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Bupropion HCl Sandoz retard 150 mg, tabletten met gereguleerde afgifte

RegistratienummerRVG 114395
ProcedurenummerNL/H/3042/001
Farmaceutische vormTablet met gereguleerde afgifte
ToedieningswegOraal gebruik
ATCN06AX12 - Bupropion
AfleverstatusUitsluitend recept
Registratiedatum16 april 2015
RegistratiehouderSandoz B.V.
Veluwezoom 22
1327 AH ALMERE
Werkzame stof(fen)BUPROPIONHYDROCHLORIDE
SAMENSTELLING
overeenkomend met
BUPROPION
Hulpstof(fen)AMMONIA (E 527)
COPOLYMEER VAN ETHYLACRYLAAT-METHACRYLZUUR (1:1)
ETHYLCELLULOSE (E 462)
HYPROLOSE (E 463)
HYPROMELLOSE (E 464)
IJZEROXIDE ZWART (E 172)
MACROGOL 1500
MACROGOL 400
MACROGOL 8000
NATRIUMSTEARYLFUMARAAT
POVIDON K 90 (E 1201)
PROPYLEENGLYCOL (E 1520)
SCHELLAK GLAZE, GEDEELTELIJK VERESTERD
SILICIUMDIOXIDE (E 551)
TRIETHYLCITRAAT (E 1505)
ZOUTZUUR (E 507)
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SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
Bupropion HCl Sandoz retard 150 mg, tabletten met gereguleerde afgifte  
Bupropion HCl Sandoz retard 300 mg, tabletten met gereguleerde afgifte 
 
2. QUALITATIVE 
AND 
QUANTITATIVE 
COMPOSITION 
 
Each modified-release tablet contains 150 mg of bupropion hydrochloride 
Each modified-release tablet contains 300 mg of bupropion hydrochloride 
 
For the full list of excipients, see section 6.1 
 
 
3. PHARMACEUTICAL 
FORM 
 
Modified-release tablet 
 
150 mg tablet: White to pale yellow, round, biconvex tablets (diameter approximately 7.5 mm) 
printed with ‘A 151’ on one side and plain on other side. 
300 mg tablet: White to pale yellow, biconvex tablets (diameter approximately 10 mm) printed 
with ‘A 152’ on side and plain on other side. 
 
4. CLINICAL 
PARTICULARS 
 
4.1 Therapeutic 
indications 
 
[To be completed nationally] is indicated for the treatment of major depressive episodes. 
 
4.2 
Posology and method of administration 
 
[To be completed nationally] tablets should be swallowed whole. The tablets should not be cut, 
crushed or chewed as this may lead to an increased risk of adverse effects including seizures. 
 
[To be completed nationally] tablets can be taken with or without food. 
 
Use in Adults 
The recommended starting dose is 150 mg, given once daily. An optimal dose was not established in 
clinical studies. If no improvement is seen after 4 weeks treatment at 150 mg, the dose may be 
increased to 300 mg, given once daily. There should be an interval of at least 24 hours between 
successive doses. 
 
The onset of action for bupropion has been noted 14 days after starting therapy. As with all 
antidepressants the full antidepressant effect of [To be completed nationally] may not be evident until 
after several weeks of treatment. 
 

Patients with depression should be treated for a sufficient period of at least 6 months to ensure that 
they are free from symptoms. 
 
Insomnia is a very common adverse event which is often transient. Insomnia may be reduced by 
avoiding dosing at bedtime (provided there is at least 24 hours between doses). 
 
Paediatric Population 
 
[To be completed nationally] is not indicated for use in children or adolescents aged less than 18 years 
(see section 4.4). The safety and efficacy of [To be completed nationally] in patients under 18 years of 
age have not been established. 
 
Use in Older People 
 
Efficacy has been shown equivocally in older people. In a clinical trial, older people followed the 
same dose regimen as for the adults (see Use in Adults). Greater sensitivity in some older individuals 
cannot be ruled out. 
 
Use in Patients with Hepatic Insufficiency 
 
[To be completed nationally] should be used with caution in patients with hepatic impairment (see 
section 4.4). Because of increased variability in the pharmacokinetics in patients with mild to 
moderate impairment the recommended dose in these patients is 150 mg once a day. 
 
