Wellbutrin (Tablets) Instructions for Use

Marketing Authorization Holder

Biovail Corporation (Canada)

ATC Code

N06AX12 (Bupropion)

Active Substance

Bupropion (Rec.INN registered by WHO)

Dosage Forms

	Wellbutrin	Extended-release film-coated tablets, 150 mg: 7, 30, or 90 pcs.
		Extended-release film-coated tablets, 300 mg: 7 or 30 pcs.

Dosage Form, Packaging, and Composition

Extended-release film-coated tablets from creamy-white to pale yellow, round, marked with “GS5FV” in black on one side and no inscriptions on the other side.

Excipients: polyvinyl alcohol, glyceryl tribehenate.

Coating composition: ethylcellulose-100, povidone, macrogol-1450, methacrylic acid and ethyl acrylate copolymer [1:1] (contains 0.7% sodium lauryl sulfate, 2.3% polysorbate-80), silicon dioxide, triethyl citrate, black ink.

Black ink composition: pharmaceutical glaze, black iron oxide, propylene glycol.

7 pcs. – high-density polyethylene bottles (1), containing a container with a desiccant – cardboard packs.
30 pcs. – high-density polyethylene bottles (1), containing a container with a desiccant – cardboard packs.
90 pcs. – high-density polyethylene bottles (1), containing a container with a desiccant – cardboard packs.

Extended-release film-coated tablets from creamy-white to pale yellow, round, marked with “GS5YZ” in black on one side and no inscriptions on the other side.

Excipients: polyvinyl alcohol, glyceryl tribehenate.

Coating composition: ethylcellulose-100, povidone, macrogol-1450, methacrylic acid and ethyl acrylate copolymer [1:1] (contains 0.7% sodium lauryl sulfate, 2.3% polysorbate-80), silicon dioxide, triethyl citrate, black ink.

Black ink composition: pharmaceutical glaze, black iron oxide, propylene glycol.

7 pcs. – high-density polyethylene bottles (1), containing a container with a desiccant – cardboard packs.
30 pcs. – high-density polyethylene bottles (1), containing a container with a desiccant – cardboard packs.

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

Bupropion is a selective inhibitor of the reuptake of catecholamines (norepinephrine and dopamine) with little effect on the uptake of indolamines (serotonin), and does not inhibit monoamine oxidase.

Although the mechanism of action of bupropion, like other antidepressants, is currently unknown, it is assumed that its antidepressant effect is mediated by influencing the noradrenergic and/or dopaminergic mediator systems.

Clinical efficacy

The efficacy and tolerability of bupropion extended-release tablets were investigated in 7 double-blind studies; of these 7 studies, 3 were conducted in Europe in the dose range of interest (up to 300 mg/day). The following 4 studies were conducted in the USA with a flexible dose range up to 450 mg/day. Proof of long-term maintenance of effect is provided by a 1-year relapse prevention study with bupropion; 816 patients received Bupropion in the single-blind phase of this study, of whom 423 were randomized to the subsequent double-blind phase (Bupropion – 210, placebo – 213).

Bupropion was effective in patients with depression severity from mild to moderate, as well as for patients with severe depression. In the pooled comparative European studies, similar degrees of superiority of the drug over placebo were noted both in patients with mild to moderate depression (-1.8, p = 0.032) and in patients with severe depression (-2.3, p=0.041).

Pharmacokinetics

Absorption

After oral administration of bupropion extended-release tablets in healthy volunteers, the time to reach maximum plasma concentration was approximately 5 hours.

Food intake does not significantly affect the absorption of bupropion when taking extended-release tablets.

The kinetics of bupropion and its metabolites are linear during chronic therapy at doses from 150 to 300 mg/day.

Distribution

Bupropion penetrates tissues well, its apparent volume of distribution is approximately 2000 L.

