Duloxen Tablet (Delayed Release)

Duloxetine is a dual serotonin and norepinephrine reuptake inhibitor. It has since received approval for a variety of indications including the treatment of neuropathic pain, Generalized Anxiety disorder, osteoarthritis, and stress incontinence. Duloxetine continues to be investigated for the treatment of pain in cancer, surgery, and more.

Duloxetine is a serotonin norepinephrine reuptake inhibitor used to treat generalized anxiety disorder, neuropathic pain, osteoarthritis, and stress incontinence.

Indicated for:

1) Management of Major Depressive Disorder.

2) Management of Generalized Anxiety Disorder.

3) Management of diabetic peripheral neuropathy.

4) Management of fibromyalgia.

5) Management of chronic musculoskeletal pain.

6) Management of osteoarthritis of the knee in adults.

7) Management of chronic lower back pain in adults.

8) Management of stress urinary incontinence in adult women.

Off-label uses include:

1) Management of chemotherapy-induced peripheral neuropathy.

2) Management of stress urinary incontinence in adult men after prostatectomy until recovery is complete.

• 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)

Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf's nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter. This enhanced signaling allows for stronger contraction. Increased contraction of this sphincter increases the pressure needed to produce an incontinence episode in stress urinary incontinence. Duloxetine has been shown to improve Patient Global Impression of Improvement and Incontinence Quality of Life scores. It has also been shown to reduce the median incontinence episode frequency at doses of 40 and 80 mg.

Action at the dorsal horn of the spinal cord allows duloxetine to strengthen the the serotonergic and adrenergic pathways involved in descending inhibition of pain. This results in an increased threshold of activation necessary to transmit painful stimuli to the brain and effective relief of pain, particularly in neuropathic pain. Pain relief has been noted in a variety of painful conditions including diabetic peripheral neuropathy, fibromyalgia, and osteoarthritis using a range of pain assessment surveys.

While duloxetine has been shown to be effective in both animal models of mood disorders and in clinical trials for the treatment of these disorders in humans, the broad scope of its pharmacodynamic effects on mood regulation in the brain has yet to be explained.

Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling.

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.

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.

Duloxetine'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.

Duloxetine 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.}

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

Over 90% bound to plasma proteins, primarily albumin and α1 acid-glycoprotein.

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.

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

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.

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.

• 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.

• Starting Dose: 40 mg/day to 60 mg/day
• Target Dose: Acute: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance: 60 mg/day
• Maximum Dose: 120 mg/day

• Starting Dose: 60 mg/day
• Target Dose: 60 mg/day (once daily)
• Maximum Dose: 120 mg/day

• Starting Dose: 60 mg/day
• Target Dose: 60 mg/day (once daily)
• Maximum Dose: 60 mg/day

• Starting Dose: 30 mg/day
• Target Dose: 60 mg/day (once daily)
• Maximum Dose: 60 mg/day

• Starting Dose: 30 mg/day
• Target Dose: 60 mg/day (once daily)
• Maximum Dose: 60 mg/day