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  • CLASSES

    Antismoking Agents

    DEA CLASS

    OTC, Rx

    DESCRIPTION

    Natural alkaloid of complex pharmacology inherent to the autonomic nervous system
    Used primarily for non-prescription (OTC) therapy to aide smoking cessation (patches, gum, lozenges); vaping solutions and electronic cigarretes are not FDA-monitored
    Prescription-only products (nasal spray, inhalation) are also available

    COMMON BRAND NAMES

    Commit, Habitrol, Nicoderm CQ, NICOrelief, Nicorette, Nicotrol

    HOW SUPPLIED

    Commit/NICOrelief/Nicorette/Nicotine/Nicotine Polacrilex Transmucosal Lozenge: 2mg, 4mg
    Habitrol/Nicoderm CQ/Nicotine Topical Film ER: 7mg, 24h
    Habitrol/Nicoderm CQ/Nicotine Transdermal Film ER: 7mg, 14mg, 21mg, 24h, 7-14-21mg
    NICOrelief/Nicorette/Nicotine/Nicotine Polacrilex Buccal Gum Chewing: 2mg, 4mg
    NICOrelief/Nicorette/Nicotine/Nicotine Polacrilex Transmucosal Gum Chewing: 2mg, 4mg
    Nicotrol Nasal Spray Met: 0.5mg, 1actuation
    Nicotrol Respiratory (Inhalation) Inhalant: 10mg

    DOSAGE & INDICATIONS

    For use as an adjunct to psychosocial interventions for tobacco cessation (smoking cessation), including the treatment of nicotine withdrawal.
    Non-prescription products for the treatment of tobacco cessation.
    Transdermal dosage (i.e., nicotine transdermal patch)
    Adults (Monotherapy)

    SMOKER of MORE THAN 10 CIGARETTES/DAY: Apply one 21-mg patch to intact skin once daily for 4 to 6 weeks; follow specific product directions. Following the initial regimen, reduce to the 14 mg/day patch for 2 weeks and then the 7 mg/day patch for 2 weeks, then stop. SMOKER of 10 CIGARETTES/DAY OR LESS: Apply one 14-mg patch to intact skin once daily for 4 to 6 weeks; follow specific product directions. Following the initial regimen, reduce to one 7 mg/day patch for 2 weeks, then stop. GENERAL INFORMATION: The patch may be worn for 16 hours or 24 hours per day. If cigarette cravings are present upon waking, the patch should be worn for 24 hours/day. Remove the previously applied patch before applying a new patch. The manufacturer recommends choosing a start date for quitting and beginning using nicotine patch the day the patient stops smoking. It is okay if the patient is not successful at the quit attempt and has a cigarette. Patients can still continue their quit attempts and keep using nicotine patch as directed. Patients should discard their cigarettes and get back to their quit plans. The FDA has determined that there are no significant concerns with using nicotine replacement therapy products like nicotine patch at the same time as another nicotine-containing product like a cigarette.

    Adults (combination therapy with bupropion SR [e.g., Zyban])

    A standardized regimen has not been established. Practitioners should review the complete prescribing information for both bupropion SR (Zyban) and transdermal nicotine products. In one clinical trial with 4 treatment arms, patients in the bupropion SR plus transdermal nicotine group initially received bupropion SR 150 mg/day PO while still smoking; the bupropion SR dose was then increased after 3 days to 150 mg twice daily. Transdermal nicotine 21 mg/day was added after approximately 1 week when the patients reached the target quit date. During weeks 8 and 9 of the study, transdermal nicotine was tapered to 14 mg/day and 7 mg/day, respectively. Although the abstinence rate was higher for the combination treatment than for bupropion SR monotherapy, nicotine replacement monotherapy, or placebo, statistical significance was not achieved. Monitor for treatment-emergent hypertension during combined treatment with bupropion SR and nicotine transdermal systems.

    Adolescents† (Monotherapy)

    Several studies have used nicotine replacement therapy (NRT) with patches in adolescents as an adjunct to smoking cessation strategies; trials have generally stratified NRT dosing to the cigarettes per day (CPD) consumed at entry. SMOKER of MORE THAN 20 CIGARETTES/DAY: Apply one 21-mg patch to intact skin once daily for 4 to 6 weeks. Then, reduce to the 14 mg/day patch for 2 weeks and then the 7 mg/day patch for 2 weeks, then stop. SMOKER of 20 CIGARETTES/DAY OR LESS or WEIGHT LESS THAN 45 kg: Apply one 14-mg patch to intact skin once daily for 4 to 6 weeks. Then, reduce to one 7 mg/day patch for 2 weeks, then stop. GENERAL INFORMATION: Follow specific product directions. The patch may be worn for 16 hours or 24 hours per day. If cigarette cravings are present upon waking, the patch should be worn for 24 hours/day. Remove the previously applied patch before applying a new patch. It is unclear at this time how effective NRT is at promoting abstinence, as it is often noted that the smoking patterns of adolescents vary from those of adult smokers, and adolescents may have different social and adherence patterns that affect response to NRT. More study is needed.

    Oral dosage (nicotine 2 mg or 4 mg chewing gum; e.g., Nicorette gum)


     

    Adults

    During weeks 1 to 6, chew 1 piece of gum every 1 to 2 hours as needed; during weeks 7 to 9, chew 1 piece every 2 to 4 hours as needed; during weeks 10 to 12, chew 1 piece every 4 to 8 hours as needed, then stop. Continuous use (one piece after another without interruption) is not recommended since side effects such as hiccups, pyrosis, or nausea may occur. The 4-mg dosage is recommended for patients who take their first cigarette within 30 minutes of waking and the 2-mg dosage is recommended for patients who take their first cigarette more than 30 minutes after waking. Do not exceed 24 pieces/day of either the 2-mg or 4-mg dosage. To improve the chance of quitting, use at least 9 pieces per day during the first 6 weeks. In a study of 90 highly dependent smokers, the 4-mg strength but not the 2-mg strength produced statistically significantly higher abstinence rates compared to placebo over a period of 6 weeks. However, no difference in effect has been established between the 4-mg dose and the 2-mg dose in low-dependence smokers. The manufacturer recommends choosing a start date for quitting and beginning using nicotine gum the day the patient stops smoking. It is okay if the patient is not successful at the quit attempt and has a cigarette. Patients can still continue their quit attempt and keep using nicotine gum as directed. Patients should discard their cigarettes and get back to their quit plans. The FDA has determined that there are no significant concerns with using nicotine replacement therapy products like nicotine gum at the same time as another nicotine-containing product like a cigarette.

