Nicotrol Information
Nicotrol (Nicotine) Description
Nicotrol (Nicotine) 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 (Nicotine) 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: CHN
Molecular Weight: 162.23
Ionization Constants: pKa = 7.84, pKa = 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 (Nicotine) 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 (Nicotine) NS unit delivers approximately 200 applications.
Nicotrol (Nicotine) Clinical Pharmacology
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 1 hour), but not at the same rate 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 from smoking.
Withdrawal from nicotine in addicted individuals can be 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 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. Changes in the response to a concomitantly administered adrenergic agonist or antagonist should be watched for when nicotine intake is altered during Nicotrol (Nicotine) NS therapy and/or smoking cessation (See ).
Nicotrol (Nicotine) Clinical Trials
The efficacy of Nicotrol (Nicotine) NS therapy as an aid to smoking cessation was demonstrated in three single-center, placebo-controlled, double-blind trials with a total of 730 patients. One of the trials used Nicotrol (Nicotine) NS with individual counseling while the other two used group support. Patients with severe or symptomatic cardiovascular disease, hypertension, asthma, diabetes or severe allergy were not included in the studies. The amount of Nicotrol (Nicotine) NS used was left to the discretion of each patient, with a minimum dose of 8 mg/day and a maximum dose of 40 mg/day.
In all three studies, the recommended duration of treatment was 3 months; however in two of these trials, 241 patients were permitted to continue to use the product for up to 1 year, if they wished. Among the 64 patients abstinent from cigarettes at the end of a year, 23 (36%) were still using the spray, and probable dependence on the spray was seen in several patients (See ).
Quitting was defined as from smoking for at least 4 weeks. The "quit rates" are the percentage of all persons initially enrolled who continuously abstained after week 2 or 4.
In all three studies, Nicotrol (Nicotine) NS was more effective than placebo at 6 weeks, 3 months, 6 months, and 1 year. The two studies where Nicotrol (Nicotine) NS could be used for more than 6 months did not have a better outcome at 1 year than the study in which Nicotrol (Nicotine) NS was discontinued at 6 months.
Patients treated with Nicotrol (Nicotine) NS had more relief of the urge to smoke and withdrawal symptoms compared with placebo-treated patients.
Nicotrol (Nicotine) NS allows the patient to vary the dose of nicotine on a short-term basis. As with other variable dose smoking cessation products, Nicotrol (Nicotine) NS may be useful in the management of highly dependent smokers.
Nicotrol (Nicotine) Indications And Usage
Nicotrol (Nicotine) NS is indicated as an aid to smoking cessation for the relief of nicotine withdrawal symptoms. Nicotrol (Nicotine) NS therapy should be used as a part of a comprehensive behavioral smoking cessation program.
The safety and efficacy of the continued use of Nicotrol (Nicotine) NS for periods longer than 6 months have not been adequately studied and such use is not recommended.
Nicotrol (Nicotine) Contraindications
Use of Nicotrol (Nicotine) NS therapy is contraindicated in patients with known hypersensitivity or allergy to nicotine or to any component of the product.
Nicotrol (Nicotine) 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.
Nicotrol (Nicotine) Precautions
The patient should be urged to stop smoking completely when initiating Nicotrol (Nicotine) NS therapy (See ). 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 ). Physicians should anticipate that concomitant medications may need dosage adjustment (See ).
Sustained use (beyond 6 months) of Nicotrol (Nicotine) NS by patients who stop smoking is not recommended and should be discouraged (See ).
Use of Nicotrol (Nicotine) NS is not recommended in patients with known chronic nasal disorders (e.g. allergy, rhinitis, nasal polyps and sinusitis) since such use has not been adequately studied.
A patient instruction sheet is included in the package of Nicotrol (Nicotine) 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 ).
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.
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 Category D (See sections).
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 (Nicotine) 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 (Nicotine) 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.
Nicotrol (Nicotine) 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.
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.
Nicotrol (Nicotine) 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 (Nicotine) 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, paraethesias 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.