Use in Patients with Renal Insufficiency 
 
The recommended dose in these patients is 150mg once a day, as bupropion and its active metabolites 
may accumulate in such patients to a greater extent than usual (see section 4.4). 
 
Discontinuing therapy 
 
Although discontinuation reactions (measured as spontaneously reported events rather than on rating 
scales) were not observed in clinical studies with [To be completed nationally], a tapering off period 
may be considered. Bupropion is a selective inhibitor of the neuronal re-uptake of catecholamines and 
a rebound effect or discontinuation reactions cannot be ruled out. 
 
4.3 Contraindications 
 
[To be completed nationally] is contraindicated in patients with hypersensitivity to bupropion or any 
of the excipients listed in section 6.1. 
 
[To be completed nationally] is contraindicated in patients taking any other medicinal product 
containing bupropion, as the incidence of seizures is dose dependent and to avoid overdosage. 
 
[To be completed nationally] is contraindicated in patients with a current seizure disorder or any 
history of seizures. 
 
[To be completed nationally] is contraindicated in patients with a known central nervous system 
tumour. 

 
[To be completed nationally] is contraindicated in patients who, at any time during treatment, are 
undergoing abrupt withdrawal from alcohol or any medicinal product known to be associated with a 
risk of seizures on withdrawal (in particular benzodiazepines and benzodiazepine-like agents). 
 
[To be completed nationally] is contraindicated for use in patients with severe hepatic cirrhosis. 
 
[To be completed nationally] is contraindicated in patients with a current or previous diagnosis of 
bulimia or anorexia nervosa. 
 
Concomitant use of [To be completed nationally] and monoamine oxidase inhibitors (MAOIs) is 
contraindicated. At least 14 days should elapse between discontinuation of irreversible MAOIs and 
initiation of treatment with [To be completed nationally]. For reversible MAOIs, a 24 hour period is 
sufficient. 
 
4.4 
Special warnings and precautions for use 
 
Seizures  
 
The recommended dose of modified release bupropion tablets should not be exceeded, since 
bupropion is associated with a dose-related risk of seizure. The overall incidence of seizure with 
modified release bupropion tablets in clinical trials at doses up to 450 mg/day was approximately 
0.1%.  
 
There is an increased risk of seizures occurring with the use of [To be completed nationally] in the 
presence of predisposing risk factors which lower the seizure threshold. Therefore [To be completed 
nationally] should be administered with caution to patients with one or more conditions predisposing 
to a lowered seizure threshold.  
All patients should be assessed for predisposing risk factors, which include  
 
• Concomitant administration of other medicinal products known to lower the seizure threshold (e.g. 
antipsychotics, antidepressants, antimalarials, tramadol, theophylline, systemic steroids, quinolones 
and sedating antihistamines)  
• Alcohol abuse (see also section 4.3)  
• History of head trauma  
• Diabetes treated with hypoglycaemics or insulin  
• Use of stimulants or anorectic products  
 
[To be completed nationally] should be discontinued and not recommenced in patients who experience 
a seizure while on treatment.  
 
Interactions (see section 4.5)  
 
Due to pharmacokinetic interactions, plasma levels of bupropion or its metabolites may be altered, 
which may increase the potential for undesirable effects (e.g. dry mouth, insomnia, seizures). 
Therefore, care should be taken when bupropion is given concomitantly with medicinal products 
which can induce or inhibit the metabolism of bupropion.  
 

Bupropion inhibits metabolism by cytochrome P450 2D6. Caution is advised when medicinal products 
metabolised by this enzyme are administered concurrently.  
 
In the literature it has been shown that medications that inhibit CYP2D6 may lead to reduced 
concentrations of endoxifen which is the active metabolite of tamoxifen. Therefore the use of 
bupropion, which is an inhibitor of CYP2D6, should whenever possible be avoided during tamoxifen 
treatment (see section 4.5). 
 
Neuropsychiatry 
 
Suicide/suicidal thoughts or clinical worsening 
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-
related events). This risk persists until significant remission occurs. As improvement may not occur 
during the first few weeks or more of treatment, patients should be closely monitored until such 
improvement occurs. It is general clinical experience that the risk of suicide may increase in the early 
stages of recovery. 
 
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal 
ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or 
suicide attempts, and should receive careful monitoring during treatment. 
A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with 
psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to 
placebo in patients less than 25 years old. 
 