    Adolescents†

    A few studies have used nicotine gum replacement therapy (NRT) in adolescents as an adjunct to smoking cessation strategies; trials have generally stratified NRT dosing to the cigarettes per day (CPD) consumed at entry when deciding 4-mg or 2-mg gum dosages, and followed the usual consumer package labels regarding how to administer (e.g., 10 pieces of gum per day for smokers smoking 1 pack per day, as a guideline). It is unclear at this time how effective NRT is at promoting abstinence, as it is often noted that the smoking patterns of adolescents vary from those of adult smokers, and adolescents may have different social and adherence patterns that affect response to NRT. Gum may not be acceptable in the school environment; nicotine patches may promote better abstinence rates and compliance. More study is needed.

    Oral dosage (nicotine 2 mg or 4 mg lozenge; e.g., Nicorette lozenges)
    Adults

    One lozenge PO every 1 to 2 hours as needed during the first 6 weeks of treatment. Then, reduce to 1 lozenge PO every 2 to 4 hours as needed in weeks 7 to 9 and finally, 1 lozenge PO every 4 to 8 hours as needed in weeks 10 to 12, then stop. Do not exceed 5 lozenges/6 hours or 20 lozenges/day. Continuous use (one lozenge after another without interruption) is not recommended since side effects such as hiccups, pyrosis, or nausea may occur. The 4-mg dosage is recommended for patients who take their first cigarette within 30 minutes of waking and the 2-mg dosage is recommended for patients who take their first cigarette more than 30 minutes after waking. The manufacturer recommends choosing a start date for quitting and beginning using nicotine lozenge the day the patient stops smoking. It is okay if the patient is not successful with the quit attempt and has a cigarette. Patient can still continue their quit attempt and keep using nicotine lozenge as directed. Patients should discard their cigarettes and get back to their quit plans. The FDA has determined that there are no significant concerns with using nicotine replacement therapy products like nicotine lozenge at the same time as another nicotine-containing product like a cigarette.

    Prescription products for the treatment of tobacco cessation.
    Nasal dosage (nicotine nasal spray; i.e., Nicotrol NS nasal spray)
    Adults

    1 spray (containing 0.5 mg nicotine/spray) into each nostril 1 to 2 times each hour as needed whenever the patient feels the need to smoke. Two sprays (1 into each nostril) is considered 1 dose. Max: 5 doses (total of 10 sprays) per hour or 40 doses (total of 80 sprays) per day. Initially, encourage use of at least 8 doses (16 sprays) per day, the minimum effective dose. The recommended duration of treatment is 3 months. Treatment for longer periods has not been shown to improve outcome. The safety of use for periods longer than 6 months has not been established. Patients should be instructed to stop smoking completely while using this product.

    Oral inhalation dosage (nicotine oral inhaler; i.e., Nicotrol Inhaler)
    Adults

    24 to 64 mg (6 to 16 cartridges) per day for up to 12 weeks followed by a gradual reduction in dosage over a period of up to 12 weeks. Use for more than 6 months has not been studied and is not recommended. Patients should be instructed to stop smoking completely while using this product.

    MAXIMUM DOSAGE

    Adults

    21 mg/day transdermally; 24 pieces/day chewing gum; 20 lozenges/day; 40 sprays/day of nostril nasal spray; 64 mg/day for oral inhalation.

    Geriatric

    21 mg/day transdermally; 24 pieces/day chewing gum; 20 lozenges/day; 40 sprays/day of nostril nasal spray; 64 mg/day for oral inhalation.

    Adolescents

    Safety and efficacy have not been established; off-label studies suggest 24 pieces chewing gum/day; 21 mg/day transdermal patch if weight 45 kg or more and 14 mg/day transdermal patch if weight less than 45 kg.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines are not available. Consider dose reduction and monitor closely for adverse effects in patients with moderate or severe hepatic impairment (Child-Pugh score 7 or more).

    Renal Impairment

    Specific guidelines are not available. Consider dose reduction and monitor closely for adverse effects in patients with moderate or severe renal impairment.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Oral Administration (Chewing Gum)
    Instruct patient how to chew nicotine gum and to carefully follow the instructions and use exactly as directed.
    The gum should be chewed slowly until it tingles, then it should be "parked" between the cheek and tongue. When the tingling is gone, begin chewing until the tingling returns. Repeat this process until most of the tingling is gone (about 30 minutes).
    DO NOT SWALLOW THE GUM.
    It is okay if the patient is not successful at the quit attempt and has a cigarette. The patient can still continue their quit attempt and keep using nicotine gum as directed. The patient should discard their cigarettes and get back to their quit plan.
     
    Oral Administration (Lozenge)
    Instruct the patient to carefully follow the directions that come with the nicotine lozenge and use exactly as directed.
    Allow the lozenge to slowly dissolve in mouth. Occasionally move the lozenge from one side of mouth to the other until completely dissolved (about 20—30 minutes).
    It is okay if the patient is not successful at the quit attempt and has a cigarette. The patient can still continue their quit attempt and keep using nicotine lozenges as directed. The patient should discard their cigarettes and get back to their quit plan.

    Topical Administration
    Transdermal Patch Formulations

    Determine if the nicotine patch is to be worn for 16 or 24 hours. Habitrol, Nicoderm, and ProStep are designed to be worn for 24 hours and then removed. The Nicotrol brand is to be applied upon waking and removed at bedtime.
    Apply to any hairless site. Avoid applying to areas with cuts, calluses, scars, oil, burns, or irritation.
    Wash hands and the area the patch will be applied to with a non-moisturizing soap and water immediately before application. Let dry completely.
    Apply using firm pressure over patch for 10 seconds to ensure contact with skin, especially around the edges. If patch becomes loose or falls off, replace with another one. Do not cut or trim patch. Patches should not be affected by showering or bathing.
    It is okay if the patient is not successful at the quit attempt and has a cigarette. The patient can still continue their quit attempt and keep using the nicotine patches as directed. The patient should discard of their cigarettes and get back to their quit plan.

    Inhalation Administration
    Oral Inhalation Administration

    Nicotrol Inhaler System
    Instruct patients on proper use of the inhaler and cartridges (see manufacturer-provided patient information leaflet dispensed with the product).
    Patients should be instructed to stop smoking completely while using this product.
    Best results are obtained by frequent continuous puffing (20 minutes).
    Each cartridge delivers a total of 4 mg of nicotine to the patient.

