Yelate

Yelate Uses, Dosage, Side Effects, Food Interaction and all others data.

Yelate is a combined serotonin (5-HT) and noradrenaline (NE) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors. Yelate dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas of animals.

Yelate, 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. Yelate 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.

Trade Name Yelate
Availability Prescription only
Generic Duloxetine
Duloxetine Other Names (S)-duloxetine, Duloxetina, Duloxetine
Related Drugs Rexulti, Buprenex, Subutex, aspirin, prednisone, ibuprofen, sertraline, tramadol, trazodone, escitalopram
Type
Formula C18H19NOS
Weight Average: 297.415
Monoisotopic: 297.118734925
Protein binding

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

Groups Approved
Therapeutic Class Serotonin-norepinephrine reuptake inhibitor (SNRI)
Manufacturer
Available Country South Africa
Last Updated: September 19, 2023 at 7:00 am
Yelate
Yelate

Uses

Yelate 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.

Yelate 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 Yelate works

Yelate is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Yelate 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 Gq 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-HT1A, 5-HT1B, 5-HT1D, 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 Gi/Go 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.

Yelate'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 Gq coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction.

Dosage

Yelate 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 Yelate 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 Yelate -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

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

CNS medicinal products: Caution is advised when Yelate 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.

Yelate 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.

Yelate 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.

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

Yelate 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.

Volume of Distribution

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

Elimination Route

Yelate 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, Yelate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

Contraindication

Yelate 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 Yelate overdose in humans. There is no specific antidote to Yelate. 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 Yelate from the gastrointestinal tract.

Storage Condition

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

Innovators Monograph

You find simplified version here Yelate

Yelate contains Duloxetine see full prescribing information from innovator Yelate Monograph, Yelate MSDS, Yelate FDA label

FAQ

What is Yelate used for?

Yelate is used to treat depression and anxiety. It's also used to treat nerve pain, such as fibromyalgia, and can be used to treat stress urinary incontinence in women. Yelate comes as capsules and is only available on prescription. Yelate is also a medication used to neuropathic pain.

How safe is Yelate?

Generally, Yelate is safe and well-tolerated across indications, with few reported serious side effects. Common adverse events are consistent with the pharmacology of the molecule and are mainly referable to the gastrointestinal and the nervous systems.

How does Yelate work?

Yelate work by increasing the amount of mood-enhancing chemicals serotonin and noradrenaline in the brain.

What are the common side effects of Yelate?

Common side effects include feeling sick, a dry mouth, headache, constipation and feeling sleepy.

Is Yelate safe during pregnancy?

In general, it appears that the use of Yelate during pregnancy is associated with an increase in the risk of spontaneous abortion, but no increase in other adverse outcomes, such as major fetal malformations. Exposure to Yelate during pregnancy is unlikely to meaningfully increase the risk of congenital malformations overall, preterm birth, or pre-eclampsia.

Is Yelate safe during breastfeeding?

Yelate can be safely administered to a woman who is breastfeeding her infant.

Can I drink alcohol with Yelate?

Yelate may cause liver damage, and taking it with alcohol may increase that risk. You should avoid or limit the use of alcohol while being treated with Yelate.

Can I drive after taking Yelate?

You shouldn't drive, use heavy machinery, or do other dangerous activities until you know how it affects you.

When should be taken of Yelate?

It is best to take Yelate at the same time each day. Most people take it in the morning. If you find that you feel drowsy after taking it in the morning, try taking it in the evening.

How often should I take Yelate ?

Yelate is usually taken 1 or 2 times per day with or without food.

How long does Yelate take to work?

Yelate normally takes 2 to 4 weeks to work.

How long does Yelate stay in my system?

Once the last dosage of Yelate has been taken, it can take up to two and a half days to leave the body almost completely. However, 50 percent of the Yelate will have left the body within approximately 12 hours, with a range between 8 and 17 hours.

How long can I take Yelate?

Most doctors recommend that you take antidepressants for 6 months to a year after you no longer feel depressed or anxious.

Can I take Yelate for long time?

Yes, Yelate is safe to take for a long time.

Who should not take Yelate?

You should not use duloxetine if you are allergic to it. Do not take Yelate within 5 days before or 14 days after you have used an MAO inhibitor, such as isocarboxazid, linezolid, methylene blue injection, phenelzine, or tranylcypromine. A dangerous drug interaction could occur.

What happens if I miss a dose?

Take the Yelate as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

What happens if I overdose of Yelate ?

Seek emergency medical attention. Overdose symptoms may include vomiting, dizziness or drowsiness, seizures, fast heartbeats, fainting, or coma.

What happen If I stop taking Yelate?

Stopping Yelate abruptly may result in one or more of the following withdrawal symptoms: irritability, nausea, feeling dizzy, vomiting, nightmares, headache, and/or paresthesias (prickling, tingling sensation on the skin). Depression is also a part of bipolar illness.

Is Yelate safe for heart patients?

Yelate does not appear to be associated with significant cardiovascular risks in patients with conditions for which the drug has been approved or studied.

Can Yelate slow my heart rate?

These data demonstrate that duloxetine has modest effects on heart rate and BP and no clinically meaningful effect on electrocardiogram profiles in a relatively healthy cohort of clinical trial patients.

Can Yelate affects my kidney?

Kidney problems were very rarely reported in clinical trials and in everyday clinical experience. There was no indication in clinical trials that the risk of kidney failure was higher in Yelate-treated patients than in placebo- treated patients.

Is Yelate harmful to kidneys?

Yelate should not damage your kidney function with Stage 3 chronic kidney disease.

Can Yelate affects my liver?

Yelate can also induce liver injury in cases without those risk factors. We recommend that clinicians should monitor liver function carefully following Yelate treatment.

Does Yelate cause infertility?

The current study indicates that Yelate administered at a dose of 60 mg does not have an impact on sperm quality.

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