Bupropion and hydroxybupropion are moderately bound to plasma proteins (84% and 77%, respectively). The degree of protein binding of the metabolite threo-hydroxybutyrate is approximately 50% of that of bupropion.

Metabolism

Bupropion undergoes intensive metabolism. Three active metabolites are detected in plasma: hydroxybupropion and the amino alcohol isomers – threo-hydroxybutyrate and erythro-hydroxybutyrate. This fact may have clinical significance, as the plasma concentrations of the metabolites are high or even exceed the plasma concentration of bupropion. Erythrohydrobupropion is not quantitatively detected in plasma after a single dose of the drug. Active metabolites are further metabolized to inactive ones and excreted by the kidneys.

In vitro studies have shown that Bupropion is metabolized to its main metabolite hydroxybupropion mainly via the CYP2B6 isoenzyme, while the cytochrome P450 isoenzyme system is not involved in the formation of threo-hydroxybutyrate.

In vitro, Bupropion and hydroxybupropion are relatively weak competitive inhibitors of the CYP2D6 isoenzyme system (Ki – inhibition constant is 21 and 13.3 µmol, respectively). In volunteers characterized by a high level of metabolism involving the CYP2D6 isoenzyme, simultaneous administration of bupropion and desipramine led to a two- and five-fold increase in C_max and AUC of desipramine. This effect persisted for at least 7 days after the last dose of bupropion.

Since Bupropion is not metabolized by the CYP2D6 isoenzyme, it is not expected that desipramine will affect the pharmacokinetics of bupropion. Caution is recommended when prescribing bupropion concomitantly with drugs that are substrates for the CYP2D6 isoenzyme system.

In studies involving volunteers or patients receiving recommended doses of bupropion for 10-45 days, no induction of enzyme systems under the influence of bupropion or hydroxybupropion was detected.

The C_max of hydroxybupropion in plasma is approximately 10 times higher than the maximum concentration of the parent substance at steady state.

The time to reach C_max for erythro-hydroxybutyrate and threo-hydroxybutyrate is approximately the same as for hydroxybupropion.

In a study in healthy volunteers, concomitant administration of ritonavir at a dose of 100 mg twice daily led to a decrease in the AUC and C_max of bupropion by 22% and 21%, respectively. The AUC and C_max of bupropion metabolites decreased from 0 to 44%. In another study conducted in healthy volunteers, ritonavir at a dose of 600 mg twice daily reduced the AUC and C_max of bupropion by 66% and 62%, respectively. The AUC and C_max of bupropion metabolites decreased by 42% and 78%, respectively.

In a study in healthy volunteers, with concomitant administration of the combined drug lopinavir 400 mg/ritonavir 100 mg twice daily, a decrease in the AUC and C_max of bupropion by 57% was observed. The AUC and C_max of hydroxybupropion decreased by 50% and 31%, respectively.

The C_max of hydroxybupropion in plasma is reached 7 hours after taking bupropion extended-release tablets.

Elimination

After oral administration of 200 mg of carbon-14 labeled bupropion, 87% and 10% of the radioactive dose was found in urine and feces, respectively. The fraction of the bupropion dose excreted unchanged was only 0.5%, which is associated with the active metabolism of bupropion. Less than 10% of the isotope-labeled dose was found in urine as an active metabolite.

The oral clearance of bupropion is approximately 200 L/h, the elimination half-life is 20 h.

The T_1/2 of hydroxybupropion is approximately 20 h, the AUC at steady state is approximately 17 times greater than that of bupropion. The T_1/2 of threo-hydroxybutyrate and erythro-hydroxypropionate is longer (37 and 33 h, respectively), the AUC is 8 and 1.6 times higher than that of bupropion. The time to reach steady state for bupropion and its metabolites is within 8 days.