    Intranasal Inhalation Administration

    Nicotrol NS Nasal Spray
    Instruct patients on proper use of the inhaler.
    Patients should be instructed to stop smoking completely while using this product.
    Each actuation delivers 0.5 mg of nicotine. One dose represents 1 spray in each nostril (total dose = 2 sprays).
    Before using for the first time, instruct patients to prime the device by pumping the nasal spray into a tissue 6—8 times until a fine mist appears. If the nasal sprays is not used for 24 hours, prime the device 1 or 2 times until the mist appears.
    Instruct patients to administer the nasal spray with the head tilted slightly back.
    Instruct patients to breathe through their mouth while administering; do not sniff or inhale while spraying the nasal spray. If the medication begins to run out of the nose after administration, the patient may sniff gently to keep the nasal spray in the nose. Instruct patients not to blow their nose until at least 2—3 minutes after administration.
    Avoid contact with skin, eyes, and mouth.

    STORAGE

    Generic:
    - Store between 68 to 77 degrees F
    Commit:
    - Protect from light
    - Store between 68 to 77 degrees F
    - Store in a dry, well ventilated place
    Habitrol:
    - Store between 68 to 77 degrees F
    Nicoderm CQ:
    - Store between 68 to 77 degrees F
    NICOrelief :
    - Protect from light
    - Store between 68 to 77 degrees F
    Nicorette:
    - Protect from light
    - Store between 68 to 77 degrees F
    Nicotrol:
    - Protect from light
    - Store at or below 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    For any smoker, with or without concomitant disease, the risk of nicotine replacement therapy 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.

    Soya lecithin hypersensitivity, tobacco smoking

    Nicotine products are contraindicated in patients with known hypersensitivity to nicotine or any components of the specific product. For example, Nicorette brand mint-flavor nicotine lozenges should be avoided in patients with soya lecithin hypersensitivity. Patients should be aware that nicotine from drug products can be additive to the nicotine from tobacco. The manufacturer of nicotine oral inhaler and nicotine nasal spray warns that patients should discontinue tobacco smoking and the use of any other tobacco product while using nicotine replacement products. However, after 30 years of non-prescription use, the FDA has reviewed the data and determined that there are no significant safety concerns with using over the counter (OTC) nicotine replacement therapy (NRT) products like nicotine gum, lozenges, and transdermal patches at the same time as another nicotine-containing product like a cigarette. The patient can smoke a cigarette, continue using their OTC nicotine replacement therapy, then attempt to quit again. If a patient has been tobacco smoking, healthcare professionals should warn patients receiving these products that tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes and thus tobacco smoking can increase the metabolism of many therapeutic drugs. Conversely, sudden smoking cessation may cause increased serum levels or effects of concomitant drug therapies (despite the use of a nicotine replacement product). Examples of drugs that may be affected include: caffeine, clozapine, oxazepam, olanzapine, pentazocine, phenothiazines, propoxyphene, propranolol (and possibly other beta-adrenergic blockers), theophylline, tricyclic antidepressants (e.g., imipramine), and warfarin. A decreased dosage of these drugs may be required at the cessation of smoking.

    Acute bronchospasm, asthma

    Acute bronchospasm has been reported in patients with pre-existing asthma who used nicotine nasal spray; the use of the nasal spray is not recommended in patients with severe reactive airway disease. The nicotine oral inhaler has not been specifically studied in patients with asthma, but the manufacturer states that other forms of nicotine replacement might be preferable in patients with bronchospastic airway disease because nicotine is a direct airway irritant and could cause bronchospasm. In addition, tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes and thus tobacco smoke can increase the metabolism of many therapeutic drugs. Because the process of smoking cessation may result in decreased clearance of medications used to treat asthma, patients with this condition are encouraged to check with their health care provider before pursuing nicotine therapy for smoking cessation.

    Angina, cardiac arrhythmias, diabetes mellitus, hypertension, hyperthyroidism, myocardial infarction, pheochromocytoma, sodium restriction, thyroid disease, thyrotoxicosis

    Cardiovascular effects of nicotine typically include peripheral vasoconstriction, tachycardia, and blood pressure elevation. The risks of nicotine replacement therapy in patients with certain cardiovascular and peripheral vascular diseases should be weighed against the benefits of including nicotine replacement in a smoking cessation program. The use of patches in a subject with preexisting cardiovascular disease does not appear to pose a greater risk than smoking itself, as long as the subject refrains from smoking while wearing the patch. Transdermal nicotine has been used safely as an aid to smoking cessation in patients with cardiac disease; however, those with a recent history (within the past 2 weeks) of unstable angina, myocardial infarction, CABG surgery, or cardiac arrhythmia were excluded. In general, nicotine replacement therapy should not be used in patients with serious cardiac arrhythmias, during the immediate post-myocardial infarction period, or in patients with severe or worsening angina pectoris. Nicotine therapy should be used with caution in patients with hypertension, pheochromocytoma, insulin-dependent diabetes mellitus, vasospastic diseases (e.g., Buerger's disease, Prinzmetal's angina), or thyroid disease resulting in hyperthyroidism or thyrotoxicosis, because increases in blood pressure, heart rate, and plasma glucose can follow the effects of nicotine-induced catecholamine release. Nicotine should also be used cautiously in patients on sodium restriction to help control high blood pressure and/or fluid retention. In a comparative trial, the combination of nicotine (Habitrol) and bupropion (Zyban) for smoking cessation resulted in a higher incidence of treatment-emergent hypertension compared to either agent alone or to placebo. Most patients in the trial had evidence of preexisting hypertension. Monitoring for treatment-emergent hypertension is recommended in patients receiving the combination of nicotine and bupropion as well as for those receiving nicotine alone.

    Nasal polyps

    The use of nicotine nasal spray is not recommended in patients with chronic nasal conditions such as allergies, rhinitis, nasal polyps, and sinusitis. Topical application of nicotine is irritating to the nasal mucosa, even in patients without pre-existing nasal conditions; use for longer than 6 months is not recommended.

    Geriatric

    Clinical studies of nicotine dosage forms in geriatric patients have not included sufficient numbers of patients > 65 years of age to determine if they respond differently to treatment than younger adults. However, clinical experience has not identified differences between older and younger patients. In general, dosage selection for elderly patients should be cautious, starting at the lower end of the dosage range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and concomitant disease.

