Zybutrin
Bupropion hydrochloride
Film coated tablet
Category:
Antidepressant
(PDR.net)
Chemistry:
(±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1- propanone hydrochloride, with a molecular weight of 276.2g/mol. The empirical formula is C13H18ClNO•HCl.
(RXList)
Pharmacokinetics:
The drug readily crosses the blood-brain barrier. Plasma protein binding is about 84%.
Metabolism takes place in the liver, producing several metabolites; the 3 major active metabolites are hydroxybupropion, threohydrobupropion, and erythrohydrobupropion. CYP2B6 is involved in forming hydroxybupropion, the major metabolite, previously known as morpholinol. All active metabolites are present in higher concentrations in the plasma than the parent compound. In mice, hydroxybupropion appears to have one-half the potency of bupropion; the other metabolites are one-tenth to one-half as potent. Bupropion appears to induce its own metabolism, but this does not appear to be clinically significant. The terminal elimination half-life of immediate-release bupropion is approximately 14 hours with a range of 8—24 hours. Less than 1% is excreted unchanged in the urine. Over 60% is excreted as metabolites in the urine within 24 hours; over 80% is eliminated in 96 hours. Less than 10% of metabolites are excreted in the feces.
Steady-state concentrations of bupropion and its metabolites are achieved in 5—8 days; however, antidepressant effects have an onset of roughly 1—3 weeks.
Oral Route
Based on animal data, the oral bioavailability is roughly 5—20%; oral bioavailability in humans has not been determined.
Peak plasma concentrations are achieved within 1.5 hours after administration of immediate-release bupropion. Peak plasma concentrations of the active metabolite hydroxybupropion occur about 3 hours after administration of immediate-release bupropion. Peak plasma concentrations of hydroxybupropion are about 10 times those of bupropion at steady state.
(PDR.net)
Indications:
Treatment of major depression and as an alternative treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents.
(PDR.net)
Contraindications:
- Bupropion is contraindicated in patients with a history of hypersensitivity to bupropion or any inactive ingredients in the formulations. Delayed hypersensitivity reactions, consisting of arthralgia, myalgia, fever and rash have been reported in association with bupropion and may resemble serum sickness. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have also been reported.
- Bupropion is contraindicated in patients with a pre-existing seizure disorder or conditions that increase the risk of seizures . Bupropion should be discontinued and not re-initiated in patients who experience a seizure during treatment. The incidence of seizures with bupropion is dose-dependent.
- Bupropion is contraindicated with concurrent use of MAOI therapy intended to treat psychiatric disorders because of an increased risk of hypertensive reactions. At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and bupropion initiation. Conversely, allow at least 14 days after stopping bupropion before starting an MAOI intended to treat psychiatric disorders. Starting bupropion in a patient being treated with an MAOI such as linezolid or methylene blue is also contraindicated; however, there may be circumstances when it is necessary to initiate urgent treatment with linezolid or intravenous methylene blue in a patient taking bupropion. If acceptable alternatives are not available and benefits are judged to outweigh the risks of hypertensive reactions, bupropion should be promptly discontinued before initiating treatment with linezolid or methylene blue.
(PDR.net)
Warnings & Precautions:
- Do not exceed maximum recommended single or total daily dosages of any bupropion product. Patients who are taking bupropion for smoking cessation should not also take bupropion for depressive disorders, and vice-versa.
- When bupropion is used for the treatment of ADHD in pediatrics, careful screening and monitoring is recommended by the American Heart Association. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients.
- In patients who exhibit adverse changes in symptoms, worsening of depressive symptoms, or suicidality, a decision should be made to change or discontinue treatment. If discontinuing bupropion, the medication should be tapered as rapidly as possible, but with recognition that discontinuing treatment abruptly can also cause adverse symptoms. Bupropion should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
- Patients with Tourette's syndrome or tics should be closely monitored for emerging or worsening tics during treatment with bupropion.
- The use of antidepressants, such as bupropion, has been associated with the development of mania or hypomania in susceptible individuals. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant, including a detailed personal and family history of bipolar disorder, depression, and suicidal thoughts or actions.
- Rarely, bupropion may cause a fast or irregular heart beat or increases in blood pressure in some patients. It should be used with caution in patients with a recent history of acute myocardial infarction or unstable cardiac disease, including heart failure. patients should have their blood pressure checked prior to bupropion initiation and periodically throughout treatment.
- Both initial and maintenance doses should be reduced in elderly patients if hepatic or renal impairment or debilitating disease is present. Bupropion may also cause weight loss which may be significant for elderly or otherwise debilitated patients.
