Duloxetine Biomed

 (Delayed-Release Capsules)

 

 

Composition: Each Duloxetine Biomed Delayed-Release Capsule (Enteric Coated pellets) contains 20, 30, or 60 mg Duloxetine (as Duloxetine hydrochloride).

Duloxetine Biomed Duloxetine is an antidepressant and pain inhibitor, Duloxetine Biomed is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI).

 

CLINICAL PHARMACOLOGY

Mechanism of Action: Although the exact mechanisms of the antidepressant and central pain inhibitory action of duloxetine are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO).

 

Pharmacokinetics

Duloxetine has an elimination half-life of about 12 hours, its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2.

Absorption and Distribution: Orally administered duloxetine is well absorbed. There is a median 2-hour lag until absorption begins (T _lag) (after drug reaches the intestine) because of change in release area, with maximal plasma concentrations (C _max) of duloxetine occurring 6 hours post dose. Food does not affect the C _max of duloxetine. The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and (alpha)₁ -acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.

Metabolism and Elimination: Biotransformation and disposition of duloxetine have been determined following oral administration of ¹⁴ C-labeled duloxetine, indicating that it undergoes extensive metabolism to numerous metabolites. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces.

 

Indications and Usage

• Major Depressive Disorder: Duloxetine Biomed is indicated for the acute and maintenance treatment of major depressive disorder (MDD). A major depressive episode implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation.
• Generalized Anxiety Disorder: Duloxetine Biomed is indicated for the acute treatment of generalized anxiety disorder (GAD). Generalized anxiety disorder is an excessive anxiety and worry for at least 6 months. It must be associated with at least 3 of the following symptoms: Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and/or sleep disturbance.

 

 

 

 

• Diabetic Peripheral Neuropathic Pain: Duloxetine Biomed is indicated for the management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy.

• Fibromylagia Duloxetine Biomed is indicated for the management of fibromylagia.

 

Contraindications

• Duloxetine Biomed is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
• Concomitant use in patients taking (MAO) inhibitors is contraindicated due to the risk of serious drug interactions with serotonergic drugs. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and are then started on MAOI.
• Duloxetine use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow– angle glaucoma.

 

Warnings and Precautions

• Suicide is a known risk of depression and certain other psychiatric disorders, these disorders themselves are the strongest predicators of suicide. Families and caregivers of patients should observe closely all patients especially pediatrics being treated with antidepressants for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of therapy, at times of dose changes.
• A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed that treating such an episode with an antidepressant alone may increase possible precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Duloxetine is not approved for treating bipolar depression.

• Consideration should be given to discontinuing duloxetine in patients who experience symptomatic orthostatic hypotension and/or syncope during therapy particularly after dose increase, in patients taking medications that induce orthostatic hypotension (Antihypertensives, potent CYP1A2 inhibitors).

• The development of potentially serious serotonin syndrome or neuroleptic malignant syndrome (NMS) – like reactions have been reported with SNRIs and SSRIs alone, including Duloxetine Biomed treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impairs metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Patients should be monitored for the emergence of these reactions.

• Patients should be cautioned about the risk of bleeding associated with the concomitant use of duolextine and NSAIDs, aspirin, or other drugs that affect coagulation.

•  Adverse reactions following abrupt or tapered discontinuation of Duloxetine Biomed in MDD Patients may occur. A gradual dose reduction rather than abrupt cessation is recommended. If intolerable symptoms occur, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

• Duloxetine Biomed should be used cautiously in patients with a history of mania.
• Duloxetine Biomed should be prescribed with care in patients with a history of a seizure disorder.

• In clinical trials, Duloxetine Biomed treatment was associated with increases in blood pressure. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment.

• Discontinuing s Duloxetine Biomed hould be considered in patients with symptomatic hyponatremia that occurs as a result of treatment with SSRI and SNRI and appropriate medical intervention should be instituted. Elderly patients, patients taking diuretics or who are otherwise volume depleted may be at greater risk.