Close supervision of patients and in particular those at high risk should accompany drug therapy 
especially in early treatment and following dose changes. Patients (and caregivers of patients) should 
be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and 
unusual changes in behaviour and to seek medical advice immediately if these symptoms present. 
It should be recognised that the onset of some neuropsychiatric symptoms could be related either to 
the underlying disease state or the drug therapy (see Neuropsychiatric symptoms including mania and 
bipolar disorder below; see section 4.8). 
 
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing 
the medicinal product, in patients who experience the emergence of suicidal ideation/behaviour, 
especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting 
symptoms. 
 
Neuropsychiatric symptoms including mania and bipolar disorder 
 
Neuropsychiatric symptoms have been reported (see section 4.8). In particular, psychotic and manic 
symptomatology has been observed, mainly in patients with a known history of psychiatric illness. 
Additionally a major depressive episode may be the initial presentation of bipolar disorder. It is 
generally believed (though not established in controlled trials) that treating such an episode with an 
antidepressant alone can increase the likelihood of precipitation of a mixed/manic episode in patients 
at risk for bipolar disorder. Limited clinical data on use of bupropion in combination with mood 
stabilisers in patients with a history of bipolar disorder suggests a low rate of switch to mania. Prior to 
initiating treatment with an antidepressant, patients should be adequately screened to determine if they 
are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including 
a family history of suicide, bipolar disorder, and depression. 

 
Data in animals suggest a potential for abuse. However, studies on abuse liability in humans and 
extensive clinical experience show that bupropion has low abuse potential. 
 
Clinical experience with bupropion in patients receiving electroconvulsive therapy (ECT) is limited. 
Caution should be exercised in patients receiving ECT therapy concomitantly with bupropion 
treatment. 
 
Hypersensitivity 
 
[To be completed nationally] should be discontinued promptly if patients experience hypersensitivity 
reactions during treatment. Clinicians should be aware that symptoms may progress or recur following 
the discontinuation of [To be completed nationally] and should ensure symptomatic treatment is 
administered for an adequate length of time (at least one week). Symptoms typically include skin rash, 
pruritus, urticaria or chest pain, but more severe reactions may include angioedema, 
dyspnoea/bronchospasm, anaphylactic shock, erythema multiforme or Stevens - Johnson syndrome. 
Arthralgia, myalgia and fever have also been reported in association with rash and other symptoms 
suggestive of delayed hypersensitivity (see section 4.8). In most patients symptoms improved after 
stopping bupropion and initiating treatment with antihistamine or corticosteroids, and resolved over 
time. 
 
Cardiovascular disease 
 
There is limited clinical experience of the use of bupropion to treat depression in patients with 
cardiovascular disease. Care should be exercised if it is used in these patients. However, bupropion 
was generally well tolerated in studies for smoking cessation in patients with ischaemic cardiovascular 
disease (see section 5.1). 
 
Blood pressure 
 
Bupropion has been shown not to induce significant increases in blood pressure in non-depressed 
patients with Stage I hypertension. However, in clinical practice, hypertension, which in some cases 
may be severe (see section 4.8) and require acute treatment, has been reported in patients receiving 
bupropion. This has been observed in patients with and without pre-existing hypertension. 
 
A baseline blood pressure should be obtained at the start of treatment, with subsequent monitoring 
especially in patients with pre-existing hypertension. Consideration should be given to discontinuation 
of [To be completed nationally] if a clinically significant increase in blood pressure is observed. 
 
Concomitant use of bupropion and a nicotine transdermal system may result in elevations of blood 
pressure. 
 
Specific patient groups 
 
Children and adolescents (<18 years) - Treatment with antidepressants is associated with an increased 
risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder and 
other psychiatric disorders. 
 

Hepatically-impaired – 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 [To be 
completed nationally] should be used with caution in patients with mild to moderate hepatic 
impairment (see section 4.2). 
 
All patients with hepatic impairment should be monitored closely for possible undesirable effects 
(e.g., insomnia, dry mouth, seizures) that could indicate high drug or metabolite levels. 
 
Renally-impaired – Bupropion is mainly excreted into the urine as its metabolites. Therefore in 
patients with renal impairment, bupropion and its active metabolites may accumulate to a greater 
extent than usual. The patient should be closely monitored for possible undesirable effects (e.g. 
insomnia, dry mouth, seizures) that could indicate high drug or metabolite levels (see section 4.2). 
 
