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Pharmacotherapeutic group: Drug used in nicotine dependence. ATC code: N07B A01.
Pharmacology: Pharmacodynamics: Nicotine is an agonist at nicotine receptors in the peripheral and central nervous system and has pronounced CNS and cardiovascular effects. Abrupt cessation of the established, regular use of tobacco-containing products results in the characteristic syndrome, with withdrawal symptoms including cravings (urges to smoke).
Clinical studies have shown that nicotine replacement products can help smokers abstain from smoking by raising blood nicotine levels and relieving these withdrawal symptoms.
Craving Relief: Compared with nicotine gum or nicotine lozenge, the absorption of nicotine from the oromucosal spray is more rapid. In an open-label, single-dose, crossover craving study in 200 healthy smokers it was observed that two sprays of 1 mg reduced the urges to smoke significantly more than nicotine lozenge 4 mg, starting at 60 seconds after administration, and a difference between the formulations was observed for 10 minutes.
In another open-label, single-dose, crossover craving study in 61 healthy smokers it was observed that 2 sprays of 1 mg reduced the urge to smoke significantly more than the reference product, starting 30 seconds after administration in the study population, including the subset of subjects rating their baseline urges to smoke as severe. In addition, 53/58 (91%) and 45/58 (78%) of subjects reached 25% and 50% reduction in urges to smoke over the study period (i.e. 2h), respectively.
Smoking cessation: Two placebo-controlled efficacy studies have been performed. In the first study, 83/318 (26.1%) of participants using oromucosal spray managed to quit smoking at week 6 compared to 26/161 (16.1%) in the placebo group. At weeks 24 and 52 50/318 (15.7%) and 44/318 (13.8%), respectively in the oromucosal spray group and 11/161 (6.8%) and 9/161 (5.6%), respectively in the placebo group managed to quit smoking. In the second study, 30/597 (5.0%) of participants in the oromucosal spray group were smoke free at week 6 compared to 15/601 (2.5%) in the placebo group.
Pharmacokinetics: Variations in delivery format have been found to have significant effects on rate and extent of absorption. The pharmacokinetics of the oromucosal spray has been studied in 4 studies. The studies included 141 subjects.
Absorption: A maximum concentration of 5.3 ng/mL is reached within 13 minutes after administration of a 2 mg dose. Comparing the AUC over the first 10 minutes after administration the estimates of the oromucosal spray at a dose of 1 and 2 mg exceeds those of nicotine gum as well as nicotine lozenge at doses of 4 mg (0.48 and 0.64 h*ng/mL vs. 0.33 and 0.33 h*ng/mL).
AUC∞ estimates show the bioavailability of nicotine administered by oromucosal spray is similar to that of nicotine gum or lozenge. The AUC∞ of the oromucosal spray 2 mg measured 14.0 h*ng/mL in comparison with 23.0 h*ng/mL and 26.7 h*ng/mL for nicotine gum 4 mg and nicotine lozenge 4 mg, respectively.
Steady-state average nicotine plasma concentrations achieved after administration of the maximum dose (i.e. 2 sprays of the oromucosal spray 1 mg every 30 minutes) are in the order of magnitude approximately 28.8 ng/mL as compared with 23.3 ng/mL for nicotine gum 4 mg (1 gum, hourly) and 25.5 ng/mL for nicotine lozenge 4 mg (1 lozenge, hourly).
Distribution: The volume of distribution following intravenous administration of nicotine is about 2 to 3 L/kg.
Plasma protein binding of nicotine is less than 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 any significant effects on the nicotine pharmacokinetics.
Biotransformation: The major nicotine-eliminating organ is the liver, although the kidney and lung also metabolise 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.
Elimination: The average plasma clearance of nicotine is 70 L/hour and the half-life is 2-3 hours. The primary urinary metabolites are cotinine (12% of the dose) and trans-3-hydroxy-cotinine (37% of the dose). About 10% of nicotine is excreted unchanged in the urine. As much as 30% of nicotine may be excreted unchanged in the urine with high flow rates and acidification of the urine below pH 5.
Linearity/non-linearity: There is only a small deviation from dose-linearity of AUC∞ and Cmax as shown when single doses of 1, 2, 3 and 4 sprays of the 1 mg oromucosal spray are given.
Renal Impairment: Progressive severity of renal impairment is associated with decreased total clearance of nicotine. Nicotine clearance was on average decreased by 50% in subjects with severe renal impairment.
Raised nicotine levels have been seen in smokers undergoing hemodialysis.
Hepatic Impairment: The pharmacokinetics of nicotine are unaffected in patients with mild liver impairment (Child-Pugh score 5) and decreased by 40-50% in patients with moderate liver impairment (Child-Pugh score 7). There is no information available in subjects with a Child-Pugh score >7.
Elderly: A minor reduction in total clearance of nicotine, not justifying adjustment of dosage, has been demonstrated in healthy elderly patients.
Toxicology: Preclinical safety data: In vitro genotoxicity testing of nicotine has yielded predominantly negative results. There are some equivocal results when testing at high nicotine concentrations. In vivo tests of genotoxicity have been negative.
Animal experiments have shown that nicotine exposure results in decreased birthweight, decreased litter size and decreased survival of offspring. Results of carcinogenicity assays do not provide any clear evidence of a tumorigenic effect of nicotine.