Special patient groups

Elderly patients

Pharmacokinetic studies in elderly patients have shown varying results. A single-dose study showed that the pharmacokinetics of bupropion and its metabolites in elderly patients do not differ from those in young adult patients. Another pharmacokinetic study of single and multiple doses showed that Bupropion and its metabolites accumulate more in elderly patients. Clinical experience has not revealed differences in the tolerability of the drug between elderly and young patients, but increased sensitivity to the drug in elderly patients cannot be ruled out.

Patients with renal impairment

The elimination of bupropion and its main metabolites may be reduced in patients with renal impairment. Exposure to bupropion and/or its metabolites is increased in patients with end-stage renal failure or moderate to severe renal impairment.

Patients with hepatic impairment

The pharmacokinetics of bupropion and its active metabolites did not have statistically significant differences in patients with mild to moderate cirrhosis compared to healthy volunteers, despite high individual variability. In patients with severe cirrhosis, the C_max and AUC of bupropion are significantly reduced (by approximately 70% and 3 times, respectively) and have greater variability compared to the corresponding values in healthy volunteers, T_1/2 also increases (by approximately 40%). For metabolites, the mean C_max decreases (by approximately 30-70%), the mean AUC increases (by approximately 30-50%), the mean T_max increases (approximately 20 h), the mean T_1/2 also increases (approximately 2-4 times) compared to the values in healthy volunteers.

Indications

• Treatment of depression. Upon achieving an adequate response, continuation of bupropion therapy for the prevention of exacerbations and relapses of depressive episodes.

ICD codes

Dosage Regimen

Bupropion extended-release tablets should be swallowed whole, not chewed, broken, or crushed, as this may lead to an increased risk of adverse reactions, including seizure disorders.

Treatment of depression

The clinical effect appears 14 days after the start of therapy. As with all antidepressants, the antidepressant effect may occur after several weeks of treatment.

The maximum single dose of bupropion extended-release should not exceed 450 mg. The interval between bupropion doses should be at least 24 hours after the last dose. The dose should not be increased by more than 100 mg per day over three days.

Adults

Initiation of treatment

The initial dose of bupropion is 150 mg once a day, in the morning.

If an adequate therapeutic response is not achieved, it is recommended to increase the dose to the usual target dose for adults of 300 mg/day once daily.

Dose increase above 300 mg/day

Dose increase to the maximum daily dose of 450 mg once/day is possible for patients who do not show clinical improvement after several weeks of therapy at a dose of 300 mg/day.

Maintenance therapy

Acute episodes of depression require continuous treatment for a duration of 6 months after achieving the initial therapeutic response. The efficacy of bupropion (300 mg/day) has been proven for long-term therapy (up to 1 year).

Children and adolescents

The safety and efficacy of bupropion in patients under 18 years of age have not been established.

Treatment of depression in special patient groups

Elderly patients

Elderly patients are more likely to develop hypersensitivity reactions, so the dose or frequency of administration of the drug should be reduced.

Patients with renal impairment

Treatment of such patients should be started with a lower dose of the drug, since Bupropion and its metabolites may accumulate in such patients to a greater extent than usual. The dose of bupropion extended-release tablets for such patients should not exceed 150 mg once a day.

Patients with hepatic impairment

Since the variability in pharmacokinetics increases in patients with mild or moderate hepatic impairment, an increase in the interval between drug administrations may be required for them.

The dose of bupropion extended-release tablets in patients with severe cirrhosis should not exceed 150 mg once every 2 days.

Adverse Reactions

The following is a list of adverse events identified in clinical studies, grouped by organ system. Frequency criteria for adverse reactions: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000).

Immune system disorders

Metabolism and nutrition disorders

Psychiatric and behavioral disorders

Nervous system disorders

Eye disorders

Ear and labyrinth disorders

Cardiac and vascular disorders

Gastrointestinal disorders

Skin and subcutaneous tissue disorders

Musculoskeletal and connective tissue disorders

Renal and urinary disorders

General disorders and administration site conditions

Insomnia is a very common transient adverse reaction; if necessary, the dose or frequency of administration of the drug should be reduced. The drug should not be taken before bedtime, observing a 24-hour interval between doses.