Interference with urine testing 
 
Having an amphetamine-like chemical structure, bupropion interferes with the assay used in some 
rapid urine drug screens, which can result in false positive readings, particularly for amphetamines. A 
positive result should usually be confirmed with a more specific method. 
 
4.5 
Interaction with other medicinal products and other forms of interaction 
 
Since monoamine oxidase A and B inhibitors also enhance the catecholaminergic pathways, by a 
different mechanism from bupropion, concomitant use of [To be completed nationally] and 
monoamine oxidase inhibitors (MAOIs) is contraindicated (see section 4.3) as there is an increased 
possibility of adverse reactions from their co-administration. At least 14 days should elapse between 
discontinuation of irreversible MAOIs and initiation of treatment with [To be completed nationally]. 
For reversible MAOIs a 24 hour period is sufficient. 
 
The effect of bupropion on other medicinal products 
 
Although not metabolised by the CYP2D6 isoenzyme, bupropion and its main metabolite, 
hydroxybupropion inhibit the CYP2D6 pathway. Co-administration of bupropion and desipramine to 
healthy volunteers known to be extensive metabolisers of the CYP2D6 isoenzyme resulted in large (2- 
to 5-fold) increases in the Cmax and AUC of desipramine. Inhibition of CYP2D6 was present for at 
least 7 days after the last dose of bupropion. 
 
Concomitant therapy with medicinal products with narrow therapeutic indices that are predominantly 
metabolised by CYP2D6 should be initiated at the lower end of the dose range of the concomitant 
medicinal product. Such medicinal products include certain antidepressants (e.g. desipramine, 
imipramine), antipsychotics (e.g. risperidone, thioridazine), beta-blockers (e.g. metoprolol), serotonin 
selective reuptake inhibitors (SSRIs) and Type 1C antiarrhythmics (e.g. propafenone, flecainide). If 
[To be completed nationally] is added to the treatment regimen of a patient already receiving such a 
medicinal product, the need to decrease the dose of the original medicinal product should be 
considered. In these cases the expected benefit of treatment with [To be completed nationally] should 
be carefully compared with the potential risks. 
 

Drugs which require metabolic activation by CYP2D6 in order to be effective (e.g. tamoxifen), may 
have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as 
bupropion (see section 4.4). 
 
Although citalopram (a SSRI) is not primarily metabolised by CYP2D6, in one study, bupropion 
increased the Cmax and AUC of citalopram by 30% and 40%, respectively. 
 
The effect of other medicinal products on bupropion 
 
Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the 
cytochrome P450 CYP2B6 (see section 5.2). Co-administration of medicinal products that may affect 
the metabolism of bupropion via CYP2B6 isoenzyme (e.g. CYP2B6 substrates: cyclophosphamide, 
ifosfamide, and CYP2B6 inhibitors: orphenadrine, ticlopidine, clopidogrel), may result in increased 
bupropion plasma levels and lower levels of active metabolite hydroxybupropion. The clinical 
consequences of the inhibition of the metabolism of bupropion via CYP2B6 enzyme and the 
consequent changes in the bupropion-hydroxybupropion ratio are currently unknown. 
 
Since bupropion is extensively metabolised, caution is advised when bupropion is coadministered with 
medicinal products known to induce metabolism (e.g. carbamazepine, phenytoin, ritonavir, efavirenz) 
or inhibit metabolism (e.g. valproate), as these may affect its clinical efficacy and safety. 
 
In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or 
ritonavir 100 mg plus lopinavir 400 mg twice daily reduced the exposure of bupropion and its major 
metabolites in a dose dependent manner by approximately 20 to 80% (see section 5.2). Similarly, 
efavirenz 600 mg once daily for two weeks reduced the exposure of bupropion by approximately 55% 
in healthy volunteers. The clinical consequences of the reduced exposure are unclear, but may include 
decreased efficacy in the treatment of major depression. Patients receiving any of these drugs with 
bupropion may need increased doses of bupropion but the maximum recommended dose of bupropion 
should not be exceeded. 
 
Other interaction information 
 
Administration of [To be completed nationally] to patients receiving either levodopa or amantadine 
concurrently should be undertaken with caution. Limited clinical data suggest a higher incidence of 
undesirable effects (e.g. nausea, vomiting, and neuropsychiatric events – see section 4.8) in patients 
receiving bupropion concurrently with either levodopa or amantadine. 
 
