Nausea, somnolence , insomnia, and dizziness are the main side effects, reported by about 10 to 20 percent of patients. In a trial for mild major depressive disorder MDD , the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea Duloxetine and other SSRIs have been shown to cause sexual side effects in some patients, both males and females. Although usually reversible, these sexual side effects can sometimes last for months, years, or longer, even after the drug has been completely withdrawn.
Antidepressants may cause the amount of sodium in the blood to drop — a condition called hyponatraemia. This can cause symptoms such as drowsiness, confusion, muscle twitching, and convulsions. Elderly people may be particularly susceptible to this effect. There may also be an increased risk in people with cirrhosis and those who are dehydrated or taking diuretic medicines.
Anyone who develops any of these symptoms while taking this medicine should consult their doctor so that their blood sodium level can be checked if necessary. Duloxetine as Cymbalta comes with suicide risk warning for children and adolescents under Since duloxetine is a newer drug FDA approved in , peer-reviewed articles have been published on its adverse effects, and the effects of long-term use are still unknown.
Reported adverse events which were temporally correlated to Cymbalta therapy include rash, reported rarely, and the following adverse events, reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema , aspartate aminotransferase increased, bilirubin increased, glaucoma , hepatitis , hyponatremia , jaundice , orthostatic hypotension especially at the initiation of treatment , Stevens-Johnson syndrome , syncope especially at initiation of treatment , and urticaria.
During marketing of other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances e. Although these events are generally self-limiting, some have been reported to be severe.
This withdrawal phenomenon is known as the SSRI discontinuation syndrome. Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose, rather than abrupt cessation, is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
Many patients on the drug longer than the nine weeks of Lilly's discontinuation test trials anecdotally report evidence of serious withdrawals from Cymbalta, lasting from weeks to many months. All adult and pediatric patients being treated with duloxetine for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially when decreasing the dose.
A study by Bymaster and colleagues found that duloxetine inhibited binding to the human norephinepherine NE and serotonin 5-HT transporters with K i values of 7. Venlafaxine inhibited binding to the human NE and 5-HT transporters with K i values of and 82 nM, respectively, and with a K i ratio of Thus, duloxetine more potently blocks serotonin and norephinepherine transporters in vitro and in vivo than venlafaxine , [22] arguably making it the most potent of all commercially available SNRIs.
Duloxetine and venlafaxine have not been measured against milnacipran. Milnacipran is not yet available in the United States.
Duloxetine received a second FDA approval a month after it was approved for depression when it also became the first FDA-approved treatment for pain caused by diabetic peripheral neuropathy on September 7, At 20mg per day Cymbalta showed no clinical improvement over placebo.
At 60mg per day Cymblata showed modest improvement for diabetic pain over baseline, with 51 percent of patients treated with Cymbalta reporting at least a 30 percent sustained reduction in pain. In comparison, 31 percent of patients treated with placebo reported this magnitude of sustained pain reduction.
At 60mg per day In November , Eli Lilly and Company and Boehringer Ingelheim , a German pharmaceutical company, signed a long-term agreement jointly to develop and commercialize duloxetine hydrochloride. In a 9,person trial of duloxetine for the treatment of SUI in women, eleven suicide attempts and three cases of suicidal ideation were reported. The trials — including year-old Traci Johnson [27] and four other patients who committed suicide during Lilly trials for duloxetine — were cleared by the FDA, stating that underlying depression — not the drug — causes sufferers to become suicidal.
Johnson was in a Lilly trial testing duloxetine as Yentreve, a urinary stress incontinence medication, and not in an anti-depressant trial. In light of suicide risks, some critics claim that the FDA approval of duloxetine for MDD and diabetic neuropathy is irresponsible. On the other hand, the number of participants in the SUI studies was large, and trials of duloxetine for MDD and diabetic neuropathy showed no increase in suicidality.
At the time of its release in , duloxetine was by far the most promising medicine in Eli Lilly's pipeline. With Cymbalta's patents set to expire on June 11, , Lilly says it is working on at least two new antidepressants to ensure its place in the SSRI antidepressant market. Eli Lilly originally patented duloxetine on June 11, , and has asked the U. Patent and Trademark Office for an extension on the exclusivity of the chemical compound beyond to June 11, with an official patent extension application on January 5, As of Feb.
Approximately 6. On October 19 , Eli Lilly issued a press release saying they had done trials which found that Cymbalta, at 60 mg once or twice daily, significantly reduced pain in more than half of women treated for fibromyalgia FM , with and without major depression, according to week data presented at the annual meeting of the American College of Rheumatology.
Critics argue that randomized controlled trials of FM are difficult due to factors such as a lack of understanding of the pathophysiology and a heterogeneous FM patient population. In the study testing the efficacy of Cymbalta for FM, participants completed several questionnaires to measure the amount of pain and discomfort the disease caused them at the beginning of the study, and then at the end of each of the first two weeks and every second week for the remaining 12 weeks of the study.
Researchers also tested the participants for depression. Women who took Cymbalta had significantly less pain and discomfort than those who took the placebo. For men, who made up only 11 percent of the study, there was no effect from taking the medication compared with a placebo. Reportedly, depression played no part in whether or not the drug worked to control pain. The change in the level of women's pain was particularly pronounced after a month of taking the drug, then leveled off a bit before dropping again near the end of the study.
The federal agency said it would approve the drug once "manufacturing issues" had been sorted out, as Lilly had quality-control problems at two plants at the time.