 

 

 

• Duloxetine Biomed is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Duloxetine Biomed consideration should be given to the possibility that they might be drug-related. Some instances of urinary retention associated with duloxetine use, might need hospitalization and/or catheterization.

• Duloxetine Biomed should be used cautiously in patients with controlled narrow– angle glucoma.
• In DPNP trials, Duloxetine Biomed treatment worsens glycemic control in some patients with diabetes.

 

Adverse Reactions

Common: Nausea, vomiting, fatigue, somnolence, dizziness.

Occurring at an incidence of 2% or more: Nausea, vomiting, diarrhea, headache, rash, pruritis, dry mouth, fatigue, asthenia, somnolence, dizziness, constipation, dyspepsia, upper respiratory tract infection, musculoskeletal pain or spasms, cough, decreased appetite, hyperhidrosis, blurred vision, weight increased, dysgeusia, tremor, insomnia, anxiety, paraesthesia, abnormal dreams, libido decreased, erectile dysfunction or disorder, yawning, hot flush, dysarthria, small increases in ALT- AST- CPK- Alkaline phosphatase. 

   

Drug Interactions

Inhibitors of CYP1A2: when duloxetine 60 mg was Co-administered with fluvoxamine 100 mg, a potent inhibitor of CYP1A2, duloxetine AUC was increased approximately 6-fold, C _max was increased about 2.5-fold and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism which include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin would be expected to have similar effects and these combinations should be avoided.

Inhibitors of CYP2D6: Concomitant use of duloxetine (40 mg once daily) with Paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine).

Dual Inhibition of CYP1A2 and CYP2D6: Concomitant administration of duloxetine 40 mg twice daily with Paroxetine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subject resulted in 6-fold increase in duloxetine AUC and C _max.

Drugs that interfere with hemostasis (e.g, NSAIDs, Aspirin, and Warfarin): Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued.

Potential for Interaction with Drugs that Affect Gastric Acidity: Caution is advised in using Duloxetine Biomed in patients with conditions that may slow gastric emptying (e.g., some diabetics). Co-administration of Duloxetine Biomed with aluminum- and magnesium-containing antacids or Duloxetine Biomed with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption.

Drugs Metabolized by CYP1A2: In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., Theophylline, Caffeine) resulting from induction is not anticipated.

Drugs Metabolized by CYP2D6: Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg BID) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. Coadministration of Duloxetine Biomed with  drugs that are extensively metabolized by CYP2D6 and that have narrow therapeutic index, including certain antidepressants (TCAs) (such as nortriptyline, amitripytline and imipramine), phenothiazines and type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with care. Because of the serious ventricular arrhythmias, a Duloxetine Biomed nd thioridazine should not be coadministered.

Drugs Metabolized by CYP2C9: Duloxetine does not inhibit the in vitro enzyme activity of CYP2C9. Inhibition of the metabolism of CYP2C9 substrates is therefore not anticipated.

 

 

 

 

Drugs Metabolized by CYP3A, CYP2C19: Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A, CYP2C19 activity at therapeutic concentrations.

Serotonergic Drugs: Caution is advised when Duloxetine Biomed is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid, lithium, tramadol. The concomitant use of Duloxetine Biomed with other SSRIs, SNRIs or tryptophan is not recommended.

Triptans: There have been reports of serotonin syndrome with use of an SSRI and triptan. If concomitant treatment of Duloxetine Biomed with triptan is clinically warranted, careful observation of the patient is advised, especially during treatment initiation and dose increases.

Alcohol: Duloxetine Biomed did not increase the impairment of mental and motor skills caused by alcohol.

Drugs highly bound to plasma protein: Because duolextine is highly bound to plasma protein, administration of Duloxetine Biomed to a patient taking another drug that is highly bound to plasma protein may cause increased free concentrations of the other drug, potentially resulting in adverse reactions.

 

Special Populations

Pregnancy and Delivery: (Pregnancy Category C)

There are no adequate and well-controlled studies in pregnant women; the effect of duloxetine on delivery is unknown. Therefore, duloxetine should be used during pregnancy and delivery only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers: Duloxetine is excreted into the milk of lactating women. Because the safety of duloxetine in infants is not known, nursing while in Duloxetine Biomed is not recommended. However, if the physician determined that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required. 