- Patients should be warned to use caution when driving or operating machinery or performing other tasks that require mental alertness until they know how bupropion will affect them. Some patients have reported lower alcohol tolerance during treatment with bupropion.
- Caution is recommended when prescribing bupropion to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy.
- It is generally recommended to avoid abrupt discontinuation of antidepressants. If discontinuing bupropion, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms.
(PDR.net)
Pregnancy and Breast – feeding:
Pregnancy
Bupropion is classified as FDA pregnancy risk category C. When treating a pregnant woman, the physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, tapering of the medication prior to delivery may be considered.
Breast – feeding
Bbupropion and its metabolites are excreted into human breast milk, and caution should be exercised when bupropion is administered to a breast-feeding woman. Peak breast milk concentrations of bupropion and its metabolites are present within 2 to 4 hours after an oral dose.
(PDR.net)
Drug Interactions:
- In patients receiving medicinal products known to lower the seizure threshold, bupropion, must only be used if there is a compelling clinical justification for the potential medical benefit.
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 hydrochloride 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.
- 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, paroxetine), antipsychotics (e.g. risperidone, thioridazine), beta-blockers (e.g. metoprolol), and Type 1C antiarrhythmics (e.g. propafanone, flecainide). If bupropion, 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.
- 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.
- Co-administration of digoxin with bupropion may decrease digoxin levels.
The effect of other medicinal products on bupropion:
- Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 CYP2B6. 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 hydroxy-bupropion.
- Since bupropion is extensively metabolised, caution is advised when bupropion is co-administered 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.
- Nicotine, administered transdermally by patches, did not affect the pharmacokinetics of bupropion and its metabolites.
Other interactions:
- Administration of bupropion, to patients receiving either levodopa or amantadine concurrently should be undertaken with caution.
- The consumption of alcohol during bupropion, treatment should be minimised or avoided.
- At least 14 days should elapse between discontinuation of irreversible MAOIs and initiation of treatment with bupropion. For reversible MAOIs, a 24 hour period is sufficient.
(www.medicines.org.uk)
Adverse Reactions:
Hypersensitivity reactions such as urticaria, Insomnia , Depression, Agitation, Anxiety, Tremor, Concentration disturbance, Headache, Dizziness, Taste disorders, Dry mouth, Gastrointestinal disturbance including nausea and vomiting, Abdominal pain, Constipation, Rash, Pruritus, Sweating, Fever.
(www.medicines.org.uk)
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 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.
(www.medicines.org.uk)
DOSAGE AND ADMINISTRATION:
For the treatment of major depression:
Adult
Initially, 100 mg PO twice daily; titrate after no less than 3 days to 100 mg PO 3 times per day if needed; no single dose should exceed 150 mg. The onset of antidepressant effects takes 1 to 3 weeks, maximal effect may not be noted for 4 weeks. Generally, acute episodes of depression require several months of sustained pharmacologic Reassess the patient periodically to determine the individual need for continued treatment. Use the lowest dosage that maintains remission.
Children and Adolescents 6 years and older
Dosage not established. Suggested dosage ranges from 1.4 to 6 mg/kg/day PO, titrated upward slowly and administered in divided doses. the maximum dosage is generally 250 to 300 mg/day PO. Safety data are not extensive; most patients have also been diagnosed with ADHD.
As an alternative treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents:
Children and Adolescents 6 years and older
Not FDA-approved. Initial dose range: 1.4 to 3 mg/kg/day PO, titrated upward slowly and administered in divided doses. Average effective dose: 3 mg/kg/day PO. Max: 6 mg/kg/day PO or 150 to 300 mg/day PO, depending on age/weight. Bupropion has been considered an alternative for some patients when other FDA-approved treatments have failed.
Patients with renal impairment
Consider reduced dosage and/or dosage frequency in patients with a CrCl < 90 mL/min.
Patients with hepatic impairment
In patients with moderate to severe hepatic impairment (Child-Pugh Score 7—15), initiate therapy at a lower dosage and do not exceed 75 mg/day PO of immediate-release bupropion .Consider reduced dosage or dosage frequency in patients with mild hepatic impairment (Child-Pugh Score 5—6); however, no guidelines are available.
Method of administration
-May administer with food, if needed to minimize gastric upset.
-To avoid or limit the risk of insomnia, do not administer doses at bedtime.
-It is advisable to separate doses by at least 6 hours. The total daily dose is usually administered in three divided doses.
( PDR.net)
Storage:
store below 30˚ C and keep away from humidity & light.
How supplied:
Alu-Alu Blister of 10 tablets in Paper boxes of 30 tablets ,Paper leaflet in a shrink wrap
References:
1) PDR.net
2) http://www.medicines.org.uk