Contraindications

• Hypersensitivity to bupropion or any other component of the drug;
• Seizure disorders;
• Abrupt withdrawal of alcohol or sedatives (including benzodiazepines);
• Concomitant use of other bupropion-containing drugs (the occurrence of seizures is a dose-dependent effect);
• History of bulimia or anorexia nervosa (seizures may occur);
• Concomitant use with MAO inhibitors. Bupropion therapy should not be started for at least 2 weeks after discontinuation of irreversible MAO inhibitors.
• Age under 18 years.

With caution should be used in patients with impaired liver function, impaired renal function, cardiovascular diseases, and a reduced seizure threshold.

Use in Pregnancy and Lactation

The safety of bupropion use in pregnant women has not been established.

Bupropion may be prescribed during pregnancy only in cases where the expected benefit of its use outweighs the potential risk.

A retrospective study (n=7005 infants) did not reveal an increase in the incidence of congenital malformations (2.3%) or cardiovascular malformations (1.1%) associated with maternal use of bupropion in the first trimester of pregnancy (n=1213 infants), compared with the use of other antidepressants in the first trimester (n=4743 infants – 2.3% and 1.1%, respectively); or with the use of bupropion not in the first trimester (n=1049 infants; 2.2% and 1.0%, respectively).

Since Bupropion and its metabolites pass into breast milk, it is recommended to discontinue breastfeeding during bupropion therapy.

Use in Hepatic Impairment

Should be used with caution in patients with impaired liver function.

Use in Renal Impairment

Should be used with caution in patients with impaired renal function.

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Clinical studies have not revealed differences in the tolerability of bupropion in elderly patients compared to younger patients. However, the possibility of increased sensitivity in some elderly patients cannot be ruled out, so a reduction in the dose or frequency of administration may be required.

Special Precautions

Seizure Disorders

The recommended dose of bupropion should not be exceeded, as the risk of seizures associated with bupropion use is dose-dependent. In general, the incidence of seizures with bupropion extended-release tablets at a dose of 450 mg/day in clinical studies was approximately 0.1%.

The occurrence of seizures associated with bupropion use is related to the presence of risk factors. Therefore, Bupropion should be prescribed with extreme caution to patients who have one or more conditions that lead to a lowered seizure threshold, including:

• History of head trauma;
• CNS tumors;
• History of seizure disorders;
• Concomitant therapy with other drugs that lower the seizure threshold.

In addition, caution should be exercised in clinical situations associated with an increased risk of seizures, including abuse of alcohol or sedatives, use of hypoglycemic drugs or insulin, and use of stimulants or appetite suppressants (sibutramine).

If seizures occur during treatment, Bupropion should be discontinued; resumption of bupropion therapy is not recommended.

Hypersensitivity Reactions

If hypersensitivity reactions develop, Bupropion should be discontinued immediately. The physician should be aware that symptoms may persist after discontinuation of bupropion and appropriate medical intervention may be required.

Hepatic Impairment

Bupropion undergoes extensive active metabolism in the liver to form active metabolites, which are further metabolized. Bupropion should be used with caution in patients with impaired liver function; consideration should be given to increasing the dosing interval in patients with mild to moderate hepatic impairment.

Bupropion should be used with extreme caution in patients with severe liver cirrhosis. In such patients, a reduction in the frequency of administration is required, as the maximum concentrations of bupropion are significantly increased and cases of accumulation in such patients are more frequent than usual. All patients with hepatic impairment should be closely monitored for the development of adverse reactions (e.g., insomnia, dry mouth, seizures), which may be a sign of high concentrations of bupropion or its metabolites.