Although clinical data do not identify a pharmacokinetic interaction between bupropion and alcohol, 
there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in 
patients drinking alcohol during bupropion treatment. The consumption of alcohol during [To be 
completed nationally] treatment should be minimised or avoided. 
 
There have been no pharmacokinetic studies with bupropion and co-administered benzodiazepines. 
Based on in vitro metabolic pathways, there is no basis for such an interaction. After coadministration 
of bupropion with diazepam in healthy volunteers, there was less sedation than when diazepam was 
administered alone. 
 

There has been no systematic evaluation of the combination of bupropion with antidepressants (other 
than desipramine and citalopram), benzodiazepines (other than diazepam), or neuroleptics. There has 
also been limited clinical experience with St Johns Wort. 
 
Concomitant use of [To be completed nationally] and a nicotine transdermal system (NTS) may result 
in elevations of blood pressure. 
 
4.6 Fertility, 
pregnancy and lactation 
 
Pregnancy  
 
Some epidemiological studies of pregnancy outcomes following maternal exposure to bupropion in 
the first trimester have reported an association with increased risk of certain congenital cardiovascular 
malformations specifically ventricular septal defects and left outflow tract heart defects. These 
findings are not consistent across studies. Animal studies do not indicate direct or indirect harmful 
effects with respect to reproductive toxicity (see section 5.3). [To be completed nationally] should not 
be used during pregnancy unless the clinical condition of the woman requires treatment with 
bupropion and alternative treatments are not an option.  
 
Breastfeeding  
 
Bupropion and its metabolites are excreted in human breast milk. A decision on whether to abstain 
from breast-feeding or to abstain from therapy with [To be completed nationally] should be made 
taking into account the benefit of breast-feeding to the newborn/infant and the benefit of [To be 
completed nationally] therapy to the mother.  
 
Fertility  
 
There are no data on the effect of bupropion on human fertility. A reproductive study in rats revealed 
no evidence of impaired fertility (see section 5.3). 
 
4.7 
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 skill. Patients should therefore exercise caution before driving or use of 
machinery until they are reasonably certain [To be completed nationally] does not adversely affect 
their performance. 
 
4.8 Undesirable 
effects 
 
The list below provides information on the undesirable effects identified from clinical experience, 
categorised by incidence and System Organ Class body system.  
 
Undesirable effects are ranked under headings of frequency using the following convention; very 
common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, 
<1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). 
 
Blood and lymphatic system 
Unknown Anaemia, 
leucopenia 
and 
thrombocytopenia 
disorders 

Immune system disorders*  
Common  
Hypersensitivity reactions such as urticaria  
Very Rare   More severe hypersensitivity reactions including 
angioedema, dyspnoea/bronchospasm and 
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. 
Metabolism and nutrition 
Common  
Anorexia  
disorders  
Uncommon Weight 
loss 
 
Very Rare   Blood glucose disturbances  
Psychiatric disorders  
Very 
Insomnia (see section 4.2)  
common  
Common  
Agitation, anxiety  
Uncommon  Depression (see section 4.4), confusion  
Very rare  
Aggression, hostility, irritability, restlessness, 
hallucinations, abnormal dreams including 
nightmares, depersonalisation, delusions, paranoid 
ideation  
Not known  Suicidal ideation and suicidal behavior***, 
psychosis  
Nervous system disorders  
Very 
Headache  
Common  
Common  
Tremor, dizziness, taste disorders  
Uncommon Concentration 
disturbance 
 
Rare  
Seizures (see below)**  
Very Rare   Dystonia, ataxia, Parkinsonism, incoordination, 
memory impairment, paraesthesia, syncope  
Eye disorders  
Common  
Visual disturbance  
Ear and labyrinth disorders  
Common  
Tinnitus  
Cardiac disorders  
Uncommon  Tachycardia  
Very Rare   Palpitations  
Vascular disorders  
Common  
Increased blood pressure (sometimes severe), 
flushing  
Very Rare   Vasodilation, postural hypotension  
Gastrointestinal disorders  
Very 
Dry mouth, gastrointestinal disturbance including 
Common  
nausea and vomiting  
Common  
Abdominal pain, constipation  
Hepatobiliary disorders  
Very Rare   Elevated liver enzymes, jaundice, hepatitis  
Skin and subcutaneous tissue 
Common  
Rash, pruritus, sweating  
disorders*  
Very Rare   Erythema multiforme, Stevens Johnson syndrome, 
exacerbation of psoriasis  
Musculoskeletal and connective 
Very Rare   Twitching  
tissue disorders  
Renal and urinary disorders  
Very Rare   Urinary frequency and/or retention  
General disorders and 
Common  
Fever, chest pain, asthenia  

