Nicotine polacrilex Chewing Gum
NICOGUM
COMPOSITION
NICOGUM Chewing Gum
Each piece contains:
Nicotine polacrilex β¦β¦. 2 mg
Or
Nicotine polacrilex β¦β¦. 4 mg
DOSAGE FORM
Chewing gum
PHARMACOLOGY
Pharmacodynamics
The principal mechanism of action of nicotine replacement therapy (NRT) is to
partially replace the nicotine formally obtained from tobacco. It provides small
and sustained quantities of nicotine without the harmful gases of smoking, to
reduce the severity of withdrawal symptoms and cravings. Amelioration of
withdrawal symptoms is observed with relatively low blood levels of nicotine,
which also provides for an alternative source of some reinforcing and cognitive
effects. A second possible mechanism of benefit has been suggested to be the
potential for nicotine medications to desensitize the nicotinic acetylcholine
receptors (nAchRs). Such desensitization would result in a reduced effect of
nicotine from cigarettes, such that if a person relapses to smoking while taking
NRT, the cigarette would be less satisfying and the person less likely to resume.
Hence, NRT also provide a coping mechanism, making cigarettes less rewarding
to smoke.
Pharmacokinetics
Absorption:
Nicotine is a weak base with a pKa of 8.0. In its ionized state, such as in acidic
environments, nicotine does not rapidly cross membranes. Nicotine from the
chewing gum is released slowly and depends on the intensity of chewing. This
nicotine is buffered to alkaline pH in the oral mucosa to facilitate absorption.
Concentrations of nicotine in the blood rise gradually and plateau at about 30
minutes, with levels persisting and declining slowly over the next 2 hours. This
slow increase in blood and, especially, brain levels results in low abuse liability of
the gum. The absolute dose of nicotine absorbed systemically from nicotine gum
is much less than the nicotine content of the gum, because some amount of
nicotine is swallowed with subsequent first-pass metabolism. Nicotine is poorly
absorbed from the stomach because it is ionized in the acidic gastric fluid. The
bioavailability of nicotine from the gum ranges between 55-78%.
Nicotine absorption pharmacokinetics of cigarette and gum after single
dose
Type of nicotine
administration Cmax (ng/ml) Tmax (min) Bioavailability
(%)
Smoking (1 cigarette,5 min)
(? 2 mg/cigarette)
15-30
(venous)
20-60 (arterial)
5-8 (venous)
3-5 (arterial)
80-90 (of
inhaled
nicotine)
Gum (30 min, total dose in gum)
2 mg
4 mg
6-9 (venous)
10-17
(venous)
30
30
78
55
Distribution:
After absorption, nicotine enters the bloodstream where, at pH 7.4, it is about
69% ionized and 31% un-ionized. Binding to plasma proteins is less than 5%.
The drug is distributed extensively to body tissues, with steady-state volume of
distribution averaging 2.6 of body weight. Nicotine binds to brain tissues with high
affinity, and the receptor binding capacity is increased in smokers compared with
non-smokers. Nicotine accumulates markedly in gastric juice and saliva. Nicotine
also accumulates in breast milk (milk/plasma ratio: 2.9) and crosses the placental
barrier easily.
Metabolism:
Nicotine is metabolized primarily in the liver by the action of CYP450 enzymes. In
vitro and in vivo studies show that CYP2A6 is the enzyme that is primarily
responsible for the oxidation of nicotine and cotinine, a primary metabolite of
nicotine. The second most active hepatic P450 enzyme in nicotine oxidation is
CYP2B6, when investigated using hepatic tissues or expression systems in vitro,
especially at high nicotine concentrations. About 90% of a systemic dose of
nicotine can be accounted for as nicotine and metabolites in the urine. Based on
studies with simultaneous infusion of labelled nicotine and cotinine, it has been
determined that 70-80% of nicotine is converted to cotinine. About 4-7% of
nicotine is excreted as nicotine N-oxide and 3-5% as nicotine glucuronide.
Cotinine is excreted unchanged in the urine to a small degree (10-15%). The
remainder is converted to metabolites, primarily trans-3-hydroxycotinine (33-
40%), cotinine glucuronide (12-17%), and trans-3-hydroxycotinine glucuronide
(7-9%). Extrahepatic nicotine metabolism in humans is probably of little
importance for systemic nicotine clearance.