    Hepatic disease, renal failure, renal impairment

    The pharmacokinetics of nicotine in patients with hepatic or renal impairment have not been formally evaluated. Nicotine is extensively metabolized by the liver and total body clearance is dependent on hepatic blood flow; therefore, some effect of significant hepatic disease on nicotine metabolism should be expected. The manufacturer states that only severe renal impairment (e.g. renal failure) would be expected to affect nicotine clearance.

    Pregnancy

    The harmful effects of cigarette/tobacco smoking on maternal and fetal health are clearly established; effects include low birth weight, an increased risk of spontaneous abortion, and increased perinatal mortality. Smoking cessation interventions in pregnancy, including the use of medications when necessary, reduce the proportion of women who continue to smoke in late pregnancy, and reduce low birthweight and preterm birth. Pregnant smokers should be encouraged to stop smoking through educational and behavioral interventions before using pharmacological agents like nicotine. Pregnant patients should seek qualified healthcare professional advice prior to use of non-prescription smoking cessation products. Pregnant smokers should be encouraged to stop smoking through educational and behavioral interventions before using pharmacological agents. Nicotine replacement therapy should be used during pregnancy only if the likelihood of smoking cessation justifies the potential risk of nicotine replacement by the patient or the risk that the patient will continue to smoke. Conflicting information exists in many resources in regard to pregnancy safety of nicotine replacement therapy products. The specific effects of nicotine replacement therapy on fetal development are unknown; nicotine may increase fetal heart rate. Spontaneous abortion has been reported in pregnant women during nicotine replacement therapy; although a causal relationship has not been established, nicotine may have been a contributing factor. Studies of pregnant rhesus monkeys have shown that intravenous nicotine can decrease uterine blood flow and may produce acidosis, hypercarbia, and hypotension in the fetus. Teratogenicity has been noted in mice.

    Breast-feeding

    Nicotine replacement therapy should be used with caution in women who are breast-feeding because safety in the nursing infant has not been systematically examined. Nicotine does pass to the breast milk. Although some clearance of orally absorbed nicotine in the infant will occur through first-pass metabolism in the liver, the efficiency of nicotine removal is probably lowest at birth. In general, it is thought that the proper use of nicotine gum, transdermal patches, or intranasal nicotine would be expected to produce lower concentrations of nicotine in milk than would cigarette smoking. Second-hand smoke from cigarettes clearly has potential adverse effects to the exposed infant. The decision of whether to use nicotine replacement therapy in a woman who is breast-feeding should be evaluated in comparison to the risks associated with exposure of the infant to nicotine and other tobacco contaminants in the breast milk as well as those of passive exposure to tobacco smoke. In one small study (n = 15), the extent of infant exposure to nicotine and its metabolite cotinine during breast-feeding was assessed during maternal smoking and subsequent use of nicotine transdermal patches for smoking cessation. Nicotine and cotinine concentrations in milk were not significantly different between smoking (mean of 17 cigarettes/day) and use of the 21 mg/day patch. However, there were significant reductions in nicotine and cotinine concentrations in the milk during use of the 14 mg/day and 7 mg/day patch than while smoking. The absolute infant dose of nicotine and cotinine decreased by about 70% from smoking or using the 21 mg patch to use of the 7 mg patch. The patch treatment had no significant effect on infant milk intake. The authors concluded that nicotine replacement patches for smoking cessation are a safer option than continuing to smoke while breast-feeding.

    Peptic ulcer disease

    Nicotine may delay healing in peptic ulcer disease. Therefore, nicotine should be used with caution in patients with active peptic ulcers. Nicotine replacement in a smoking cessation program should only be used when the benefits outweigh the potential risks.

    Accidental exposure, children, infants, potential for overdose or poisoning

    The safety and effectiveness of nicotine replacement therapy (NRT) in children and adolescents who smoke has not been established. However, no specific medical risk is known or expected in nicotine dependent older adolescents; carefully consider the benefits and risks in the older adolescent patient. Several studies have used nicotine gum or transdermal patches in adolescents as adjuncts to smoking cessation strategies; it is unclear at this time how effective NRT is at promoting abstinence, as it is often noted that the smoking patterns of adolescents vary from those of adult smokers, and adolescents may have different adherence patterns to NRT, etc. All nicotine replacement products must be stored and discarded carefully in a manner that is not accessible to infants, children, or pets to help avoid potential for overdose or poisoning, or accidental exposure. The amount of nicotine tolerated by adults could produce toxic nicotine symptoms in children or pets and could be fatal in some situations. Products may still have nicotine remnant in them when discarded; both used and unused containers or patches must be kept out of reach of children or pets. Suspected nicotine poisoning in a child or infant should be considered a medical emergency and treated immediately.

    Dental disease

    Nicotine chewing gum is relatively contraindicated in patients with dental disease and in patients with temporomandibular joint (TMJ) disorder because injury to teeth or aggravation of TMJ can result from chewing.

    Esophagitis, gastroesophageal reflux disease (GERD), hiatal hernia

    Nicotine is relatively contraindicated in patients with a history of esophagitis, hiatal hernia, or gastroesophageal reflux disease (GERD) because these conditions can be exacerbated by nicotine's pharmacologic effects. Mouth or throat inflammation may be irritated by the nicotine chewing gum formulation.

    Eczema

    Nicotine transdermal systems may cause skin irritation in patients with topic dermatitis or eczema. Patients with an allergy to adhesive tape or who have allergic-type skin disorders are more likely to develop rashes from the use of nicotine transdermal systems.

    Magnetic resonance imaging (MRI)

    Because some nicotine transdermal systems (i.e. patches) contain aluminum or other metal components, patients should be instructed to remove the patch before undergoing magnetic resonance imaging (MRI). Metal components contained in the backing of some transdermal systems can overheat during an MRI scan and cause skin burns in the area where the patch is adhered.

    Depression

    Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes and thus tobacco smoke can increase the metabolism of many therapeutic drugs. Because the process of smoking cessation may result in decreased clearance of medications used to treat depression, patients with this condition are encouraged to check with their health care provider before pursuing nicotine therapy for smoking cessation.