administration site conditions  
 
* Hypersensitivity may manifest as skin reactions. See “Immune system disorders” and “Skin and 
subcutaneous tissue disorders”. 
 
** The incidence of seizures is approximately 0.1% (1/1,000). The most common type of seizures is 
generalised tonic-clonic seizures, a seizure type which can result in some cases in post-ictal confusion 
or memory impairment (see section 4.4). 
 
*** Cases of suicidal ideation and suicidal behavior have been reported during bupropion therapy or 
early after treatment discontinuation (see section 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions {via the national reporting system 
listed in Appendix V}*. 
 
4.9 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, loss of consciousness and/or electrocardiogram (ECG) changes such as conduction 
disturbances (including QRS prolongation), arrhythmias and tachycardia. QTc prolongation has also 
been reported but was generally seen in conjunction with QRS prolongation and increased heart rate. 
Although most patients recovered without sequelae, deaths associated with bupropion have been 
reported rarely in patients ingesting large overdoses of the drug.  
 
Treatment: In the event of overdose, hospitalisation is advised. ECG and vital signs should be 
monitored.  
 
Ensure an adequate airway, oxygenation and ventilation. The use of activated charcoal is 
recommended. No specific antidote for bupropion is known. Further management should be as 
clinically indicated. 
 
5. PHARMACOLOGICAL 
PROPERTIES 
 
5.1   Pharmacodynamic properties
 
 
Pharmacotherapeutic group: Other antidepressants, ATC code: N06 AX12. 
 
Mechanism of action 
 
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 either 
monoamine oxidase. 
 

The mechanism of action of bupropion as an antidepressant is unknown. However, it is presumed that 
this action is mediated by noradrenergic and/or dopaminergic mechanisms. 
 
Clinical efficacy 
 
The antidepressant activity of bupropion was studied in a clinical programme involving a total of 1155 
bupropion XR patients and 1868 bupropion SR patients with Major Depressive Disorder (MDD). 
Seven of the studies examined the efficacy of bupropion XR: 3 were conducted in the EU at doses up 
to 300 mg/day and 4 were conducted in the US over a flexible dose range of up to 450 mg/day. In 
addition, 9 studies in MDD with bupropion SR are considered to be supportive based on the 
bioequivalence of bupropion XR (once daily) to the SR (twice daily) tablet. 
 
Bupropion XR demonstrated statistical superiority over placebo as measured by improvement in the 
Montgomery-Asberg Depression Rating Scale (MADRS) total score in 1 of 2 identical studies 
utilising doses in the range 150-300 mg. Response and remission rates were also statistically 
significantly higher with bupropion XR compared to placebo. In a third study in elderly patients, 
statistical superiority over placebo was not achieved on the primary parameter, mean change from 
baseline in MADRS (Last Observation Carried Forward endpoint) although statistically significant 
effects were seen on a secondary (Observed Case) analysis. 
 
Significant benefit was shown on the primary endpoint in 2 of 4 US studies with bupropion XR (300-
450 mg). Of the 2 positive studies, one was a placebo controlled study in patients with MDD and one 
was an active controlled study in patients with MDD. 
In a relapse prevention study, patients responding to 8 weeks of acute treatment with open-label 
bupropion SR (300 mg/day) were randomised to either bupropion SR or placebo for a further 44 
weeks. Bupropion SR demonstrated a statistically significant superiority compared to placebo (P < 
0.05) on the primary outcome measure. The incidence of maintenance of effect during the 44 week 
double blind follow-up period was 64% and 48% for bupropion SR and placebo, respectively. 
 
Clinical safety 
 
The prospectively observed proportion of cardiac birth defects in pregnancies with prenatal exposure 
to bupropion in the first trimester in the international Pregnancy Registry was 9/675 (1.3%). 
 
