfere with absorption of nicotine.

Adverse Reactions: Adverse reactions reported in association with the use of Nicorette Plus include both local effects and systemic effects representing the pharmacological action of nicotine.

Local Side Effects: Mechanical effects of gum chewing include traumatic injury to oral mucosa or teeth, jaw ache, and eructation secondary to air swallowing. These side effects may be minimized by modifying chewing technique. Changes in the oral mucosa such as stomatitis, glossitis, gingivitis, pharyngitis, and aphthous ulcers, in addition to changes in taste perception, can occur spontaneously during smoking cessation efforts and may not be related to the use of Nicorette Plus.

Oral adverse events occurring with a frequency of 1% or greater in 1 801 patients using Nicorette Plus in 2 clinical trials were throat irritation 5%, stomatitis (excluding aphthous and ulcerative stomatitis) 4%, taste perversion 3%, tooth disorder (e.g., occlusal stress as a result of chewing, loosening of fillings, gum sticking to dentures etc.) 2%, aphthous stomatitis 2%, gingivitis 1% and glossitis 1%.

Other oral events reported were gingival bleeding, taste loss, tongue discoloration and tongue ulceration.

Systemic Side Effects: Adverse events which occurred in 1 801 patients who participated in 2 clinical trials of Nicorette Plus are listed by body system. Incidences of 1% or greater are shown in brackets. The list also includes other events which have been reported, including events reported postmarketing.

Cardiovascular: chest pain (1%), edema, flushing, hypertension, palpitations, tachyarrhythmias, tachycardia.

CNS: headache (11%), dizziness (4%), insomnia (2%), fatigue (1%), abnormal dreaming, agitation, anxiety, apathy, confusion, convulsions, depersonalization, depression, drug dependence, emotional lability, euphoria, hypoesthesia, impaired concentration, irritability, lightheadedness, migraine, nervousness, nightmare, numbness, paresthesia, sleep disorder, syncope, tinnitus, tremor.

Dermatologic: acne, erythema, itching, pruritus, rash, urticaria.

Gastrointestinal: dyspepsia (9%), nausea (9%), abdominal pain (1%), diarrhea (1%), eructation (1%), flatulence (1%), vomiting (1%), abdominal distention, alteration of liver function tests, colitis, constipation, diarrhea, diverticulitis, gastritis, gastroesophageal reflux, increased salivation, nonspecific gastrointestinal distress, peptic ulcer, ulcer.

Respiratory: cough (1%), breathing difficulty, bronchitis, bronchospasm, congestion, epistaxis, hoarseness, laryngitis, nasal irritation, rhinitis, rhinorrhea, sinusitis, sneezing.

Other: hiccups (10%), pain (2%), dry mouth (1%), malaise (1%), abnormal lacrimation, abnormal serum folate test, allergic reaction, anorexia, arthralgia, back pain, dehydration, dysmenorrhea, dysphagia, dysphonia, earache, ear disorder, fever, halitosis, hot flushes, hypothyroidism, leg cramps, lymphadenopathy, malaise, mucus membrane disorder, myalgia, nail disorder, oliguria, sweating, systemic nicotine intoxication, thirst, vision abnormality, weakness.

Reports of myocardial infarction, congestive heart failure, cerebrovascular accident and cardiac arrest, including death have been received. Although a cause and effect relationship between these reports and the use of Nicorette Plus has not been established, the possibility that nicotine was involved cannot be ruled out.

Rare reports of miscarriage have been received and a relationship to drug therapy as a contributing factor cannot be excluded.

Rare reports of severe allergic reactions have been received.

Symptoms And Treatment Of Overdose: Overdosage could occur if many pieces were chewed simultaneously or in rapid succession. The risk of poisoning by swallowing the gum is small because absorption in the absence of chewing is slow and incomplete. The consequences of overdosage will most likely be minimized by the early nausea and vomiting known to occur with excessive nicotine intake. Should an overdosage occur the symptoms would be those of acute nicotine poisoning.Symptoms: Mild to moderate poisoning causes nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, headache, dizziness, disturbed hearing and vision, mental confusion, and marked weakness. Faintness and prostration will likely ensue and hypotension may occur; breathing is difficult; the pulse may be rapid, weak, and irregular; circulatory collapse may be followed by terminal convulsions. Death may result within a few minutes from respiratory failure caused by paralysis of the respiratory muscles.

The oral minimum acute lethal dose for nicotine in human adults is 40 to 60 mg. In human volunteer studies, ten 4 mg nicotine polacrilex pieces were deliberately swallowed and blood nicotine levels followed over a 24-hour period. At no time did the blood nicotine level exceed 5 ng/mL in that period, a level that is considerably less than that produced by smoking a mild cigarette. An analysis of the Nicorette Plus pieces recovered from the feces of the volunteers showed that only 32% of the original nicotine content had been released.

Treatment: In a conscious, alert patient, prompt evacuation of the stomach should be performed. When evacuation is complete, activated charcoal may be administered by mouth, if necessary.

In comatose patients, a clear airway must be established immediately and ventilatory support may be required. Other therapeutic measures are purely symptomatic and should be conducted according to the attending physician’s assessment of the patient. When the patient’s clinical status stabilizes, consideration may be given to gastric lavage and administration of activated charcoal. Hypotension and/or cardiovascular collapse may occur and should be treated vigorously.

Dosage And Administration: Nicorette Plus should be regarded as an adjunct to, and a pharmaceutical and psychological reinforcer of a program to quit smoking, and not as a long-term nicotine substitute. Nicorette Plus consumption should be terminated once the patient has successfully broken the smoking habit. This can take up to 6 months in some smokers. It is strongly recommended that Nicorette Plus pieces be carried by the patient for up to 3 months following cigarette abstention in case a sudden overpowering urge to smoke occurs.

For optimum results, the initial treatment should be based on the patient’s level of nicotine dependence.

If the score is 6 or less, Nicorette 2 mg is recommended for use. If the score is 7 or greater, Nicorette Plus (4 mg) should be used.

Most patients require approximately 10 pieces of Nicorette Plus/day during the first month of treatment. Patients should be instructed not to exceed 20 pieces of Nicorette Plus/day.

One piece should be chewed for up to half an hour when the desire to smoke arises.

Availability And Storage: Each off-white, mint- or fruit-flavored square, buffered to maintain a pH of 8.5 in the mouth, contains: nicotine 4 mg. Nonmedicinal ingredients: gum, magnesium oxide, menthol, peppermint oil, sodium carbonate, xylitol and yellow D&C #10. Blister packs of 30 and 105 pieces. Store at room temperature, between 15 and 30°C. Protect from light.

NICORETTE® PLUS Hoechst Marion Roussel Nicotine Polacrilex Smoking Cessation Aid

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