Joytor-30/Joytor-60

Joytor-30: Opaque blue/opaque white non brittle hard gelatin capsule of size "3" containing white to off-white coloured pellets.
Each hard gelatin capsule contains: Duloxetine Hydrochloride, USP (as gastro-resistant pellets) 30 mg.
Joytor-60: Opaque blue/opaque green non brittle hard gelatin capsule of size "1" containing white to off-white coloured pellets.
Each hard gelatin capsule contains: Duloxetine Hydrochloride, USP (as gastro-resistant pellets) 60 mg.

Antidepressant.
Pharmacology: Pharmacodynamics: Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas of animals.
Neurochemical and behavioral studies in laboratory animals showed an enhancement of both serotonin and noradrenaline neurotransmission in the CNS. Duloxetine also normalized pain thresholds in several preclinical models of neuropathic and inflammatory pain and attenuated pain behavior in a model of persistent pain. The presumed mechanism of action of duloxetine in the treatment of both the emotional and somatic symptoms of depression is thought to be due to its inhibition of neuronal uptake of serotonin and noradrenaline, and a resultant increase in serotonergic and noradrenergic neurotransmission in the CNS.
Pharmacokinetics: Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolized by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of duloxetine demonstrate large intersubject variability (generally 50-60%), partly due to gender, age, smoking status and CYP2D6 metabolizer status.
Duloxetine is well absorbed after oral administration with a C_max occurring 6 hours post dose. The absolute oral max bioavailability max of duloxetine ranged from 32% to 80% (mean of 50%). Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11%). These changes do not have any clinical significance.
Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine binds to both albumin and alpha-l acid glycoprotein. Protein binding is not affected by renal or hepatic impairment Duloxetine is extensively metabolized and the metabolites are excreted principally in urine. Both cytochromes P450-CYP2D6 and P450-CYP1A2 catalyze the formation of the two major metabolites glucuronide conjugate of 4-hydroxy duloxetine and sulphate conjugate of 5-hydroxy, 6-methoxy duloxetine.

Duloxetine is indicated for the treatment of major depressive disorder.
Duloxetine is indicated for the treatment of diabetic neuropathic pain.
Duloxetine is indicated for the treatment of generalized anxiety disorder.
Duloxetine is indicated for the treatment of fibromyalgia with or without depression.
Duloxetine is indicated for the treatment of chronic pain (CP) states associated with: Diabetic Peripheral Neuropathic Pain (DPNP); Fibromyalgia (FM); Chronic Lower Back Pain (CLBP); Osteoarthritis (OA).

Duloxetine is a hard gastro-resistant capsule formulation for oral use.
The starting and recommended maintenance dose of Duloxetine hydrochloride is 60 mg once daily with or without food.
Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day administered in evenly divided doses, havebeen evaluated from a safety perspective in clinical trials. However, there is no clinical evidence suggesting that patients not responding to the initial recommended dose may benefit from dose up titrations.
Hepatic impairment: Duloxetine should not be used in patients with liver disease resulting in hepatic impairment (see Contraindications and Pharmacology: Pharmacokinetics under Actions).
Renal insufficiency: No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 mL/min). See Contraindications for severe renal impairment.
Elderly: No dosage adjustment is recommended for elderly patients solely on the basis of age. However, as with any medicine, caution should be exercised when treating the elderly (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Children and adolescents: Duloxetine is not intended for use in children. The safety and efficacy in patients under the age of 18 years have not been established.
Discontinuation of treatment: Abrupt discontinuation should be avoided. When discontinuing duloxetine, it is generally recommended that the dose be tapered of at least one to two weeks before discontinuation in an effort to decrease the risk of discontinuation symptoms. As a general recommendation, the dose should be reduced by half or administered on alternate days during this period. The precise regimen followed should however take into account the individual circumstances of the patient, such as duration of treatment, dose at discontinuation, etc.

In cases of acute ingestions up to 3000 mg, alone or in combination with other drugs, were reported with none being fatal. However, in post marketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, vomiting and tachycardia seizures.
In animal studies, the major signs of overdose toxicity are related to the central nervous and gastrointestinal systems. These include central nervous system effects such as tremors, clonic convulsions, ataxia, emesis, and decreased appetite.
No specific antidote is known, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. An airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption. Duloxetine has a large volume of distribution and forced diuresis, hemoperfusion, and exchange perfusion are unlikely to be beneficial.