In a retrospective study there was no greater proportion of congenital malformations or cardiovascular 
malformations amongst more than a thousand first trimester exposures to bupropion compared with 
the use of other antidepressants. 
 
In a retrospective analysis using data from the National Birth Defects Prevention Study, a statistically 
significant association was observed between the occurrence of a left outflow tract heart defect in the 
infant and self-reported maternal bupropion use in early pregnancy. No association was observed 
between maternal bupropion use and any other type of cardiac defect or with all categories of heart 
defects combined. 
 
A further analysis of data from the Slone Epidemiology Center Birth Defects Study found no 
statistically significant increase of left outflow tract heart defects with maternal bupropion use. 
However, a statistically significant association was observed for ventricular septal defects following 
the use of bupropion alone during the first trimester. 
 

In a study in healthy volunteers, no clinically significant effect of modified release bupropion tablets 
(450 mg/day) compared with placebo was observed on QTcF interval after 14 days of dosing to steady 
state. 
 
5.2 Pharmacokinetic 
properties 
 
Absorption  
 
After oral administration of 300 mg bupropion hydrochloride once daily as the modified release tablet 
to healthy volunteers, maximum plasma concentrations (Cmax) of approximately 160 ng/ml are 
observed at approximately 5 hours. At steady state, the Cmax and AUC values of hydroxybupropion 
are approximately 3 and 14 times that of bupropion, respectively. The Cmax of threohydrobupropion 
at steady state is similar to that of bupropion and the AUC is approximately 5 times higher while the 
plasma concentrations of erythrohydrobupropion are comparable to those of bupropion. Peak plasma 
levels of hydroxybupropion are reached at 7 hours while those for threohydrobupropion and 
erythrohydrobupropion are reached at 8 hours. The AUC and Cmax values of bupropion and its active 
metabolites hydroxybupropion and threohydrobupropion increase dose proportionally over a dose 
range of 50-200 mg following single doses and over a dose range of 300-450 mg/day following 
chronic dosing.  
 
The absolute bioavailability of bupropion is not known; urinary excretion data, however, show that at 
least 87% of the dose of bupropion is absorbed.  
 
The absorption of bupropion modified release tablets is not significantly influenced when taken 
concurrently with food. 
 
Distribution  
 
Bupropion is widely distributed with an apparent volume of distribution of approximately 2000 L.  
Bupropion, hydroxybupropion and threohydrobupropion bind moderately to plasma proteins (84%, 
77% and 42%, respectively).  
 
Bupropion and its active metabolites are excreted in human breast milk. Animal studies show that 
bupropion and its active metabolites pass the blood-brain barrier and the placenta. Positron Emision 
Tomography studies in healthy volunteers demonstrate that bupropion penetrates the CNS and binds 
to the striatal dopamine reuptake transporter (approximately 25% at 150 mg twice daily).  
 
Biotransformation 
 
 
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. The active metabolites are further metabolised to inactive 
metabolites (some of which have not been fully characterised but may include conjugates) and 
excreted in the urine.  
 
In vitro 
studies indicate that bupropion is metabolised to its major active metabolite hydroxybupropion 
primarily by the CYP2B6, while CYP1A2, 2A6, 2C9, 3A4 and 2E1 are less involved. In contrast, 

formation of threohydrobupropion involves carbonyl reduction but does not involve cytochrome P450 
isoenzymes (see section 4.5).  
The inhibition potential of threohydrobupropion and erythrohydrobupropion towards cytochrome 
P450 has not been studied.  
 
Bupropion and hydroxybupropion are both inhibitors of the CYP2D6 isoenzyme with Ki values of 21 
and 13.3μM, respectively (see section 4.5).  
 
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 hydrochloride 
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 hydrochloride is 
approximately 200 L/hr and the mean elimination half-life of bupropion is approximately 20 hours.  
 
The elimination half-life of hydroxybupropion is approximately 20 hours. 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.  
 
The insoluble shell of the modified release tablet may remain intact during gastrointestinal transit and 
be eliminated in the faeces.  
 
Special Patient Groups: 
 
Patients with renal impairment  
 
The elimination of bupropion and its active major metabolites may be reduced in patients with 
impaired renal function. Limited data in patients with end-stage renal failure or moderate to severely 
impaired renal function indicate that exposure to bupropion and/or its metabolites was increased (see 
section 4.4). 
 