Patients with Renal Impairment and Elderly Patients

Bupropion undergoes extensive metabolism in the liver to form active metabolites, which are subsequently excreted by the kidneys. Therefore, treatment of patients with renal impairment should be initiated at lower doses, as Bupropion and its metabolites may accumulate in such patients more frequently than usual. Such patients should be closely monitored for the development of adverse reactions (e.g., insomnia, dry mouth, seizures), which may be signs of high concentrations of bupropion or its metabolites.

Clinical studies have not revealed differences in the tolerability of bupropion in elderly patients compared to younger patients. However, the possibility of increased sensitivity in some elderly patients cannot be ruled out, so a reduction in the dose or frequency of administration may be required.

Use in Children and Adolescents Under 18 Years of Age

Treatment with antidepressants is associated with an increased risk of suicidal thoughts and behavior in children and adolescents with major depressive disorder and other psychiatric disorders.

Clinical Worsening and Suicide Risk Associated with Psychiatric Disorders in Adults

In patients with depression, worsening of symptoms and/or the emergence of suicidal thoughts and behavior may occur regardless of whether they are receiving antidepressants. Since improvement may not occur for the first several weeks of treatment or longer, patients should be closely monitored for clinical worsening (including the development of new symptoms) and suicidal behavior/thoughts, especially at the beginning of the treatment course and during dose changes (increase or decrease). This risk persists until significant remission is achieved. Clinical experience with all antidepressants shows that the suicide risk may increase in the early stages of recovery.

Patients at the greatest risk of suicide are those with a history of suicidal behavior or thoughts, young patients, and patients with suicidal thoughts prior to initiation of treatment. Such patients should be closely monitored during treatment. In addition, a meta-analysis of placebo-controlled clinical trials of antidepressant use in adult patients with major depression or other psychiatric disorders demonstrated an increased risk of suicidal thoughts and behavior associated with antidepressant use compared to placebo in patients under 25 years of age.

Patients and their caregivers should be warned about the need for careful monitoring of the patient’s condition (including the appearance of new symptoms), and in case of worsening of their condition and/or the appearance of suicidal thoughts/behavior or self-harm, and in case of their occurrence, seek medical help immediately.

These symptoms may be associated with the underlying disease or with the drug therapy being administered.

In case of clinical worsening (including the appearance of new symptoms) and/or the appearance of suicidal thoughts/behavior, especially if the symptoms are severe, have a sudden onset, and were not present before starting treatment, a decision should be made to change the treatment regimen, including possible discontinuation of the drug.

Psychiatric Disorders, Including Mania and Bipolar Disorder

Psychotic disorders and mania have been observed, mainly in patients with a history of mental illness. Furthermore, a major depressive episode may be the initial manifestation of bipolar disorder. It is generally believed (although not proven by controlled clinical trials) that treating such an episode with antidepressants alone may increase the likelihood of an accelerated development of a mixed/manic episode in patients at risk for bipolar disorder.

Limited clinical data on the use of bupropion in combination with mood stabilizers in patients with a history of bipolar disorder demonstrate a low frequency of transition to the manic phase.

Before starting treatment, careful screening should be performed to assess the risk of bipolar disorder (including family history of suicide, bipolar disorder, and depression).

Cardiovascular Diseases

There is limited clinical data on the use of bupropion for the treatment of depression in patients with cardiovascular diseases. Caution should be exercised when using bupropion in such patients. However, Bupropion was generally well tolerated in smoking cessation studies in patients with coronary artery disease.

In studies of patients without depression (including both smokers and non-smokers) with untreated grade 1 arterial hypertension, Bupropion did not have a statistically significant effect on blood pressure. However, cases of elevated blood pressure (sometimes severe) have been reported during routine monitoring. Concomitant use of bupropion and a transdermal nicotine system may cause an increase in blood pressure.

Before prescribing a combination of bupropion and a transdermal nicotine system for the treatment of nicotine dependence, the information for the use of the corresponding transdermal system should be taken into account, and blood pressure monitoring should be ensured.