    Seizure disorder, seizures

    Nicotine products should be used cautiously in patients with seizures or a seizure disorder. There have been reports of seizures induced by smoking cessation agents including nicotine replacement therapy. In the setting of overdose, nicotine has been associated with seizures in humans.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known

    Moderate

    psychological dependence / Delayed / 32.0-32.0
    physiological dependence / Delayed / 32.0-32.0
    dyspnea / Early / 0-5.0
    palpitations / Early / 4.0-4.0
    confusion / Early / 3.0-3.0
    aphasia / Delayed / 1.0-1.0
    migraine / Early / 0-1.0
    amnesia / Delayed / 0-1.0
    withdrawal / Early / 5.0
    depression / Delayed / 5.0
    hypertension / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    erythema / Early / Incidence not known
    oral ulceration / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known

    Mild

    nasal irritation / Early / 81.0-94.0
    throat irritation / Early / 0-40.0
    rhinitis / Early / 0-23.0
    headache / Early / 18.0-18.0
    back pain / Delayed / 6.0-6.0
    nausea / Early / 5.0-5.0
    tremor / Early / 0-5.0
    appetite stimulation / Delayed / 0-5.0
    arthralgia / Delayed / 5.0-5.0
    flatulence / Early / 4.0-4.0
    menstrual irregularity / Delayed / 4.0-4.0
    acne vulgaris / Delayed / 3.0-3.0
    abdominal pain / Early / 3.0-3.0
    myalgia / Early / 3.0-3.0
    dysmenorrhea / Delayed / 3.0-3.0
    pruritus / Rapid / 2.0-2.0
    purpura / Delayed / 0-1.0
    rash / Early / 0-1.0
    xerostomia / Early / 0-1.0
    hiccups / Early / 0-1.0
    diarrhea / Early / 0-1.0
    emotional lability / Early / 5.0
    insomnia / Early / 5.0
    restlessness / Early / 5.0
    anxiety / Delayed / 5.0
    dizziness / Early / 5.0
    fatigue / Early / 5.0
    hyperhidrosis / Delayed / 5.0
    cough / Delayed / 10.0
    sinusitis / Delayed / 3.0
    urticaria / Rapid / Incidence not known
    weight gain / Delayed / Incidence not known
    dental pain / Delayed / Incidence not known
    dyspepsia / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    irritability / Delayed / Incidence not known
    otalgia / Early / Incidence not known
    rhinorrhea / Early / Incidence not known
    epistaxis / Delayed / Incidence not known
    lacrimation / Early / Incidence not known
    sneezing / Early / Incidence not known
    ocular irritation / Rapid / Incidence not known
    hoarseness / Early / Incidence not known
    flushing / Rapid / Incidence not known
    dysosmia / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    nasal congestion / Early / Incidence not known
    dysgeusia / Early / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Minor) Nicotine activates neuroendocrine pathways and may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Acetaminophen; Guaifenesin; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Acetaminophen; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Acetohexamide: (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Acrivastine; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Adenosine: (Major) Nicotine has been reported to enhance the cardiovascular effects of adenosine; an increase in angina-like chest pains, heart rate or a decrease in blood pressure may be noted. While no special cautions are recommended when adenosine is used therapeutically to treat supraventricular tachycardia, it may be advisable for patients to avoid nicotine products or tobacco prior to electrophysiologic studies or stress testing where adenosine will be administered.
    Albiglutide: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Alogliptin: (Minor) Monitor blood glucose concentrations for needed alogliptin dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Alogliptin; Metformin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed alogliptin dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Alogliptin; Pioglitazone: (Minor) Monitor blood glucose concentrations for needed alogliptin dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Nicotine may increase plasma glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Alpha-blockers: (Moderate) Nicotine use may reduce the clinical effects of the alpha-blockers. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Alpha-glucosidase Inhibitors: (Minor) Nicotine activates neuroendocrine pathways and may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Amitriptyline: (Moderate) Physiological changes resulting from tobacco smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking. Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes, likely due to the hydrocarbons of tobacco smoke. Sudden smoking cessation may result in a reduced clearance of TCAs, despite the initiation of nicotine replacement products.
    Amphetamine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Amphetamine; Dextroamphetamine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Articaine; Epinephrine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Atazanavir; Cobicistat: (Minor) Caution is warranted when cobicistat is administered with nicotine as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nicotine is an inducer of CYP2D6; cobicistat is a CYP2D6 substrate.
    Benzphetamine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Bromocriptine: (Minor) Use caution during use of tobacco or other nicotine-containing products while taking bromocriptine. Concurrent use of vasoconstrictors, such as nicotine, may result in enhanced vasoconstriction from ergot-based medications. Published reports of interactions between bromocriptine, an ergot derivative, and tobacco smoking or nicotine are not available. Safety and efficacy of bromocriptine for helping patients with smoking cessation is under investigation, but safety of use with nicotine products concurrently or if the patient continues to smoke is not established.
    Brompheniramine; Carbetapentane; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Brompheniramine; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Brompheniramine; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Bupivacaine; Epinephrine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Bupropion: (Moderate) Combination of nicotine and bupropion may induce clinically significant blood pressure elevations in some patients. Close monitoring of blood pressure is recommended if this combination is prescribed.
    Bupropion; Naltrexone: (Moderate) Combination of nicotine and bupropion may induce clinically significant blood pressure elevations in some patients. Close monitoring of blood pressure is recommended if this combination is prescribed.
    Canagliflozin: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Canagliflozin; Metformin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Carbetapentane; Guaifenesin; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Carbetapentane; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Carbetapentane; Phenylephrine; Pyrilamine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Carbetapentane; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Carbinoxamine; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Carbinoxamine; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Cetirizine; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlophedianol; Guaifenesin; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlordiazepoxide; Amitriptyline: (Moderate) Physiological changes resulting from tobacco smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking. Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes, likely due to the hydrocarbons of tobacco smoke. Sudden smoking cessation may result in a reduced clearance of TCAs, despite the initiation of nicotine replacement products.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlorpheniramine; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlorpheniramine; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Chlorpropamide: (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Clomipramine: (Moderate) Physiological changes resulting from tobacco smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking. Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes, likely due to the hydrocarbons of tobacco smoke. Sudden smoking cessation may result in a reduced clearance of TCAs, despite the initiation of nicotine replacement products.
    Cobicistat: (Minor) Caution is warranted when cobicistat is administered with nicotine as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nicotine is an inducer of CYP2D6; cobicistat is a CYP2D6 substrate.
    Codeine; Guaifenesin; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Codeine; Phenylephrine; Promethazine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Dapagliflozin: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Dapagliflozin; Metformin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Dapagliflozin; Saxagliptin: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Darunavir; Cobicistat: (Minor) Caution is warranted when cobicistat is administered with nicotine as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nicotine is an inducer of CYP2D6; cobicistat is a CYP2D6 substrate.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Minor) Caution is warranted when cobicistat is administered with nicotine as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nicotine is an inducer of CYP2D6; cobicistat is a CYP2D6 substrate.
    Desipramine: (Moderate) Physiological changes resulting from tobacco smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking. Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes, likely due to the hydrocarbons of tobacco smoke. Sudden smoking cessation may result in a reduced clearance of TCAs, despite the initiation of nicotine replacement products.
    Desloratadine; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Dexbrompheniramine; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Dextroamphetamine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Diphenhydramine; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Dobutamine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Donepezil; Memantine: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, like nicotine, could result in elevated serum concentrations of one or both drugs.
    Dopamine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Doxazosin: (Moderate) Nicotine use may reduce the clinical effects of the alpha-blockers. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Doxepin: (Moderate) Physiological changes resulting from tobacco smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking. Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes, likely due to the hydrocarbons of tobacco smoke. Sudden smoking cessation may result in a reduced clearance of TCAs, despite the initiation of nicotine replacement products.
    Doxorubicin Liposomal: (Major) Nicotine is a mild CYP2D6 inducer and doxorubicin is a major substrate of CYP2D6. Inducers of CYP2D6 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of nicotine and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Doxorubicin: (Major) Nicotine is a mild CYP2D6 inducer and doxorubicin is a major substrate of CYP2D6. Inducers of CYP2D6 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of nicotine and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Dulaglutide: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Minor) Caution is warranted when cobicistat is administered with nicotine as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nicotine is an inducer of CYP2D6; cobicistat is a CYP2D6 substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Caution is warranted when cobicistat is administered with nicotine as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nicotine is an inducer of CYP2D6; cobicistat is a CYP2D6 substrate.
    Empagliflozin: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Empagliflozin; Linagliptin: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent (e.g., linagliptin) dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Empagliflozin; Linagliptin; Metformin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed antidiabetic agent (e.g., linagliptin) dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Empagliflozin; Metformin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Epinephrine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Ergot alkaloids: (Major) Concurrent use of vasoconstrictors, such as nicotine, with ergot alkaloids may result in enhanced vasoconstriction. Nicotine acts indirectly as a sympathomimetic agent by releasing catecholamines, potentially resulting in effects such as hypertension, coronary spasm, coronary ischemia, or cardiac arrhythmias, which may be additive with ergot alkaloids. Patients should avoid smoking tobacco or using other nicotine-containing products while taking ergot compounds if possible.
