ZYBAN
Tablets
Bupropion hydrochloride tablets
150mg
Pharmaceutical form
Modified release film-coated
tablet.
Clinical particulars
Therapeutic Indications
Zyban tablets are indicated for the
treatment of nicotine dependence as an aid to smoking
cessation.
Posology and Method of
Administration
Use in Adults
It is recommended that treatment is
started while the patient is still smoking and a "target stop date"
set within the first two weeks of treatment with Zyban, preferably
in the second week.
The initial dose is 150mg taken daily
for three days increasing to 150mg twice daily. There should be an
interval of at least 8 hours between successive doses.
The maximum single dose should not
exceed 150mg and the total daily dose should not exceed 300mg.
Patients should be treated for at least
7 weeks.
- Discontinuation should be considered
if the patient has not made significant progress towards
abstinence by the seventh week of therapy, since it is unlikely
that they will stop smoking during that attempt.
Systematic evaluation of bupropion
hydrochloride 300mg/day for the prevention of relapse demonstrated
that treatment for up to 1 year was well tolerated and efficacious
in preventing relapse.
- As many patients attempting to stop
smoking experience multiple relapses, whether treatment with Zyban
should be continued for longer periods should be determined on an
individual basis.
- The recommended posology does not
require modification if Zyban is used in combination with Nicotine
Transdermal Systems for nicotine dependence. (See Special Warnings
And Special Precautions for Use).
Use in Children and Adolescents.
The safety and efficacy of Zyban tablets
in patients under 18 years of age have not been
established.
Use in patients with liver
impairment
Zyban should be used with caution in
patients with liver impairment.
Because of increased variability in the
pharmacokinetics in patients with mild to moderate hepatic
cirrhosis, a reduced frequency of dosing should be considered (See
Special Warnings and Special Precautions for Use).
Zyban should be used with extreme
caution in patients with severe hepatic cirrhosis. The dose should
not exceed 150mg on alternate days in these patients (See Special
Warnings and Special Precautions for Use).
Contra-indications
Zyban is contraindicated in patients
with hypersensitivity to bupropion or any of the other components of
the preparation.
Zyban is contraindicated in patients
with a seizure disorder.
Zyban is contraindicated in patients
with a current or previous diagnosis of bulimia or anorexia nervosa
as a higher incidence of seizures was seen in this patient
population when an immediate release form of bupropion was
administered.
Concomitant use of Zyban and monoamine
oxidase inhibitors is contraindicated. At least 14 days should
elapse between discontinuation of monoamine oxidase inhibitors
(MAOIs) and initiation of treatment with Zyban Tablets.
Zyban Tablets contain bupropion and
should not be administered to patients currently being treated with
any other preparation containing bupropion as the incidence of
seizures is dose dependent.
Special Warnings and Special
Precautions for Use
The recommended dose of Zyban should not
be exceeded, since bupropion is associated with a dose-related risk
of seizure. At doses up to the maximum recommended daily dose (150mg
of Zyban twice daily), the incidence of seizures is approximately
0.1% (1/1,000).
The risk of seizures occurring with the
use of Zyban appears to be strongly associated with the presence of
predisposing risk factors. Therefore Zyban should be administered
with extreme caution to patients with one or more conditions
predisposing to a lowered seizure threshold. These include:
- history of head trauma
- central nervous system (CNS) tumour
- history of seizures
- concomitant administration of other
medications known to lower the seizure threshold.
In addition, caution should be used in
those clinical circumstances associated with an increased risk of
seizures. These include alcohol abuse, abrupt withdrawal from
alcohol or sedatives, diabetes treated with hypoglycaemics or
insulin and use of stimulants or anorectic products.
Zyban should be discontinued if patients
experience hypersensitivity or anaphylactic reactions (e.g.: skin
rash, pruritus, urticaria, chest pain, oedema or dyspnoea) during
treatment. (See Undesirable Effects)
Bupropion is extensively metabolised in
the liver to active metabolites, which are further metabolised. No
statistically significant differences in the pharmacokinetics of
bupropion were observed in patients with mild to moderate hepatic
cirrhosis compared with healthy volunteers, but bupropion plasma
levels showed a higher variability between individual patients.