Pharmacokinetic parameters of nicotine, cotinine and trans-3-
hydroxycotinine after intravenous administration
Clearance
(ml/min)
Renal
clearance
Non renal
clearance
Volume of
Distribution
(l/kg)
T1/2(min)
Nicotine
1110-1500
35-90
1050-1460
2.2-3.3
100-150
Cotinine
42-55
3-9
36-52
0.69-0.93
770-1130
Trans-3-
hydroxycotinine
82
50
32
0.66
396
Excretion:
Nicotine and metabolites are mainly excreted by glomerular filtration and tubular
secretion, with variable reabsorption depending on urinary pH. With uncontrolled
urine pH, renal clearance averages about 35-90 ml/min, accounting for the
elimination of about 5% of total clearance. About 1% of nicotine is excreted in the
faeces, while some nicotine and cotinine is excreted in the sweat. Renal
excretion of cotinine is a minor route of elimination, averaging about 12% of total
clearance. In contrast, 100% of nicotine N-oxide and 63% of trans-3-
hydroxycotinine are excreted unchanged in the urine.
Special Conditions
Elderly
Compared with young adults, clearance of nicotine is decreased in the elderly
with total clearance being lower by 23% and renal clearance lower by 49%.
Lower nicotine metabolism in the elderly may be because of reduced liver blood
flow, as no decrease in CYP2A6 protein levels or nicotine metabolism in liver
microsomes due to age has been detected. Volume of distribution of nicotine is
lower in elderly subjects due to decrease in lean body mass.
Pregnancy and Menstrual Cycle
Results from a recently completed large-scale (N=290) twin study with
intravenous infusions of both nicotine and cotinine clearly show that nicotine and
cotinine clearances are higher in women compared with men, and oral
contraceptive use further accelerates nicotine and cotinine clearances in women.
Clearance is increased by 60% and 140% for nicotine and cotinine, respectively,
in pregnancy compared with postpartum. The finding that, in pregnancy, cotinine
clearance is increased more than nicotine clearance indicates that this increase
in clearance is most likely caused by the induction of CYP2A6 and not by an
increase in hepatic blood flow. These results suggest that CYP2A6 activity is
induced by sex hormones; however, supporting experimental in vitro data are still
lacking.
Pathological Conditions
The total metabolism by CYP2A6 is reduced in patients with alcoholic liver
disease and viral hepatitis. Kidney failure not only decreases renal clearance of
nicotine and cotinine, but also metabolic clearance of nicotine. Metabolic
clearance of nicotine is reduced by 50% in subjects with severe renal impairment
compared with healthy subjects.
INDICATIONS
NICOGUM Chewing Gum is indicated for smoking cessation therapy.
It reduces withdrawal symptoms, including nicotine craving, associated with
quitting smoking.
DOSAGE AND ADMINISTRATION
Under 18 years of age, the relative risks and benefits of pharmacotherapy need
to be considered. No randomized controlled trials on the effectiveness of NRT in
young smokers have been published until date.
Stop smoking completely when you begin using the gum.
How to Use
If smoking 25 or more cigarettes a day, use 4 mg nicotine gum.
If smoking less than 25 cigarettes a day, use 2 mg nicotine gum.
Use according to the following 12-week schedule:
Weeks 1-6 Weeks 7-9 Weeks 10-12
One piece of gum every
1-2 hours
One piece of gum every
2-4 hours
One piece of gum every
4-8 hours
Remember: Do not use more than 24 pieces of gum a day.
Steps to follow for maximum benefit:
1. Chew each gum piece very slowly several times.
2. Stop chewing when you get a peppery taste or a slight tingling in the mouth.
This usually happens after about 1 minute or 15 chews, but may vary from
person to person.
3. Shift the chewing gum to one corner or side of your mouth, and leave it there.
4. When the peppery taste or tingle is almost gone (in about a minute), again
start chewing the gum piece slowly. Stop when the taste or tingle returns.
5. Shift the gum to a different place in your mouth every time.
6. Repeat steps 4 to 7 until most of the nicotine is gone from the NICOGUM
Chewing Gum (usually happens in about 30 mins; the peppery taste or tingle
will not return).
7. Wrap the used gum in paper and throw it away in the dustbin.
8. To improve the chances of quitting, use at least nine pieces of NICOGUM
Chewing Gum a day. If strong or frequent cravings are experienced, a
second piece can be used within the hour. However, continuous use of one
gum piece after another is not recommended, since this may cause hiccups,
heartburn, nausea, or other side effects.
9. It is important to complete the NICOGUM quit programme at the end of 12
weeks, and to stop using NICOGUM Chewing Gum at that time.
CONTRAINDICATIONS
NICOGUM Chewing Gum is contraindicated in patients with a hypersensitivity to
nicotine polacrilex or any other components of the chewing gum.