    Ertugliflozin; Metformin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Ertugliflozin; Sitagliptin: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Exenatide: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Fexofenadine; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Food: (Moderate) It is advisable not to ingest acidic foods or beverages during or immediately before the use of nicotine gum, as the absorption of nicotine from nicotine polacrilex relies on mildly alkaline saliva.
    Glimepiride: (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Glimepiride; Rosiglitazone: (Minor) Nicotine may increase plasma glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed. (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Glipizide: (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Glipizide; Metformin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Glyburide: (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Glyburide; Metformin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Guaifenesin; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Guaifenesin; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Heparin: (Minor) Nicotine may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance in most patients since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Hydrocodone; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Hydrocodone; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Ibuprofen; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Imipramine: (Moderate) Physiological changes resulting from tobacco smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking. Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes, likely due to the hydrocarbons of tobacco smoke. Sudden smoking cessation may result in a reduced clearance of TCAs, despite the initiation of nicotine replacement products.
    Incretin Mimetics: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Insulin Degludec; Liraglutide: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Insulin Glargine; Lixisenatide: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Insulins: (Minor) Nicotine may increase plasma glucose. Monitor blood sugar for needed insulin dosage adjustments in insulin-dependent diabetic patients whenever a change in either nicotine intake or smoking status occurs. In addition, the use of inhaled insulin is not recommended in patients who smoke. Smoking tobacco can alter the effect of inhaled insulin in several ways. First, nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Second, tobacco smoking is known to aggravate insulin resistance. Finally, compared with non-smokers, insulin exposure after inhalation may be greater in patients who smoke. If inhaled insulin is used in this population, patients should be instructed to monitor blood glucose concentrations closely. If a change in smoking status or nicotine intake occur, patients should continue to monitor their blood glucose concentrations closely and clinicians should adjust the dose of insulin when indicated.
    Isoproterenol: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Lidocaine; Epinephrine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Linagliptin: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent (e.g., linagliptin) dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Linagliptin; Metformin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed antidiabetic agent (e.g., linagliptin) dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine concentrations) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Liraglutide: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Lixisenatide: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with nicotine. Loperamide is metabolized by the hepatic enzyme CYP2D6; nicotine is a mild inducer of this enzyme.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with nicotine. Loperamide is metabolized by the hepatic enzyme CYP2D6; nicotine is a mild inducer of this enzyme.
    Loratadine; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Meglitinides: (Minor) Nicotine activates neuroendocrine pathways and may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Memantine: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, like nicotine, could result in elevated serum concentrations of one or both drugs.
    Metformin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Metformin; Repaglinide: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Nicotine activates neuroendocrine pathways and may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Metformin; Rosiglitazone: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Nicotine may increase plasma glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Metformin; Saxagliptin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Metformin; Sitagliptin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Methamphetamine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Midodrine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Miglitol: (Minor) Nicotine activates neuroendocrine pathways and may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Naproxen; Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Nateglinide: (Minor) Nicotine activates neuroendocrine pathways and may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Norepinephrine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Nortriptyline: (Moderate) Physiological changes resulting from tobacco smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking. Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes, likely due to the hydrocarbons of tobacco smoke. Sudden smoking cessation may result in a reduced clearance of TCAs, despite the initiation of nicotine replacement products.
    Oxymetazoline: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Perphenazine; Amitriptyline: (Moderate) Physiological changes resulting from tobacco smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking. Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes, likely due to the hydrocarbons of tobacco smoke. Sudden smoking cessation may result in a reduced clearance of TCAs, despite the initiation of nicotine replacement products.
    Phenoxybenzamine: (Moderate) Nicotine use may reduce the clinical effects of the alpha-blockers. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Phentolamine: (Moderate) Nicotine use may reduce the clinical effects of the alpha-blockers. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Pioglitazone: (Minor) Nicotine may increase plasma glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Pioglitazone; Glimepiride: (Minor) Nicotine may increase plasma glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed. (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Pioglitazone; Metformin: (Minor) Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments of metformin may be needed. Nicotine may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. (Minor) Nicotine may increase plasma glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Pramlintide: (Minor) Monitor blood glucose concentrations for needed dosage adjustments in patients receiving antidiabetic agents whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways and may increase plasma glucose.
    Prazosin: (Moderate) Nicotine use may reduce the clinical effects of the alpha-blockers. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Prilocaine; Epinephrine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Promethazine; Phenylephrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Protriptyline: (Moderate) Physiological changes resulting from tobacco smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking. Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes, likely due to the hydrocarbons of tobacco smoke. Sudden smoking cessation may result in a reduced clearance of TCAs, despite the initiation of nicotine replacement products.
    Pseudoephedrine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Pseudoephedrine; Triprolidine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Regadenoson: (Major) Nicotine has been reported to enhance the cardiovascular effects of adenosine receptor agonists; an increase in angina-like chest pain, heart rate, or a decrease in blood pressure may be noted. While no special cautions are recommended for regadenoson, it may be advisable for patients to avoid nicotine products or tobacco prior to electrophysiologic studies or stress testing where adenosine receptor agonists will be administered.
    Repaglinide: (Minor) Nicotine activates neuroendocrine pathways and may increase plasma glucose; tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Ritodrine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Rosiglitazone: (Minor) Nicotine may increase plasma glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Saxagliptin: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Semaglutide: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. Cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Simvastatin; Sitagliptin: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Sitagliptin: (Minor) Monitor blood glucose concentrations for needed antidiabetic agent dosage adjustments in diabetic patients whenever a change in either nicotine intake or smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose.
    Sulfonylureas: (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Terazosin: (Moderate) Nicotine use may reduce the clinical effects of the alpha-blockers. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Tetrahydrozoline: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Thiazolidinediones: (Minor) Nicotine may increase plasma glucose. Blood glucose concentrations should be monitored more closely whenever a change in either nicotine intake or smoking status occurs; dosage adjustments in antidiabetic agents may be needed.
    Thiotepa: (Moderate) The concomitant use of thiotepa and nicotine may increase the exposure of nicotine; however, the clinical relevance of this interaction is unknown. Thiotepa is a CYP2B6 inhibitor in vitro; nicotine is a CYP2B6 substrate.
    Tobacco: (Major) Nicotine from smoking cessation products can be additive to the nicotine from tobacco; patients should be warned against continued tobacco use while using nicotine replacement products. Pharmacologically, the effects of nicotine on the cardiovascular system mimic those of sympathetic stimulation; agonism of nicotinic receptors on adrenal medullary cells causes the release of epinephrine and norepinephrine. Nicotine raises systolic and diastolic blood pressure and can increase the inotropic and chronotropic actions of the heart. The degree to which these reactions occur is a function of the nicotine blood concentration. Symptoms of excessive nicotine can include nausea/vomiting, abdominal pain, diarrhea, headache, and hypertension.
    Tolazamide: (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Tolbutamide: (Minor) Nicotine may increase plasma glucose. The cessation of nicotine therapy may result in a decrease in blood glucose. Blood glucose concentrations should be monitored more closely whenever a change in nicotine intake occurs; dosage adjustments in antidiabetic agents may be needed.
    Tricyclic antidepressants: (Moderate) Physiological changes resulting from tobacco smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking. Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes, likely due to the hydrocarbons of tobacco smoke. Sudden smoking cessation may result in a reduced clearance of TCAs, despite the initiation of nicotine replacement products.
    Trimipramine: (Moderate) Physiological changes resulting from tobacco smoking cessation, with or without nicotine replacement, may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking. Tobacco smoking has been shown to increase the clearance of TCAs by inducing hepatic microsomal enzymes, likely due to the hydrocarbons of tobacco smoke. Sudden smoking cessation may result in a reduced clearance of TCAs, despite the initiation of nicotine replacement products.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and nicotine may result in increased nicotine concentrations. Vemurafenib is a CYP2A6 inhibitor and nicotine is a CYP2A6 substrate. Pharmacologically, the effects of nicotine on the cardiovascular system mimic those of sympathetic stimulation; agonism of nicotinic receptors on adrenal medullary cells causes the release of epinephrine and norepinephrine. Nicotine raises systolic and diastolic blood pressure and can increase the inotropic and chronotropic actions of the heart. The degree to which these reactions occur is a function of the nicotine blood concentration. Symptoms of excessive nicotine can include nausea/vomiting, abdominal pain, diarrhea, headache, and hypertension.