Therefore Zyban should be used with caution in patients with hepatic
impairment and reduced frequency of dosing should be considered in
patients with mild to moderate hepatic cirrhosis. (See Posology and
Method of Administration and Pharmacokinetic Properties)
Zyban should be used with extreme
caution in patients with severe hepatic cirrhosis. In these patients
a reduced frequency of dosing is required, as peak bupropion levels
are substantially increased and accumulation is likely to occur in
such patients to a greater extent than usual (See Posology and
Method of Administration and Pharmacokinetic Properties)
All patients with hepatic impairment
should be closely monitored for possible adverse effects (e.g.,
insomnia, dry mouth, seizures) that could indicate high drug or
metabolite levels.
Bupropion is extensively metabolised in
the liver to active metabolites, which are further metabolised and
excreted by the kidneys. Therefore treatment of patients with renal
impairment should be initiated at reduced dosage as bupropion and
its metabolites may accumulate in such patients to a greater extent
than usual. The patient should be closely monitored for possible
adverse effects (e.g., insomnia, dry mouth, seizures) that could
indicate high drug or metabolite levels.
Clinical experience with bupropion has
not identified any differences in tolerability between elderly and
other adult patients. However, greater sensitivity of some elderly
individuals cannot be ruled out. Elderly patients are more likely to
have decreased renal function, hence a reduced frequency of dosing
may be required. (See Pharmacokinetic properties)
As the pharmacology of bupropion
resembles that of some other antidepressants, there is a risk that
Zyban may precipitate a manic episode in patients with bipolar
disorder during the depressed phase of their illness and may
activate latent psychosis in other susceptible patients.
Prior to initiation of combination
therapy with a Nicotine Transdermal System (NTS) , prescribers
should consult the prescribing information of the relevant NTS. If
combination therapy is used, monitoring for treatment-emergent
elevations of blood pressure is recommended (See Undesirable
Effects).
Interaction with Other Medicinal
Products and Other Forms of Interaction
Physiological changes resulting from
smoking cessation itself, with or without treatment with Zyban, may
alter the pharmacokinetics of some medications taken
concomitantly.
In vitro findings
indicate that bupropion is metabolised to its major active
metabolite hydroxybupropion primarily by the cytochrome P450 IIB6
(CYP2B6) (see Pharmacokinetic Properties). Care should therefore be
exercised when Zyban is co-administered with drugs known to affect
the CYP2B6 isoenzyme (e.g. orphenadrine, cyclophosphamide,
ifosfamide).
Although bupropion is not metabolised by
the CYP2D6 isoenzyme, bupropion and its main metabolite,
hydroxybupropion, inhibit the CYP2D6 pathway, as shown by in
vitro studies and an in vivo study. In a human
pharmacokinetic study, co-administration of bupropion hydrochloride
and desipramine to healthy volunteers known to be extensive
metabolisers of the CYP2D6 isoenzyme resulted in a five-fold
increase in AUC and a two-fold increase in Cmax of
desipramine. Inhibition of CYP2D6 was present for at least 7 days
after the last dose of bupropion hydrochloride.
Concomitant use of Zyban with other
medicinal products metabolised by the CYP2D6 isoenzyme has not been
formally studied. Therefore, concomitant therapy with medicinal
products predominantly metabolised by this isoenzyme with narrow
therapeutic indices including certain antidepressants (e.g.
desipramine, imipramine, paroxetine), antipsychotics (e.g.
risperidone, thioridazine), beta-blockers (e.g. metoprolol), and
Type 1C antiarrythmics (e.g. propafanone, flecainide) should be
initiated at the lower end of the dose range of the concomitant
medicinal product. If Zyban is added to the treatment regimen of a
patient already receiving a medicinal product metabolised by CYP2D6,
the need to decrease the dose of the original medicinal product
should be considered, particularly for those concomitant medicinal
products with a narrow therapeutic index. In these cases the
expected benefit of treatment with Zyban should be carefully
considered compared with the potential risks.
Since bupropion is extensively
metabolised, the co-administration of drugs known to induce
metabolism (e.g. carbamazepine, phenobarbitone, phenytoin) or
inhibit metabolism may affect its clinical activity.
Limited clinical data suggest a higher
incidence of adverse events in patients receiving concurrent
administration of bupropion and levodopa. Administration of Zyban to
patients receiving levodopa concurrently should be undertaken with
caution.
Use During Pregnancy and
Lactation
The safety of Zyban for use in human
pregnancy has not been established.
Evaluation of experimental animal
studies does not indicate direct or indirect harmful effects with
respect to the development of the embryo or foetus, the course of
gestation and peri-natal or post-natal development.
A fertility study in rats revealed no
evidence of impaired fertility.