Hypersensitivity to the active substance or to any of the excipients.
The concomitant use of duloxetine with non-selective irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated (see Interactions for details).
Liver disease resulting in hepatic impairment.
Duloxetine should not be used in combination with fluvoxamine, ciprofloxacin, or enoxacine (i.e. potent CYP1A2 inhibitors) since the combination results in elevated plasma concentrations of duloxetine.
Severe renal impairment (creatinine clearance less than 30 mL/min).

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders, and those considering use of these agents must balance the risk with the clinical need.

As with similar CNS active drugs, duloxetine should be used cautiously in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures.
Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing duloxetine in patients with raised intraocular pressure, or those at risk of acute narrow-angle glaucoma.
Duloxetine hard gastro-resistant capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Renal Impairment: Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on hemodialysis (creatinine clearance of less than 30 mL/min). For patients with severe renal impairment, see Contraindications and Dosage & Administration for information on patients with mild or moderate renal dysfunction.
Increased blood pressure: Duloxetine is associated with an increase in blood pressure in some patients. In patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended as appropriate.
Elevations in liver enzymes: Elevations were seen in some patients treated with duloxetine in clinical trials. These were usually transient and self-limiting, or resolved upon discontinuation of duloxetine. Severe elevations of liver enzymes (>10 times the upper limit of normal) or liver injury with a cholestatic or mixed pattern have been rarely reported, in some cases associated with excessive alcohol use or pre-existing liver disease. Duloxetine should be used with caution inpatients with substantial alcohol use or pre-existing liver disease.
Use with antidepressants: Cautions should be exercised when using duloxetine in combination with antidepressants. In particular the combination with selective reversible MAOIs is not recommended.
St. John's wort: Undesirable effects may be more common during concomitant use of duloxetine and herbal preparations containing St. John's wort (Hypericum perforatum).
Suicide: The possibility of a suicide attempt is inherent in depression and other psychiatric disorders and may persist until significant remission occurs. Close supervision of high-risk patients should accompany drug therapy.
As with other drugs with similar pharmacological action (inhibitor of serotonin reuptake [SSRI] or inhibitor of serotonin and norepinephrine reuptake [SNRI], isolated cases of suicidal ideation and suicidal behaviors have been reported during duloxetine therapy or early after treatment discontinuation.
Duloxetine hydrochloride has not been studied in patients under the age of 18 and is not intended for use in this age group.
Although a causal role for duloxetine in inducing such events has not been established some analyses from pooled studies of antidepressants in psychiatric disorders found an increased risk for suicidal ideation and/or suicidal behaviors in pediatric and young adult (<25 years of age) patients compared to placebo. Physicians should encourage patients to report any distressing thoughts or feelings at any time.
Hemorrhage: There have been reports of cutaneous bleeding abnormalities, such as ecchymoses and purpura with selective serotonin reuptake inhibitors (SSRIs). Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function, and in patients with known bleeding tendencies.
Hyponatremia: Cases of hyponatremia (some with serum sodium lower than 110 mmol/Liter) have been reported very rarely. The majority of these cases occurred in elderly patients, especially when coupled with a recent history of altered fluid balance or conditions pre-disposing to altered fluid balance. Hyponatremia may present with nonspecific signs and symptoms (such as dizziness, weakness, nausea, vomiting, confusion, somnolence, and lethargy). Signs and symptoms associated with more severe cases have included syncopal episodes, falls, and seizure.
Abnormal Bleeding: SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events, including gastrointestinal bleeding. Therefore, caution is advised in patients taking duloxetine concomitantly with anticoagulants and/or medicinal products known to affect platelet function (e.g., NSAIDs, aspirin) and in patients with known bleeding tendencies. Discontinuation of Treatment: Some patients may experience symptoms on discontinuation of duloxetine, particularly if treatment is stopped abruptly (see Dosage & Administration and Adverse Reactions).
Effects on ability to drive and use machines: Duloxetine may be associated with undesirable effects, such as sedation and dizziness. Therefore, patients should be cautioned about operating hazardous machinery, including automobiles, while taking duloxetine.
Use in Elderly: Only limited clinical data on the use of duloxetine in elderly patients with major depressive disorders is available. Therefore, caution should be exercised when treating the elderly.