    PREGNANCY AND LACTATION

    Pregnancy

    The harmful effects of cigarette/tobacco smoking on maternal and fetal health are clearly established; effects include low birth weight, an increased risk of spontaneous abortion, and increased perinatal mortality. Smoking cessation interventions in pregnancy, including the use of medications when necessary, reduce the proportion of women who continue to smoke in late pregnancy, and reduce low birthweight and preterm birth. Pregnant smokers should be encouraged to stop smoking through educational and behavioral interventions before using pharmacological agents like nicotine. Pregnant patients should seek qualified healthcare professional advice prior to use of non-prescription smoking cessation products. Pregnant smokers should be encouraged to stop smoking through educational and behavioral interventions before using pharmacological agents. Nicotine replacement therapy should be used during pregnancy only if the likelihood of smoking cessation justifies the potential risk of nicotine replacement by the patient or the risk that the patient will continue to smoke. Conflicting information exists in many resources in regard to pregnancy safety of nicotine replacement therapy products. The specific effects of nicotine replacement therapy on fetal development are unknown; nicotine may increase fetal heart rate. Spontaneous abortion has been reported in pregnant women during nicotine replacement therapy; although a causal relationship has not been established, nicotine may have been a contributing factor. Studies of pregnant rhesus monkeys have shown that intravenous nicotine can decrease uterine blood flow and may produce acidosis, hypercarbia, and hypotension in the fetus. Teratogenicity has been noted in mice.

