Doxet

Uses

Doxet Hydrochloride is used for the-

• Treatment of Major Depressive Disorder (MDD)
• Management of neuropathic pain associated with diabetic peripheral neuropathy.
• Chronic Musculoskeletal Pain
• Urinary stress incontinence.

Doxet is also used to associated treatment for these conditions: Back Pain Lower Back Chronic, Chemotherapy-induced Peripheral Neuropathy (CIPN), Chronic Musculoskeletal Pain, Diabetic Peripheral Neuropathy (DPN), Fibromyalgia, Generalized Anxiety Disorder (GAD), Major Depressive Disorder (MDD), Osteoarthritis of the Knee, Stress Urinary Incontinence (SUI)

How Doxet works

Doxet is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Doxet has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors.

Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT₂, 5-HT₃, and α₁ adrenergic receptors. 5-HT₂ and α₁ are both G_q coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP₃/PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT₃ functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate.

Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT₂, 5-HT₃, α₁-adrenergic, and α₂-adrenergic receptors. 5-HT₂, 5-HT₃, and α₁-adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT₁ and α₂ receptors are G_i/G_o coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli.

The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed.

Doxet's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α₁ receptors predominates, vasoconstriction results as the G_q coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction.

Dosage

Doxet dosage

Major Depressive Disorder (MDD): Starting dose- 20-30 mg b.i.d or 60 mg once daily, Target dose- 60 mg once daily, max. dose- 60 mg once daily

Diabetic peripheral neuropathy: Starting dose- 60 mg/day (once daily), Target dose- 60 mg once daily, max. dose- 60 mg once daily

Chronic Musculoskeletal Pain: Starting dose- 30 mg/day, Target dose- 60 mg once daily, max. dose- 60 mg once daily

Urinary stress incontinence: Starting dose- 40 mg /day, Target dose- 80 mg/day (twice daily, max. dose- 80 mg/day (twice daily).

Side Effects

The most commonly observed adverse events in Doxet hydrochloride treated patients were nausea, dizziness, dry mouth, constipation, decreased appetite, fatigue, somnolence, increased sweating, hyperhidrosis and asthenia. It may slightly increase blood pressure. No clinically significant differences were observed for QT, PR, and QRS intervals between Doxet -treated and placebo-treated patients.

Toxicity

Overdose

Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone. Signs and symptoms of overdose include: somnolence, coma, serotonin syndrome, seizure, syncope, hypo- or hypertension, tachycardia, and vomiting. No antidote exists and the drug is unlikely to be cleared by hemodialysis. Supportive care is recommended along with activated charcoal and gastric lavage to reduce absorption. If serotonin syndrome occurs specific treatment such as temperature control or cyproheptadine may be initiated.

Carcinogenicity & Mutagenicity

Increased incidence of hepatocellular carcinomas and adenomas were reported in female mice fed 140 mg/kg/day duloxetine for 2 years, equivalent to 6 times the maximum recommended human dose (MRHD). No effect was reported with doses of 50mg/kg/day (2 time MRHD) in females or 100 mg/kg/day in males (4 times MRHD). Similar investigation in rats produced no carcinogenicity at doses of 27 mg/kg/day (2 times MRHD)in females and 36 mg/kg/day in males (4 times MRHD).

No mutagenicity, clastogenicity, induction of sister chromatid exchange, or genotoxicity has been observed in toxicology investigations.

Reproductive Toxicity

Neither male or female rats displayed adverse reproductive effects at doses up to 45 mg/kg/day (4 times MRHD).

Lactation

An estimated 25% of plasma duloxetine appears in breast milk with the estimated daily infant dose being 0.14% of the maternal dose. Breast milk concentrations have been observed to peak 3 hours after administration.

Precaution

Doxet hydrochloride should ordinarily not be prescribed to patients with substantial alcohol use. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment. It should be used cautiously in patients with a history of mania, seizure disorder and controlled narrow-angle glaucoma.

Interaction

Monoamine oxidase inhibitors (MAOIs): Due to the risk of serotonin syndrome, Doxet should not be used in combination with non selective, irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with an MAOI.