Rare cases of neurological and psychiatric disorders, as well as reduced tolerance to alcohol, have been reported in patients receiving bupropion therapy. During treatment with bupropion, alcohol consumption should be minimized or avoided.

Effect on Ability to Drive and Operate Machinery

Like other drugs that affect the CNS, Bupropion may adversely affect the ability to perform tasks requiring mental alertness, as well as motor activity and cognitive skills. Patients should exercise caution when driving a car and/or operating other machinery.

Overdose

Symptoms

In addition to the symptoms described in the “Adverse Reactions” section, bupropion overdose may cause drowsiness, loss of consciousness, and ECG changes such as conduction disturbances (including QRS complex prolongation) or arrhythmias. A case of simultaneous oral ingestion of bupropion in doses 10 times the maximum therapeutic dose has been reported.

Treatment

No specific antidote for bupropion is known.

Hospitalization is recommended in case of overdose. ECG and vital signs monitoring is necessary. Airway patency, oxygenation, and pulmonary ventilation must be ensured. Administration of activated charcoal is indicated immediately after oral ingestion of bupropion. Further treatment should be based on the clinical picture and recommendations of the poison control center.

Drug Interactions

Bupropion is metabolized to form its main active metabolite, hydroxybupropion, primarily by the cytochrome P450 isoenzyme IIB6 (CYP2B6). Therefore, caution should be exercised when co-administering bupropion with drugs that affect the activity of the CYP2B6 isoenzyme (e.g., orphenadrine, cyclophosphamide, ifosfamide, ticlopidine, clopidogrel).

An in vitro study of the cytochrome P450 enzyme system showed that Bupropion and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme metabolism.

Concomitant use of bupropion with drugs that are predominantly metabolized by the CYP2D6 isoenzyme (such as beta-blockers (e.g., metoprolol), antiarrhythmic agents, selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics) should be initiated at the lower end of the dose range of the concomitant drug. If bupropion therapy is added to an existing regimen of a drug metabolized by the CYP2D6 isoenzyme, consideration should be given to reducing the dose of the concomitant drug, which is especially important for drugs with a narrow therapeutic index.

Although citalopram is not predominantly metabolized by the CYP2D6 isoenzyme, one study found that bupropion use increased its C_max and AUC by 30% and 40%, respectively.

Since Bupropion undergoes extensive metabolism, concomitant administration of drugs that are inducers (e.g., carbamazepine, phenobarbital, phenytoin, ritonavir, efavirenz) or inhibitors of cytochrome P450 isoenzymes may affect the therapeutic effect of bupropion.

In studies involving healthy volunteers, administration of ritonavir (at doses of 100 mg twice daily or 600 mg twice daily) or a combination of ritonavir (100 mg) and lopinavir (400 mg) twice daily reduced the exposure to bupropion and its metabolites in a dose-dependent manner by approximately 20-80%. Efavirenz (at a dose of 600 mg once daily) for two weeks reduced bupropion exposure by approximately 55%. This effect is presumably mediated by induction of bupropion metabolism. Consequently, in patients receiving these drugs, a higher dose of bupropion may be required; however, the dose should not exceed the maximum.

Limited clinical data revealed an increased incidence of neuropsychiatric adverse reactions in patients receiving Bupropion concomitantly with levodopa or amantadine. Caution should be exercised when co-administering bupropion to patients receiving levodopa or amantadine.

Repeated doses of bupropion did not have a statistically significant effect on the pharmacokinetics of a single dose of lamotrigine: in 12 patients, the AUC of lamotrigine glucuronide was only slightly increased.

Concomitant use of bupropion and a transdermal nicotine system may cause an increase in blood pressure.

Drugs that require metabolic activation by the CYP2D6 isoenzyme (e.g., tamoxifen) may be less effective when taken orally with CYP2D6 inhibitors such as Bupropion.

Storage Conditions

Store at a temperature not exceeding 25°C (77°F), in a place inaccessible to children.

Shelf Life

Shelf life – 1.5 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.