WARNINGS AND PRECAUTIONS
Use with caution in the following conditions:
? If patients continue to smoke, chew tobacco, use snuff, or use a nicotine
patch or other nicotine-containing products.
? In the presence of unstable heart disease, recent myocardial infarction, or
irregular heartbeat. Nicotine can increase the heart rate.
? In case of high blood pressure not controlled with medication. Nicotine can
increase blood pressure.
? Stomach ulcer or diabetes
? Using a non-nicotine stop-smoking drug.
? Taking prescription medicine for depression or asthma. The prescription dose
may need to be adjusted.
Stop if:
? Mouth, teeth or jaw problems occur.
? Irregular heartbeat or palpitations occur.
? Symptoms of nicotine overdose such as nausea, vomiting, dizziness,
diarrhoea, weakness, and rapid heartbeat occur.
Keep out of the reach of children and pets. Pieces of nicotine gum may have
enough nicotine to make children and pets sick. Wrap used pieces of gum in
paper and throw away in the trash. In case of overdose, get medical help or
contact a physician right away.
Cardiovascular Diseases
NRT is safe in smokers with stable cardiovascular disease. Despite the
vasoconstrictor effects of nicotine, studies have failed to demonstrate an
increased risk with the use of NRT in patients with cardiovascular disease. In
acute cardiovascular conditions, such as unstable angina, acute myocardial
infarction, or stroke, NRT should be used with caution because nicotine is a
vasoconstrictor.
Drug Interactions
Pharmacodynamic interactions may alter the expected response or actions of
other drugs. This should be kept in mind when prescribing NICOGUM Chewing
Gum with drugs like sedatives, opioids, antihypertensives, insulin, theophylline,
oral contraceptives, and caffeine.
There has been no clinical trial performed to study the interactions of various
drugs with NICOGUM Chewing Gum; however, there have been some studies
to show the effects of drugs on CYP2A6, the primary enzyme involved in nicotine
metabolism.
A few drugs have been shown to induce CYP2A6 in human primary hepatocyte
culture. These include prototypical inducers like rifampicin, dexamethasone and
phenobarbital, although there is wide inter-individual variability in response. Oral
contraceptive use induced nicotine and cotinine clearances by 30% and 33%,
respectively. Several compounds are inhibitors of CYP2A6-mediated nicotine
metabolism in vitro, including methoxsalen, tryptamine and coumarin.
Renal Impairment
Kidney failure not only decreases renal clearance of nicotine and cotinine, but
also metabolic clearance of nicotine. Metabolic clearance of nicotine is reduced
by 50% in subjects with severe renal impairment compared with healthy subjects.
It is speculated that accumulation of uraemic toxins may inhibit CYP2A6 activity
or down-regulate CYP2A6 expression in the liver. Hence, patients should be
considered for the therapy only if the expected benefits are more than the risks
involved and monitored closely.
Hepatic Impairment
The total metabolism by CYP2A6 is reduced in patients with alcoholic liver
disease and viral hepatitis. As nicotine is metabolized primarily by the liver,
patients should be considered for the therapy only if the expected benefits are
more than the risks involved and monitored closely.
Pregnancy and Lactation
If you are pregnant or breastfeeding, only use this medicine on the advice of your
healthcare provider. Smoking can seriously harm the foetus or the nursing infant.
Try to stop smoking without using any nicotine replacement medicine. This
medicine is believed to be safer than smoking. However, the risks to the foetus or
nursing infant from this medicine are not fully known.
UNDESIRABLE EFFECTS
Overall, NRT has a benign adverse event profile, with a relatively low rate of
discontinuation due to adverse events. Possible adverse effects seen include
mouth or throat irritation, skin irritation, nausea/vomiting, coughing, hiccupss,
dyspepsia, watering of eyes, headaches, heart palpitations, sneezing, sleep
disturbances and dream abnormalities, insomnia, rhinitis, vertigo, taste
disturbances, and muscle aches.
OVERDOSAGE
If you have any symptoms of overdose, seek medical attention
immediately.
Symptoms of nicotine overdose may include:
Abdominal pain, blurred vision, breathing abnormalities, cold sweat, confusion,
diarrhoea, dizziness, drooling, fainting, hearing difficulties, heart palpitations, low
blood pressure, nausea, pallor, rapid heartbeat, salivation, severe headaches,
sweating, tremor, upset stomach, vision problems, vomiting, and weakness.
SHELF-LIFE
2 years
STORAGE AND HANDLING INSTRUCTIONS
Store at 20-25Β°C (68-77Β°F).
Protect from light.
PACKAGING INFORMATION
NICOGUM Chewing Gum Pack of 10 gum pieces
Last updated: September 2010