Pregnancy: There are no data on the use of duloxetine in pregnant women. Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure.
The potential risk for humans is unknown. As with other serotoninergic drugs, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. Duloxetine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Discontinuation symptoms (e.g., hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures) may occur in the neonate after maternal duloxetine use near term. The majority of cases have occurred either at birth or within a few days of birth. Women should be advised to notify their physician if they become pregnant, or intend to become pregnant, during therapy.
Breastfeeding: Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg is approximately 0.14% of the maternal dose. Because the safety of duloxetine in infants is not known, breastfeeding while on duloxetine is not recommended.

The most commonly reported adverse reactions in patients treated with were nausea, headache, dry mouth, somnolence and dizziness. However, the majority of common adverse reactions were mild to moderate; they usually started early in therapy, and most tended to subside even as therapy was continued.
Tabulated summary of adverse reactions: Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See tables a and b.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia or electric shock-like sensations, particularly in the head), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhea, hyperhydrosis and vertigo are the most commonly reported reactions.
Generally, for SSRIs and SNRIs, these events are mild to moderate and self-limiting; however, in some patients they maybe severe and/or prolonged. It is therefore advised that when duloxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out.

MAOIs: Due to the risk of serotonergic syndrome, duloxetine should not be used in combination with non-selective irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with MAOIs. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping duloxetine before starting MAOIs. For selective, reversible MAOIs, like moclobemide, the risk of serotonin syndrome is lower. However, the concomitant use of duloxetine with selective, reversible MAOIs is not recommended.
Serotonin Syndrome: In rare cases, serotonin syndrome has been reported in patients using SSRIs (e.g., paroxetine,fluoxetine) concomitantly with serotonergic medicinal products. Caution is advisable if duloxetine is used concomitantly with serotonergic antidepressants like SSRIs, tricyclics like clomipramine or amitriptyline, St. John's wort (Hypericum perforatum), venlafaxine or triptans, tramadol, pethidine and tryptophan.
Drugs metabolised by CYP1A2: In a clinical study, the pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily). The study was performed in males and it cannot be excluded that females having a lower CYP1A2 activity and higher plasma concentrations of duloxetine may experience an interaction with CYP1A2 substrate.
Inhibitors of CYP1A2: Because CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP1A2 will likely result in higher concentrations of duloxetine. Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUC0-t 6-fold.Therefore, duloxetine should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine.Inducers of CYP1A2: Population pharmacokinetics studies have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers.
Drugs metabolised by CYP2D6: Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered at a dose of 60 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased by 3-fold. The co-administration of duloxetine increases steady state AUC of tolterodine (2 mg twice daily) by 71%, but does not affect the pharmacokinetics of its 5-hydroxyl metabolite. Therefore, caution should be used if duloxetine is co-administered with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic index.
Inhibitors of CYP2D6: As CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 may result in higher concentrations of duloxetine.
Paroxetine (20 mg once daily) decreased the apparent plasma clearance of duloxetine by about 37%. Caution is advised if administering duloxetine with inhibitors of CYP2D6 (e.g., SSRIs).
CNS medicinal products: The risk of using duloxetine in combination with other CNS-active medicinal products has not been systematically evaluated, except in the cases described in this section. Consequently, caution is advised when Duloxetine is taken in combinations with other centrally acting medicinal products and substances including alcohol and sedative medicinal products (e.g., benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines). Concomitant use of other drugs with serotonergic activity (e.g., SNRIs, SSRIs, triptans or tramadol) may result in serotonin syndrome.
Drugs highly bound to plasma protein: Duloxetine is highly bound to plasma proteins (>90%). Therefore, administration of duloxetine to a patient taking another drug that is highly protein bound may cause an increase in free concentrations of either drug.
Antacids and H2 antagonists: Co-administration of duloxetine with aluminium- and magnesium-containing antacids or duloxetine with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose.
Oral contraceptives and other steroidal agents: Results of in vitro studies demonstrate that duloxetine does not inhibit orinduce the catalytic activity of CYP3A. Specific in vivo drug interaction studies have not been performed.

Store at temperatures not exceeding 30°C.

Antidepressants

N06AX21 - duloxetine ; Belongs to the class of other antidepressants.

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