Pregabid D

Uses

Duloxetine 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.

Pregabalin is used for the management of neuropathic pain associated with diabetic peripheral neuropathy and management of post-herpetic neuralgia. It is also used for the adjunctive therapy for adult patients with partial onset seizures. It can be used for the management of fibromyalgia and neuropathic pain associated with spinal cord injury.

Pregabid D 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)Diabetic Peripheral Neuropathic Pain (DPN), Epilepsies, Fibromyalgia, Generalized Anxiety Disorder (GAD), Neuropathic Pain, Partial-Onset Seizures, Peripheral Neuropathic Pain, Peripheral neuropathy, Postherpetic Neuralgia

How Pregabid D works

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.

Although the mechanism of action has not been fully elucidated, studies involving structurally related drugs suggest that presynaptic binding of pregabalin to voltage-gated calcium channels is key to the antiseizure and antinociceptive effects observed in animal models.

By binding presynaptically to the alpha2-delta subunit of voltage-gated calcium channels in the central nervous system, pregabalin modulates the release of several excitatory neurotransmitters including glutamate, substance-P, norepinephrine, and calcitonin gene related peptide. In addition, pregabalin prevents the alpha2-delta subunit from being trafficked from the dorsal root ganglia to the spinal dorsal horn, which may also contribute to the mechanism of action.

Although pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA or benzodiazepine receptors.

Dosage

Pregabid D 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).

Neuropathic pain associated with diabetic peripheral neuropathy: The maximum recommended dose of Pregabalin is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Dosing should begin at 50 mg three times a day (150 mg/day) and may be increased to 300 mg/day within 1 week based on efficacy and tolerability.

Post-herpetic neuralgia: The recommended dose of Pregabalin is 75 to 150 mg two times a day, or 50 to 100 mg three times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Dosing should begin at 75 mg two times a day, or 50 mg three times a day (150 mg/day) and may be increased to 300 mg/day within 1 week based on efficacy and tolerability.

Adjunctive therapy for adult patients with partial onset seizures: Pregabalin at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults. The total daily doseshould be divided and given either two or three times daily. In general, it is recommended that patients be started on a total daily dose no greater than 150 mg/day (75 mg two times a day, or 50 mg three times a day). Based on individual patient response and tolerability, the dose may be increased to a maximum dose of 600 mg/day.

Management of Fibromyalgia: The recommended dose of Pregabalin for fibromyalgia is 300 to 450 mg/day. Dosing should begin at 75 mg two times a day (150 mg/day) and may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day).

Neuropathic pain associated with spinal cord injury: The recommended dose range is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability.

.Patients who do not experience sufficient pain relief after treatment with 300 mg/day and who tolerate pregabalin may be treated with up to 300 mg two times a day. Neurolin® capsules can be taken without regards to meals.

Side Effects

The most commonly observed adverse events in Duloxetine 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 Duloxetine -treated and placebo-treated patients.

The most common side effects include dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and abnormal thinking.

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.

In a systematic review that included 38 randomized controlled trials, there were 20 identified adverse effects that were significantly associated with pregabalin, most of which involve the central nervous system and cognition. The identified adverse effects include vertigo, dizziness, balance disorder, incoordination, ataxia, blurred vision, diplopia, amblyopia, somnolence, confusional state, tremor, disturbance in attention, abnormal thinking, asthenia, fatigue, euphoria, edema, peripheral edema, dry mouth, and constipation .

The most common symptoms of pregabalin toxicity (dose range includes 800 mg/day and single doses up to 11,500 mg) include somnolence, confusion, restlessness, agitation, depression, affective disorder and seizures.

Since there is no antidote for pregabalin overdose, patients should receive general supportive care. If appropriate, gastric lavage or emesis may help eliminate unabsorbed pregabalin (healthcare providers should take standard precautions to maintain the airway).

Pregabalin pharmacokinetic properties suggest that extra-corporeal elimination methods including haemodialysis, may be useful in situations of severe toxicity. However, there are cases where patients have presented with very high serum levels of pregabalin and have been successfully managed with supportive care alone.

Precaution

Duloxetine 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.

Discontinuation of Pregabalin without tapering may produce insomnia, nausea, headache and diarrhea. So it should be tapered gradually over a minimum of 1 week rather than discontinued abruptly. Creatinine kinase may be elevated if treated with Pregabalin. It should be discontinued rapidly if myopathy is diagnosed or suspected or if creatinine kinase is elevated markedly.

Interaction

Monoamine oxidase inhibitors (MAOIs): Due to the risk of serotonin 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 an MAOI.

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

CNS medicinal products: Caution is advised when Duloxetine 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).

Volume of Distribution

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.

After oral administration of pregabalin, the reported apparent volume of distribution is roughly 0.5 L/kg.

Although pregabalin is not very lipophilic, it is able to cross the blood brain barrier(BBB). System L transporters facilitate the transport of large amino acids across the BBB and it has been confirmed that pregabalin is a substrate. This information suggests that system L transporters are responsible for pregabalin uptake into the BBB.

In rat models, pregabalin has been shown to cross the placenta.

Elimination Route

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.}

After oral dosing administered in the fasted state, pregabalin absorption is rapid, and extensive. Pregabalin oral bioavailability is reported to be ≥90% regardless of the dose. Cmax is attained within 1.5 hours after single or multiple doses, and steady state is attained within 24-48 hours with repeated administration. Both Cmax and AUC appear to be dose proportional.

Food decreases the rate of pregabalin absorption and as a result, lowers the Cmax by an estimated 25-30% and increases the Tmax to approximately 3 hours. However, the effect of food does not appear to impact the total absorption of pregabalin in a way that is clinically relevant. As a result, pregabalin can be administered with or without food.

Half Life

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

The elimination half life of pregabalin is 6.3 hours.

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.

In young healthy subjects the mean renal clearance is estimated to be 67.0 to 80.9 mL mL/min. Given pregabalin's lack of plasma protein binding, this clearance rate suggests that renal tubular reabsorption is involved.

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.

Pregabalin is almost exclusively eliminated in the urine.

Further, based on preclinical studies, pregabalin does not appear to undergo racemization to the R enantiomer in the body.

Pregnancy & Breastfeeding use

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

Labor and Delivery: The effect of Duloxetine on labor and delivery in humans is unknown. Duloxetine 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 Duloxetine and/or it's metabolites are excreted into human milk, but nursing while on Duloxetine is not recommended.

Pregnancy category C. So it should only used if potential benefit justifies the potential risks to the fetus.

Nursing mother: It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. So it should be used in nursing mother only if there is a clear benefit over the risk.

Contraindication

Duloxetine 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.

Pregabalin is contraindicated in patients with known hypersensitivity to Pregabalin or any of its components.

Special Warning

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

Use in children & adolescents: The safety and effectiveness of Pregabalin have not been established in patients below the age of 18 years.

Use in elderly (Over 65 years of age): No dosage adjustment is necessary in elderly patients. Overdose: In overdoses up to 15 g, no unexpected adverse effects were reported.

Paediatric use: The safety and efficacy of pregabalin in paediatric patients have not been established.

Acute Overdose

There is limited clinical experience with Duloxetine overdose in humans. There is no specific antidote to Duloxetine. 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.

Storage Condition

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

Store at a cool & dry place, protected from light and moisture. Keep out of reach of the children.

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