Pediatric Use: Safety and effectiveness in pediatrics have not been established. Anyone considering the use of Duloxetine Biomed in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use: No overall differences in safety or effectiveness were observed between elderly and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is recommended for elderly patients.

Smoking Status: Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.

Hepatic Insufficiency: Patients with clinically evident hepatic insufficiency have decreased duloxetine metabolism and elimination. Duloxetine Biomed should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Duloxetine Biomed should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

Renal Impairment: Duloxetine Biomed should ordinarily not be used in patients with end-stage renal disease or severe renal impairment (Creatinine clearance <30 mL/min). Increased plasma concentration of duloxetine and especially of its metabolites occurs in end-stage renal disease patients (requiring dialysis). 

           

Dosage and Administration

Duloxetine Biomed should be swallowed whole and should not be chewed or crushed, nor should the contents be sprinkled on food or mixed with liquids. should be Duloxetine Biomed given without regard to meals.

1.Initial Treatment

Major Depressive Disorder Duloxetine Biomed should be administered at a total dose of 40- 60 mg/day (given as 20 or 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily; a 120 mg/day was shown to be effective. The safety of doses above 120 mg/daily has not been adequately evaluated.

Generalized Anxiety Disorder: For most patients, the recommended starting dose for Duloxetine Biomed is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily, a 120 mg was shown to be effective. If a decision is made to increase the dose beyond 60 mg once daily, dose increases should

 

 

 

be in increments of 30 mg once daily. Safety of doses above 120 mg/daily has not been adequately evaluated.

Diabetic Peripheral Neuropathic Pain: The recommended dose for Duloxetine Biomed is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit, and the higher dose is clearly less well tolerated. For patients for whom tolerability is a concern, a lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, a lower starting dose and a gradual increase in dose should be considered.

Fibromylagia: The recommended dose for Duloxetine Biomed is 60 mg administered once daily. Treatment should begin at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses higher than 60 mg confer additional benefit, even in patients who do not respond to a 60 mg dose. 

2.Maintenance/Extended Treatment

Major Depressive Disorder: It is generally agreed that acute episodes of major depression require several months or longer of sustained therapy. Duloxetine Biomed should be administered with total doses of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.

Generalized Anxiety Disorder: The efficacy of i Duloxetine Biomed n the treatment of GAD, that is, beyond 10 weeks, has not been systemically studied. The physician who elects to use Duloxetine Biomed for extended periods should periodically evaluate the long term usefulness of the drug for the individual patient.

Diabetic Peripheral Neuropathic Pain: As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Duloxetine Biomed must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied.

Fibromylgia: The efficacy of Duloxetine Biomed in management of fibromylagia has been demonstrated in controlled studies up to 3 months. Continued treatment should be based on individual patient response.

3.Discontinuing Cymbatine: A gradual reduction in the dose rather than abrupt cessation is recommended.

4.Switching Patients to or from a Monoamine Oxidase Inhibitor: At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with. Duloxetine Biomed In addition, at least 5 days should be allowed after stopping Duloxetine Biomed before starting an MAOI.

 

Drug Abuse and Dependence

Abuse: Duloxetine Biomed has not been systematically studied for its potential for abuse; there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Duloxetine Biomed (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

Dependence: In drug dependence studies, duloxetine did not demonstrate dependence-producing potential.

 

Overdosage

Signs and Symptoms: Sings and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, vomiting.

Management of Overdose: There is no specific antidote to Duloxetine Biomed but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and C _max by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the

 

 

 

large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken Duloxetine Biomed and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation.

 

Presentation

Duloxetine Biomed 20 mg: Box contains 20 capsules delayed release pellets. 

Duloxetine Biomed 30 mg: Box contains 20 capsules delayed release pellets. 

Duloxetine Biomed 60 mg: Box contains 20 capsules delayed release pellets.