Aplenzin

Uses

Aplenzin Hydrochloride is used for the treatment of depression. Aplenzin is also used for smoking cessation.

Aplenzin is also used to associated treatment for these conditions: Attention Deficit Hyperactivity Disorder (ADHD), BMI >30 kg/m2, Major Depressive Disorder (MDD), Seasonal Affective Disorder (SAD), Cessation, Smoking, Weight Loss

How Aplenzin works

Aplenzin is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT).

Aplenzin was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example.

When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute.

When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways.

Dosage

Aplenzin dosage

The usual adult target dose for Aplenzin is 300 mg/day, given as 150 mg, twice daily. Dosing should begin at 150 mg/day given as a single daily dose in the morning. If the 150 mg initial dose is adequately tolerated, an increase to the 300 mg/day target dose, given as 150 mg twice daily, may be made as early as day 4 of dosing. There should be an interval of at least 8 hours between successive doses.

Increasing the dosage above 300 mg/day: As with other antidepressants, the full antidepressant effect of Aplenzin Hydrochloride may not be evident until 4 weeks of treatment or longer. An increase in dosage to the maximum of 400 mg/day, given as 200 mg twice daily, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day. Aplenzin Hydrochloride should be discontinued in patients who do not demonstrate an adequate response after an appropriate period of treatment at 450 mg/day.

Maintenance: The lowest dose that maintains remission is recommended. Although it is not known how long the patient should remain on Aplenzin Hydrochloride, it is generally recognised that acute episodes of depression require several months or longer of antidepressant drug treatment.

Side Effects

Agitation, anxiety, and insomnia often occur during the initial stages of Aplenzin therapy. Other relatively common side effects reported with Aplenzin include fever, dry mouth, headache or migraine, dizziness, nausea and vomiting, constipation, tremor, sweating, and skin rashes. Hypersensitivity reactions, ranging from pruritus and urticaria, less commonly, angio-oedema, dyspnoea, and anaphylactoid reactions have been reported.

Toxicity

Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest.

Precaution

It should be used with extreme caution, in patients with history of seizure disorders or in patients with other predisposing factors such as severe hepatic cirrhosis or a CNS tumour, and in those undergoing abrupt withdrawal from alcohol or Benzodiazepines. The use of Aplenzin in patients with other risk factors for seizures (for example, alcohol abuse, a history of head trauma, diabetes, and drugs known to lower the seizure threshold) should only be undertaken when there are compelling clinical reasons. Aplenzin should be used with caution in patients with bipolar depression or psychoses and in patients with a recent history of myocardial infarction or unstable heart disease and in hepatic or renal impairment.

Interaction

Aplenzin should not be given concurrently with or within 14 days of stopping an MAOI. The use of alcohol should be minimised or avoided completely because it may alter the seizure threshold. Similarly, other drugs that lower the seizure threshold, such as other antidepressants, antimalarials, antipsychotics, sedating antihistamines, Quinolones, Tramadol, Theophylline, or systemic corticosteroids, should be used with extreme caution together with Aplenzin. Carbamazepine, Phenobarbital, or Phenytoin may induce the metabolism of Aplenzin while other drugs such as Cimetidine or Ritonavir may inhibit its metabolism. Interaction may occur between Aplenzin and Orphenadrine, Cyclophosphamide, and Ifosfamide. Caution should be exercised when it is given with drugs such as some antidepressants, antipsychotics, β blockers, and type 1C antiarrhythmics.

Food Interaction

• Avoid alcohol. Co-administration with alcohol may result in neuropsychiatric adverse effects and potentiation of CNS depressant effects.
• Take with or without food. Co-administration with food does not significantly affect pharmacokinetics.

[Moderate] GENERALLY AVOID: Excessive use or abrupt discontinuation of alcohol after chronic ingestion may precipitate seizures in patients receiving bupropion.

Additionally, there have been rare postmarketing reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who drank alcohol during treatment with bupropion.

According to one forensic report, a patient died after taking large doses of both bupropion and alcohol.

It is uncertain whether a drug interaction was involved.

Single-dose studies in healthy volunteers given bupropion and alcohol failed to demonstrate either a significant pharmacokinetic or pharmacodynamic interaction.

MANAGEMENT: The manufacturer recommends that alcohol consumption be minimized or avoided during bupropion treatment.

The use of bupropion is contraindicated in patients undergoing abrupt discontinuation of alcohol.

Aplenzin Drug Interaction

Major: amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, duloxetine, duloxetineModerate: metoprolol, metoprolol, cetirizine, cetirizineUnknown: aspirin, aspirin, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, pregabalin, pregabalin, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Aplenzin Disease Interaction

Major: liver disease, seizure disordersModerate: depression, angle closure glaucoma, mixed/manic episode, psychosis, renal dysfunctionMinor: weight loss

Elimination Route

Aplenzin is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL).

Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day.

Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day.

Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/

In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites.

Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites.

Aplenzin hydrochloride extended-release tablets (SR) can be taken with or without food. Aplenzin Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant.

Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.

Half Life

24 hours

Elimination Route

Aplenzin is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion.

Pregnancy & Breastfeeding use

Pregnancy Category C. There are no adequate and well controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.

Lactation: Aplenzin and its metabolites are secreted in human milk. Because Aplenzin is excreted in human milk, a decision should be made whether to discontinue breast feeding or to discontinue the drug.

Contraindication

It is contraindicated in patients with a seizure disorder. Aplenzin Hydrochloride is contraindicated in patients treated with other medications that contain Aplenzin because the incidence of seizure is dose dependent. Aplenzin may induce seizure and consequently its use is contraindicated in patients with epilepsy. The drug is also contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in such patients treated for bulimia with Aplenzin Hydrochloride. The concurrent administration of Aplenzin Hydrochloride and a monoamine oxidase (MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of MAO inhibitor and initiation of treatment with Aplenzin Hydrochloride. Aplenzin Hydrochloride is contraindicated in patients who have shown an allergic response to Aplenzin or the other ingredients that make up Aplenzin Hydrochloride.

Special Warning

Child and adolescent: Not recommended for child and adolescent under 18 years of age

Acute Overdose

Symptoms: In addition to those events reported under Adverse Reactions, overdose has resulted in symptoms including drowsiness, loss of consciousness and electrocardiogram (ECG) changes eg, conduction disturbances or (including QRS prolongation) arrhythmias; cases of fatal outcome have been reported.

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 or as recommended by the national poisons centre, where available.

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