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 (see section 4.4). 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 
hydroxybupropion, the mean Cmax was lower (by approximately 70%), the mean AUC tended to be 
higher (by approximately 30%), the median Tmax was later (by approximately 20 hrs), and the mean 
half-lives were longer (by approximately 4-fold) than in healthy volunteers. For threohydrobupropion 

and erythrohydrobupropion, the mean Cmax tended to be lower (by approximately 30%), the mean 
AUC tended to be higher (by approximately 50%), the median Tmax was later (by approximately 20 
hrs), and the mean half-life was longer (by approximately 2-fold) than in healthy volunteers (see 
section 4.3).  
 
Older people
 
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 (see section 4.4).  
 
In-vitro release of bupropion with alcohol 
 
 
In-vitro 
tests showed that at high alcohol concentrations (up to 40%), bupropion is released more 
rapidly from the modified release formulation (up to 20% dissolved at 2 hours) (see section 4.5). 
 
5.3 
Preclinical safety data 
 
Reproduction toxicity studies conducted in rats at exposures similar to those obtained at the maximum 
recommended human dose (based on systemic data on exposure) revealed no adverse effects on 
fertility, pregnancy and fetal development. Reproduction toxicity studies conducted in rabbits treated 
with doses up to 7 times the maximum recommended human dose based on a mg/m2 basis (no 
systemic data on exposures are available) only revealed a slight increase in skeletal variations 
(increased incidence of common anatomical variation of an accessory thoracic rib and delayed 
ossification of phalanges). Moreover at maternally toxic doses, a decrease of rabbits foetal weight was 
reported. 
 
In animal experiments bupropion doses several times higher than therapeutic doses in humans caused, 
amongst others, the following dose-related symptoms: ataxia and convulsions in rats, general 
weakness, trembling and emesis in dogs and increased lethality in both species. Due to enzyme 
induction in animals but not in humans, systemic exposures in animals were similar to the systemic 
exposures seen in humans at the maximum recommended dose. 
 
Liver changes are seen in animal studies but these reflect the action of a hepatic enzyme inducer. At 
recommended doses in humans, bupropion does not induce its own metabolism. This suggests that the 
hepatic findings in laboratory animals have only limited importance in the evaluation and risk 
assessment of bupropion. 
 
Genotoxicity data indicate that bupropion is a weak bacterial mutagen, but not a mammalian mutagen, 
and therefore is of no concern as a human genotoxic agent. Mouse and rat studies confirm the absence 
of carcinogenicity in these species. 
 
 
6. PHARMACEUTICAL 
PARTICULARS 
 
6.1 List 
of 
excipients 
 

Tablet Core 
Povidone  
Hydrochloric acid 
Sodium Stearyl Fumarate 
 
Tablet Coating 
Ethylcellulose 
Hydroxy Propylcellulose 
Methacrylic acid-Ethyl Acrylate copolymer (1:1) Type A 
Silica, Colloidal Anhydrous 
Macrogol 1500 
Triethyl Citrate 
Hypromellose  
Macrogol 400 
Macrogol 8000 
 
Printing Ink 
Shellac Glaze 
Iron Oxide Black (E172) 
Propylene glycol  
Ammonium Hydroxide 
 
6.2 Incompatibilities
 
Not applicable 
 
6.3 Shelf 

life 
1 year 
 
6.4 
Special precautions for storage 
Do not store above 25°C. 
 
Store in the original package in order to protect from moisture and light. 
 
6.5 
Nature and contents of container 
White opaque high density polyethylene (HDPE) bottles closed with a screw cap containing silica gel 
 
 
NL/H/3042/001  
10, 30, 90 tablets 
NL/H/3042/002  
10, 30, 90 tablets 
 
Not all pack sizes may be marketed. 
 
6.6 
Special precautions for disposal and other handling 

 
No special requirements for disposal 
 
7. 
MARKETING AUTHORISATION HOLDER 
 
Sandoz B.V. 
Veluwezoom 22 
1327 AH Almere 
Nederland 
 
8. 
MARKETING AUTHORISATION NUMBER(S) 
 
RVG 114395 
RVG 114396 
 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
16 april 2015 
 
10. 
DATE OF REVISION OF THE TEXT 
 
 
 





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