However, as animal reproduction studies
are not always predictive of the human response, administration of
Zyban should only be considered during pregnancy if the expected
benefits are greater than the potential risks.
As bupropion and its metabolites are
excreted in human breast milk, mothers should be advised not to
breast feed while taking Zyban.
Effects on Ability to Drive and
Use Machines
As with other CNS acting drugs bupropion
may affect ability to perform tasks that require judgement or motor
and cognitive skills. Patients should therefore exercise caution
before driving or use of machinery until they are reasonably certain
Zyban tablets do not adversely affect their performance.
Undesirable Effects
The list below provides information on
the undesirable effects identified from clinical experience,
categorised by body system.
Body (general)
Fever, chest pain, asthenia.
Cardiovascular
Tachycardia, vasodilation, postural
hypotension, increased blood pressure (in some cases severe),
flushing, syncope.
CNS
Seizures (See Special Warnings And
Special Precautions For Use), insomnia, tremor, concentration
disturbance, headache, dizziness, depression, confusion, agitation,
anxiety.
Endocrine and metabolic
Anorexia.
Gastrointestinal
Dry mouth, gastrointestinal disturbance
including nausea and vomiting, abdominal pain,
constipation.
Skin / Hypersensitivity
Rash, pruritus, sweating.
Hypersensitivity reactions ranging in
severity from urticaria to angioedema, dyspnoea/bronchospasm and
rarely anaphylactic shock. Arthralgia, myalgia and fever have also
been reported in association with rash and other symptoms suggestive
of delayed hypersensitivity. These symptoms may resemble serum
sickness.
Erythema multiforme and Stevens Johnson
syndrome have also been rarely reported.
Special Senses
Tinnitus, visual disturbance, taste
disorders.
Overdose
Acute ingestion of doses in excess of 10
times the maximum therapeutic dose has been reported. In addition to
those events reported as Undesirable Effects, overdose has resulted
in symptoms including drowsiness, hallucinations and loss of
consciousness.
Treatment: In the event of
overdose, hospitalisation is advised. Ensure an adequate airway,
oxygenation and ventilation. Gastric lavage may be indicated if
performed soon after ingestion. The use of activated charcoal is
also recommended. No specific antidote for bupropion is known.
Pharmacological
properties
Pharmacodynamic
Properties
Bupropion is a selective inhibitor of
the neuronal re-uptake of catecholamines (noradrenaline and
dopamine) with minimal effect on the re-uptake of indolamines
(serotonin), and does not inhibit monoamine oxidase. The mechanism
by which bupropion enhances the ability of patients to abstain from
smoking is unknown. However, it is presumed that this action is
mediated by noradrenergic and/or dopaminergic mechanisms.
In clinical trials, treatment with
bupropion reduced withdrawal symptoms compared to placebo and also
showed evidence of reduction in craving for cigarettes or urge to
smoke compared to placebo.
Pharmacokinetic
Properties
Absorption
Following oral administration of
bupropion tablets to healthy volunteers, peak plasma concentrations
of bupropion are achieved within 3 hours.
Bupropion and its metabolites exhibit
linear kinetics following chronic administration of 150 to 300mg per
day.
The absorption of bupropion is not
significantly affected when taken with food.
Distribution
Bupropion is widely distributed with an
apparent volume of distribution of approximately 2000L. Bupropion
and hydroxybupropion are moderately bound to plasma proteins (84%
and 77%, respectively). The extent of protein binding of the
threohydrobupropion metabolite is about half that seen with
bupropion.
Metabolism
Bupropion is extensively metabolised in
humans. Three pharmacologically active metabolites have been
identified in plasma: hydroxybupropion and the amino-alcohol
isomers, threohydrobupropion and erythrohydrobupropion. These may
have clinical importance, as their plasma concentrations are as high
or higher than those of bupropion. Peak plasma concentrations of
hydroxybupropion and threohydrobupropion are achieved approximately
6 hours following administration of a single dose of Zyban.
Erythrohydrobupropion cannot be measured in the plasma after a
single dose of Zyban. The active metabolites are further metabolised
to inactive metabolites and excreted in the urine.