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 events reported with a frequency of
Body as a Whole: edema peripheral, pain, numbness, allergyGastrointestinal: dry mouth, hiccup, diarrheaHematologic: purpuraNeurological: aphasia, amnesia, migraine, numbnessRespiratory: bronchitis, bronchospasm, sputum increasedSkin and appendages: rash, purpuraSpecial Senses: vision abnormal
Nicotrol (Nicotine) Drug Abuse And Dependence
Nicotrol (Nicotine) NS has a dependence potential intermediate between other nicotine-based therapies and cigarettes. This is the result of differences between cigarettes, Nicotrol (Nicotine) NS, nicotine gum and nicotine patches in pharmacokinetic and dosing characteristics commonly associated with abuse and dependence. Nicotrol (Nicotine) NS is distinct from other nicotine-based smoking cessation therapies in its greater speed of onset, greater capacity for self-titration of dose, and frequent and rapid fluctuations in plasma nicotine concentration.
Dependence on nicotine nasal spray occurred in the clinical trials. Feelings of dependency on the spray were reported by 32% of active spray users and 13% of placebo spray users. Such dependence may represent transference of tobacco-related nicotine dependence to Nicotrol (Nicotine) NS.
Fifteen to 20% of patients used the active spray for longer periods than recommended (6 months to 1 year) and 5% used the spray at a higher dose than recommended. Some of these patients experienced anxiety about stopping the spray and some reported craving for the spray rather than for cigarettes.
Nicotrol (Nicotine) Overdosage
The oral LD for nicotine is >5 mg/kg in dogs and >24 mg/kg in rodents. Death is due to respiratory paralysis. The oral minimum acute lethal dose for nicotine in adult humans is reported to be 40 to 60 mg (
Nicotrol (Nicotine) NS would be expected to be irritating if sprayed in the eyes, mouth or ears. Eye exposure should be treated with copious irrigation with water for 20 minutes. Large oral nicotine ingestions cause vomiting, and the consequences of an overdose will vary; should this occur, patients should contact their physician immediately. For additional emergency information, call your regional poison center.
Nicotrol (Nicotine) Dosage And Administration
It is important that patients understand the instructions for use of Nicotrol (Nicotine) NS, and have their questions answered. They should clearly understand the directions for using Nicotrol (Nicotine) 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 (Nicotine) NS, should be individualized on the basis of each patient's nicotine dependence and the occurrence of symptoms of nicotine excess (See ).
Each actuation of Nicotrol (Nicotine) 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.
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.
Nicotrol (Nicotine) Safety And Handling
As with all medicines, especially ones in liquid form, care should be taken in handling Nicotrol (Nicotine) NS during periods of opening and closing the container (See and ). If it is dropped it may break. If this occurs, the spill should be cleaned up immediately with an absorbent cloth/paper towel. Care should be taken to avoid contact of the solution with the skin. Broken glass should be picked up carefully, using a broom. The area of the spill should be washed several times. Absorbent material may be disposed of as any other household waste. Should even a small amount of Nicotrol (Nicotine) NS come in contact with the skin, lips, mouth, eyes or ears, the affected area(s) should be immediately rinsed with water only.
Nicotrol (Nicotine) NS (nicotine nasal spray) 10 mg/mL, is supplied as four 10 mL bottles (NDC 0009-5401-01). Each unit consists of a glass container, mounted with a metered spray pump.A patient information leaflet is enclosed with the package.
Store at room temperature not to exceed 86°F (30°C).
Nicotrol (Nicotine) Nicotrolns(nicotine Nasal Spray)
Read and follow carefully. If you have questions or want more information, ask your doctor or pharmacist.
Tell your doctor about any medicines you are taking—the dosages may need to be changed. Check with your doctor while using Nicotrol (Nicotine) NS.
Nicotrol (Nicotine)
Nicotrol (Nicotine) Principal Display Panel - Mg/ml Bottle Label
NDC 0009-5401-01
FOR NASAL USE ONLY KEEP OUT OF REACH OF CHILDREN