Inhibitors of CYP1A2: Because CYP1A2 is involved in Doxet metabolism, concomitant use with potent inhibitors of CYP1A2 is likely to result in higher concentrations of Doxet. Therefore, Doxet should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine.

CNS medicinal products: Caution is advised when Doxet is taken in combination with other centrally acting medicinal products or substances, including alcohol and sedative medicinal products (e.g., benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

Food Interaction

• Avoid excessive or chronic alcohol consumption. Alcohol increases the risk of liver toxicity.
• Take with or without food. Do not sprinkle the contents of the capsules on food/liquids.

[Moderate] GENERALLY AVOID: Use of duloxetine in conjunction with chronic alcohol consumption may potentiate the risk of liver injury.

Doxet alone can increase serum transaminase levels.

In clinical trials, 0.3% of patients discontinued duloxetine due to liver transaminase elevations.

The median time to detection was about two months.

Three duloxetine-treated patients had liver injury as manifested by transaminase and bilirubin elevations, with evidence of obstruction.

Substantial intercurrent ethanol use was present in each of these cases, which may have contributed to the abnormalities observed.

Doxet does not appear to enhance the central nervous system effects of alcohol.

When duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by alcohol.

MANAGEMENT: Due to the risk of liver injury, patients prescribed duloxetine should be counseled to avoid excessive use of alcohol.

Doxet should generally not be prescribed to patients with substantial alcohol use.

Doxet Hypertension interaction

[Moderate] Selective serotonin and norepinephrine reuptake inhibitor antidepressants (SNRIs) have been associated with sustained increases in blood pressure.

Therapy with SNRI antidepressants should be administered cautiously in patients with preexisting hypertension.

Blood pressure should be assessed prior to initiating treatment and monitored regularly.

The dose should be reduced or discontinued if necessary.

Doxet Drug Interaction

Moderate: aspirin, aspirin, pregabalin, pregabalin, metoprolol, metoprolol, metoprolol, metoprolol, acetaminophen / hydrocodone, acetaminophen / hydrocodone, cetirizine, cetirizineUnknown: omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Doxet Disease Interaction

Major: liver disease, renal disease, depressionModerate: diabetes, glaucoma, hypertension, hyponatremia, mania, seizures, urinary tract obstruction

Volume of Distribution

Apparent Vd of 1620-1800 L. Doxet crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma.

Elimination Route

Doxet is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%. The population absorption constant (ka) is 0.168 h^{-1 Administering duloxetine with food 3 hour delay in Tmax along with an 10% decrease in AUC. Similarly, administering the dose at bedtime produces a 4 hour delay and 18% decrease in AUC with a 29% reduction in Cmax. These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree.}

Half Life

Mean of 12 h with a range of 8-17.

Clearance

There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h. Steady state concentrations have still been shown to be dose proportional with a doubling of dose from 30 to 60 mg and from 60 to 120 mg producing 2.3 and 2.6 times the Css respectively.

Elimination Route

About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites. Another 20% is present in the feces as the parent drug, 4-hydroxy metabolite, and an uncharacterized metabolite. Biliary secretion is thought to play a role due to timeline of fecal excretion exceeding the time expected of normal GI transit.

Pregnancy & Breastfeeding use

Pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women; therefore, Doxet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery: The effect of Doxet on labor and delivery in humans is unknown. Doxet should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

Lactation: It is unknown whether or not Doxet and/or it's metabolites are excreted into human milk, but nursing while on Doxet is not recommended.

Contraindication

Doxet is contraindicated in patients with a known hypersensitivity to this drug or any of the inactive ingredients. Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated. It should be avoided in patients with uncontrolled narrow-angle glaucoma.

Special Warning

Use in children: Safety and efficacy in pediatric patients have not been established.

Acute Overdose

There is limited clinical experience with Doxet overdose in humans. There is no specific antidote to Doxet. 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 Doxet from the gastrointestinal tract.

Storage Condition

Store in a cool and dry place, protected from light and moisture.

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