Nicotine, the chief alkaloid in tobacco products, binds stereo-selectively
to nicotinic-cholinergic 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 the basis of nicotine's positively
reinforcing properties. A stimulating effect is exerted mainly in the cortex
via the locus ceruleus and a reward effect 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 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
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
NS therapy and/or smoking cessation (See PRECAUTIONS: DRUG
Each actuation of NICOTROL NS (nicotine nasal spray) delivers a metered 50 microliter spray containing
approximately 0.5 mg of nicotine. One dose is considered 1 mg of nicotine (2
sprays, one in each nostril).
Following administration of 2 sprays of NICOTROL NS (nicotine nasal spray) approximately 53% ±
16% (Mean ± SD) enters the systemic circulation. No significant difference
in rate or extent of absorption could be seen due to the deposition of nicotine
on different parts of the nasal mucosa. Plasma concentrations of nicotine obtained
from 1 dose (1 mg nicotine) of NICOTROL NS (nicotine nasal spray) rise rapidly, reaching maximum venous
concentrations of 2–12 ng/mL in 4–15 minutes. The apparent absorption half-life
of nicotine is approximately 3 minutes. There is wide variation among subjects
in their plasma nicotine concentrations from the spray. As a result, after a
1 mg dose of spray approximately 20% of the subjects reached peak nicotine concentrations
similar to those seen after smoking one cigarette (7–17 ng/mL) (See Drug
Abuse And Dependence Section). Figure 1 below plots the mean and 5th
and 95th percentile nicotine concentrations after a 1 mg single dose of the
nasal spray (n=30).
Figure 1 : Mean and Range of the 95th and 5th
Percentile Nicotine Concentrations After a 1 mg Dose of NICOTRO NS (n=30)
Table 1: Trough Plasma Nicotine Concentrations after 11 Hours
of Dosing With 1 mg, 2 mg and 3 mg of NICOTROL NS (nicotine nasal spray) per hour (n=16).
|1 mg every 60 minutes (1 mg/hr)
|1 mg every 30 minutes (2 mg/hr)
|1 mg every 20 minutes (3 mg/hr)
The data from Table 1 is derived from a three-way cross-over study of repeated
applications of NICOTROL NS (nicotine nasal spray) in sixteen smokers (8 male, 8 female) ranging in
age from 18 to 48 years. There is a slight deviation from dose-concentration
proportionality from one dose to three doses of NICOTROL NS (nicotine nasal spray) per hour as shown
in Figure 2.
Figure 2 : Mean, 95th and 5th Percentile
Trough Nicotine Plasma Concentrations in Subjects Taking NICOTRO NS for 12 Hours
Sixteen smokers (7 males and 9 females) ranging in age from 22 to 44 years
were dosed with 1 mg of NICOTROL NS (nicotine nasal spray) every hour for 10 hours. The pharmacokinetic
parameters that were obtained are presented in Table 2.
Table 2: Nicotine Pharmacokinetic Parameters at Steady- State
for 1 mg/hour of NICOTROL NS (nicotine nasal spray) Administered Hourly for Ten Hours (Mean ±
SD and Range), (n=16).
||1 mg (2 sprays)
||8 ± 3
||9 ± 3
||13 ± 5
|Cavg: average plasma nicotine concentration
for the dosing interval of 10-11 hours
Cmax: maximum measured plasma concentration after last dose administration
Tmax: time of maximum plasma concentration after last dose administration
The volume of distribution following IV administration of nicotine is approximately
2 to 3 L/kg. 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
More than 20 metabolites of nicotine have been identified, all of which are
less active than the parent compound. The primary urinary metabolites are cotinine
(15% of the dose) and trans-3-hydroxycotinine (45% of the dose). Cotinine has
a half-life of 15 to 20 hours and concentrations that exceed nicotine by 10-fold.
The major site for the metabolism of nicotine is the liver. The kidney and lung
are also sites of nicotine metabolism.
About 10% of the nicotine absorbed is excreted unchanged in the urine. This
may be increased to up to 30% with high urine flow rates and urinary acidification
below pH 5. The average plasma clearance is about 1.2 L/min in a healthy adult
smoker. The apparent elimination half-life of nicotine from NICOTROL NS (nicotine nasal spray) is 1
to 2 hours.
The data were well described by a two-compartment model with first-order input.
Based on individual fits (N=18) the following parameters were derived after
the administration of a 1 mg dose: Absorption rate constant (Ka) = 14.4 ±
7.3 hr-1 (Mean ± SD), Elimination rate constant (Ke) = 0.60
± 0.53 hr-1, Distribution rate constants (K12)
= 4.84 ± 2.57 hr-1, (K21) = 4.35 ± 2.30 hr-1,
Volume of distribution over fraction absorbed (V/F) = 2.73 ± 0.82 L/kg
in 8 female and 10 male adults weighing 76 ± 15 kg.
Intersubject variability (50% coefficient of variation) among the pharmacokinetic
parameters (AUC, Cmax and Clearance/kg) were observed for both genders. There
were no differences between females or males in the kinetics of NICOTROL NS (nicotine nasal spray) .
The extent of absorption is slightly reduced (approximately 10%) in patients
with the common cold/rhinitis. In patients with rhinitis the peak plasma concentration
is reduced by approximately 20% (concentrations are lower by 1.5 ng/mL on average)
and the time to peak concentration prolonged by approximately 30% (delayed by
7 minutes on average). The use of a nasal vasoconstrictor such as xylometazoline
in patients with rhinitis will further prolong the time to peak by approximately
40% (delayed by 15 minutes on average), but the peak plasma concentration remains
on average the same as those with rhinitis.
The efficacy of NICOTROL NS (nicotine nasal spray) 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 NS (nicotine nasal spray) 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 NS (nicotine nasal spray) 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 Drug
Abuse And Dependence).
Quitting was defined as total abstinence 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 NS (nicotine nasal spray) was more effective than placebo at 6 weeks,
3 months, 6 months, and 1 year. The two studies where NICOTROL NS (nicotine nasal spray) could be used
for more than 6 months did not have a better outcome at 1 year than the study
in which NICOTROL NS (nicotine nasal spray) was discontinued at 6 months.
Table 3: Quit Rates by Treatment (N=730 smokers in 3 Studies)
||At 6 Weeks
||At 3 Months
||At 6 Months
||At 1 Year
Patients treated with NICOTROL NS (nicotine nasal spray) had more relief of the urge to smoke and
withdrawal symptoms compared with placebo-treated patients.
NICOTROL NS allows the patient to vary the dose of nicotine on a short-term
basis. As with other variable dose smoking cessation products, NICOTROL NS (nicotine nasal spray) may
be useful in the management of highly dependent smokers.