In vitro studies indicate
that bupropion is metabolised to its major active metabolite
hydroxybupropion primarily by CYP2B6, while cytochrome P450s are not
involved in the formation of threohydrobupropion. (See Interactions
with Other Medicinal Products and Other Forms of
Interaction)
Bupropion and hydroxybupropion are both
relatively weak inhibitors of the CYP2D6 isoenzyme with
Ki values of 21 and 13.3microM, respectively. In human
volunteers known to be extensive metabolisers of the CYP2D6
isoenzyme, co-administration of bupropion and desipramine has
resulted in 2- and 5-fold increases in the Cmax and AUC,
respectively, of desipramine. This effect was present for at least 7
days after the last dose of bupropion. Since bupropion is not
metabolised by the CYP2D6 pathway, desipramine is not anticipated to
affect the pharmacokinetics of bupropion. Caution is advised when
Zyban is administered with substrates for the CYP2D6 pathway. (See
Interactions with Other Medicinal Products and Other Forms of
Interaction)
Following oral administration of a
single 150mg dose of bupropion, there was no difference in
Cmax, half-life, Tmax, AUC, or clearance of
bupropion or its major metabolites between smokers and
non-smokers.
Bupropion has been shown to induce its
own metabolism in animals following sub-chronic administration. In
humans, there is no evidence of enzyme induction of bupropion or
hydroxybupropion in volunteers or patients receiving recommended
doses of bupropion for 10 to 45 days.
Elimination
Following oral administration of 200mg
of 14C-bupropion in humans, 87% and 10% of the
radioactive dose were recovered in the urine and faeces,
respectively. The fraction of the dose of bupropion excreted
unchanged was only 0.5%, a finding consistent with the extensive
metabolism of bupropion. Less than 10% of this 14C dose
was accounted for in the urine as active metabolites.
The mean apparent clearance following
oral administration of bupropion is approximately 200L/hr and the
mean elimination half-life of bupropion is approximately 20
hours.
The elimination half-life of
hydroxybupropion is approximately 20 hours and its area under the
plasma drug concentration versus time curve (AUC) at steady state is
approximately 17 times that of bupropion. The elimination half-lives
for threohydrobupropion and erythrohydrobupropion are longer (37 and
33 hours, respectively) and steady-state AUC values are 8 and 1.6
times higher than that of bupropion, respectively. Steady-state for
bupropion and its metabolites is reached within 8 days.
Patients with renal
impairment
The effect of renal disease on the
pharmacokinetics of bupropion has not been studied. The elimination
of the major metabolites of bupropion may be affected by reduced
renal function. (See Special Warnings and Precautions).
Patients with hepatic
impairment
The pharmacokinetics of bupropion and
its active metabolites were not statistically significantly
different in patients with mild to moderate cirrhosis when compared
to healthy volunteers, although more variability was observed
between individual patients. For patients with severe hepatic
cirrhosis, the bupropion Cmax and AUC were substantially
increased (mean difference approximately 70% and 3-fold,
respectively) and more variable when compared to the values in
healthy volunteers; the mean half-life was also longer (by
approximately 40%). For the metabolites, the mean Cmax
was lower (by approximately 30 to 70%), the mean AUC tended to be
higher (by approximately 30 to 50%), the median Tmax was
later (by approximately 20 hrs), and the mean half-lives were longer
(by approximately 2 to 4-fold) than in healthy volunteers (See
Special Warnings And Special Precautions for Use).
Elderly
Pharmacokinetic studies in the elderly
have shown variable results. A single dose study showed that the
pharmacokinetics of bupropion and its metabolites in the elderly do
not differ from those in the younger adults. Another pharmacokinetic
study, single and multiple dose, has suggested that accumulation of
bupropion and its metabolites may occur to a greater extent in the
elderly. Clinical experience has not identified differences in
tolerability between elderly and younger patients, but greater
sensitivity in older patients cannot be ruled out.
Preclinical Safety
Data
The oncogenicity studies in the mouse
and rat confirm the absence of carcinogenicity in these species.
Liver changes are seen in animal studies but these reflect the
action of a hepatic enzyme inducer. At clinical doses in man there
is no evidence of any enzyme induction, which suggests that the
hepatic findings in the laboratory animals have only limited
importance in the evaluation and risk assessment of
bupropion.
Pharmaceutical
particulars
List of Excipients
| Tablet core |
Film coat
|
| Microcrystalline cellulose |
Hydroxypropyl
methycellulose |
| Hydroxypropyl methylcellulose |
Titanium
dioxide |
| Cysteine
hydrochloride |
Polyethylene glycol
|
| Magnesium
stearate |
Carnauba wax (as polish)
|
|
Edible black ink (for
printing) |
Incompatibilities
None reported.
Shelf Life
24 months.
Special Precautions for
Storage
Do not store above 25 degrees C.