    Nicotine replacement therapy should be used with caution in women who are breast-feeding because safety in the nursing infant has not been systematically examined. Nicotine does pass to the breast milk. Although some clearance of orally absorbed nicotine in the infant will occur through first-pass metabolism in the liver, the efficiency of nicotine removal is probably lowest at birth. In general, it is thought that the proper use of nicotine gum, transdermal patches, or intranasal nicotine would be expected to produce lower concentrations of nicotine in milk than would cigarette smoking. Second-hand smoke from cigarettes clearly has potential adverse effects to the exposed infant. The decision of whether to use nicotine replacement therapy in a woman who is breast-feeding should be evaluated in comparison to the risks associated with exposure of the infant to nicotine and other tobacco contaminants in the breast milk as well as those of passive exposure to tobacco smoke. In one small study (n = 15), the extent of infant exposure to nicotine and its metabolite cotinine during breast-feeding was assessed during maternal smoking and subsequent use of nicotine transdermal patches for smoking cessation. Nicotine and cotinine concentrations in milk were not significantly different between smoking (mean of 17 cigarettes/day) and use of the 21 mg/day patch. However, there were significant reductions in nicotine and cotinine concentrations in the milk during use of the 14 mg/day and 7 mg/day patch than while smoking. The absolute infant dose of nicotine and cotinine decreased by about 70% from smoking or using the 21 mg patch to use of the 7 mg patch. The patch treatment had no significant effect on infant milk intake. The authors concluded that nicotine replacement patches for smoking cessation are a safer option than continuing to smoke while breast-feeding.

    MECHANISM OF ACTION

    Nicotine's pharmacological actions are complex and include effects on both the central and peripheral nervous systems. Nicotine is classified as a stimulant of autonomic ganglia, although it possesses both stimulant and depressant actions. Stimulation at nicotinic receptors produces a variety of cholinergic and adrenergic effects. These include: tachycardia or bradycardia mediated by either stimulation or interference with sympathetic or parasympathetic pathways, stimulation of receptors in the carotic and aortic bodies, release of epinephrine from the adrenal medulla, and stimulation of the chemoreceptor-trigger zone. At the neuromuscular junction, nicotine is an agonist, but paralysis ensues due to receptor desensitization. The effects on the GI tract are secondary to parasympathetic stimulation.

    PHARMACOKINETICS

    Nicotine is administered through several dosage forms which include chewing gum, oral lozenge, inhaler, nasal spray, and transdermal patch. Nicotine is widely distributed in the body tissues, particularly the central nervous system (CNS). After a single puff on a cigarette, nicotine reaches the brain within 7 seconds. The volume of distribution following IV administration of nicotine is approximately 2 to 3 L/kg. Plasma protein binding of nicotine is less than 5%. Nicotine crosses the placenta and is excreted in breast milk (average milk to plasma ratio is 2.9:1). The concentrations of nicotine in amniotic fluid and fetal serum exceed those in maternal serum. Detectable amounts also appear in the serum and urine of infants of lactating mothers who smoke. Plasma concentrations of nicotine decline in a biphasic manner. Nicotine is extensively metabolized by the liver and clearance is dependent on liver blood flow. The liver enzymes CYP2A6, and to a lesser extent by CYP2B6 and CYP2E1, are involved in nicotine metabolism. The kidney and lung are also sites of nicotine metabolism. 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 (3HC, 45% of the dose). Cotinine has a half-life of 15 to 20 hours and concentrations that exceed nicotine by 10-fold. Cotinine is metabolized nearly exclusively by CYP2A6 to 3HC. Nicotine and cotinine are also metabolized by glucuronidation, thought to be primarily via UGT 1A4, 1A9, and 2B10. While glucuronidation is usually a minor pathway of nicotine metabolism, in people who have low CYP2A6 activity, glucuronidation can be a major determinant of nicotine clearance. 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/minute in a healthy adult smoker. The initial half-life of nicotine is 2 to 3 minutes and the terminal apparent elimination half-life of nicotine when inhaled is 1 to 2 hours. With the transdermal patches, the elimination half-life is 3 to 4 hours due to continued absorption from skin depot.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2A6
    Nicotine is primarily metabolized by the liver enzyme CYP2A6, with a minor involvement by CYP2B6 and CYP2E1. Cotinine is metabolized nearly exclusively by CYP2A6. Nicotine and cotinine are also metabolized by glucuronidation as a minor pathway, thought to be primarily via UGT 1A4, 1A9, and 2B10.

    Oral Route

    After administration of the gum or lozenge, the absorption of nicotine through the buccal mucosa occurs readily but systemic absorption is slower than that from cigarette smoke or with inhaled or nasal administration. Pharmacokinetic data for the nicotine lozenge are not available; one study reports that nicotine lozenges deliver 25% to 27% more nicotine than nicotine gum because the lozenges completely dissolve and deliver their full dose whereas the gum retains some of the nicotine. Buffering the gum product to a pH of 8.5 enhances absorption. The rate and extent of absorption during 20 to 30 minutes of rhythmic chewing vary from 50% to 90% of the content of the gum; the amount absorbed depends on the time the saliva is held in the mouth as opposed to being swallowed or expectorated. Very little nicotine is absorbed from the GI tract due to extensive first-pass metabolism through the liver. Peak nicotine plasma concentrations occur within 15 to 30 minutes after the start of chewing the gum.

    Topical Route

    After application of a transdermal patch, nicotine is well absorbed through the skin; the extent of absorption is not known. Peak nicotine plasma concentrations occur within 4 to 12 hours after application of a patch. Time to peak plasma concentrations from some of the various transdermal preparations are as follows: Habitrol: 5 to 6 hours; Nicoderm: 4 hours after application. Many brands of patches (e.g., Habitrol, Nicoderm) are designed to be worn for 24 hours and then removed and replaced. Some dosage regimens and patches have the patient apply the patch upon waking and remove the patch at bedtime. All nicotine patches deliver nicotine gradually and aim to produce sustained nicotine levels throughout the day.

    Inhalation Route

    In patients who smoke nicotine via cigarettes, there is considerable variation in nicotine blood levels from cigarette to cigarette. However, nicotine accumulates in the body over 6 to 9 hours of regular smoking. Thus, continuous smoking results in 24-hour continual nicotine exposure. Inhaled nicotine is not subject to first-pass intestinal and hepatic metabolism. After inhaled administration, nicotine is rapidly absorbed through the mucous membranes and respiratory tract; some buccal absorption occurs slowly with inhaled nicotine. The rapid rate of systemic absorption and availability to the brain reinforces nicotine use. Less than 5% of an inhaled dose from a nicotine inhaler reaches the lower respiratory tract. Peak nicotine plasma concentrations occur within 15 minutes after inhalation.

    Other Route(s)

    Intranasal Route
    After the administration of 2 sprays of nicotine nasal spray, approximately 53% enters the systemic circulation. Nicotine is rapidly absorbed via the nasal mucosa and reaches peak plasma concentrations 4 to 15 minutes after administration; however, there is significant variability in nicotine plasma concentrations between patients. In one clinical trial, a 1 mg nasal spray dose produced peak nicotine concentrations similar to those seen after smoking one cigarette in 20% of subjects.