Eli Lilly and Company and Quintiles began co-promoting Lilly's new treatment for Cymbalta after it received regulatory approval in August Through its contract sales organization, Innovex, Quintiles has provided more than sales representatives to help Lilly's substantial sales force promote Cymbalta in the United States for five years.
In exchange, Quintiles stands to earn 8. Yentreve and Ariclaim are produced by Boehringer Ingelheim and Eli Lilly and Company in a joint licensing agreement made in In Japan, duloxetine has been jointly developed with the pharmaceutical company Shionogi Ltd. As of January , Shionogi had already received approval for the indication of depression, but is still conducting additional Phase III trials.
For the treatment of pain related to diabetic peripheral neuropathy, Shionogi said it and Eli Lilly Japan K. For this use, the drug is now going through Phase II clinical trials. Each capsule of duloxetine contains enteric-coated pellets of These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. The recommended dose for diabetic peripheral neuropathic pain is 60 mg once daily. When serotonin and norepinephrine are released from nerve cells in the brain they act to "lighten mood".
When they are reabsorbed into the nerve cells, they no longer have an effect on mood. It is thought that when depression occurs, there may be a decreased amount of serotonin and norepinephrine released from nerve cells in the brain. Duloxetine works by preventing serotonin, norepinephrine, and to a lesser extent dopamine , from being reabsorbed back into the nerve cells in the brain, specifically on the 5-HT and NE and D2 receptors respectively.
This helps prolong the "mood lightening" effect of any released serotonin and norepinephrine. In this way, duloxetine is thought to help relieve depression. Serotonin and norepinephrine in the brain and spinal cord are believed to both mediate core depression symptoms and help regulate the perception of pain.
Based on pre-clinical studies, duloxetine is a balanced and potent reuptake inhibitor of serotonin and norepinephrine. While the mechanism of action of duloxetine is not fully known, scientists believe its effect on both emotional symptoms and pain perception is due to increasing the activity of serotonin and norepinephrine in the central nervous system. It may take between two to four weeks for the benefits of this medicine to appear, so the manufacturer suggests it is very important that you keep taking it, even if it doesn't seem to make much difference at first.
They go on to state that if the patient feels that the depression has gotten worse, has any of the listed side effects, or any distressing thoughts or feelings in these first few weeks, then they should talk to their prescribing doctor.
Duloxetine is also used to treat nerve pain in the feet, legs or hands that is due to nerve damage caused by poorly controlled diabetes. Duloxetine is thought to enhance the nerve signals within the central nervous system that naturally inhibit pain. Duloxetine is not effective for the numbness or tingling, nor is it effective for the other complications of diabetes. It does not treat the underlying nerve damage, but can help reduce the pain. Cymbalta is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
Concomitant use in patients taking monoamine oxidase inhibitors MAOIs is contraindicated. In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma.
Given the primary CNS effects of Cymbalta, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action. Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Just because a side effect is stated here, it does not mean that all people using this medicine will experience that or any side effect.
Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10 to 20 percent of patients. In a trial for mild major depressive disorder MDD , the most commonly reported treatment-emergent adverse events among duloxetine-treated patients were nausea Duloxetine and other SSRIs have been shown to cause sexual side effects in some patients, both males and females.
Although usually reversible, these sexual side effects can sometimes last for months, years or possibly indefinitely even after the drug has been completely withdrawn. Antidepressants may cause the amount of sodium in the blood to drop - a condition called hyponatraemia. This can cause symptoms such as drowsiness, confusion, muscle twitching or convulsions. Elderly people may be particularly susceptible to this effect. There may also be an increased risk in people with liver cirrhosis and those who are dehydrated or taking diuretic medicines.
You should consult your doctor if you develop any of these symptoms while taking this medicine so that your blood sodium level can be checked if necessary. Since duloxetine is a newer drug FDA-approval , not many peer-reviewed articles have been published on its adverse effects and effect of long term use is still unknown.
More than 40 different types of adverse effects have been reported, including completed suicide attempts and severe hepatic disorders.
Adverse events reported since market introduction that were temporally related to Cymbalta therapy include rash reported rarely and the following adverse events reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, glaucoma , hepatitis , hyponatremia, jaundice , orthostatic hypotension especially at the initiation of treatment , Stevens-Johnson syndrome , syncope especially at initiation of treatment , and urticaria.
During marketing of other SSRIs and SNRIs serotonin and norepinephrine reuptake inhibitors , there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt.
Although these events are generally self-limiting, some have been reported to be severe. This withdrawal phenomenon is known as the SSRI discontinuation syndrome.
The manufacturer of Cymbalta, Eli Lilly, warns that one should not suddenly stop taking this medicine, as this may cause withdrawal symptoms such as dizziness, pins and needles sensations, nausea, difficulty sleeping, intense dreams, headache, tremor, agitation or anxiety. Withdrawal symptoms are temporary and are not the same as addiction. Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta.
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. That leaves Ratner wondering how much higher Lilly could have boosted Cymbalta's sales if its patent had a few more years to run.
How Lilly will replace Cymbalta's lost billions is a critical question. Not that the challenge is anything new for Lilly. Zyprexa was next, with its patent expiration; that's wiped billions from Lilly's revenue picture.
Next year, another major seller, the osteoporosis treatment Evista, loses U. It also slapped a salary freeze on most of its 40,person work force. The company's also poured resources into its remaining products, trying to squeeze as much sales as it can get from the cancer compound Alimta, its generic-resistant bio-engineered insulins Humulin and Humalog, and a handful of other key products. And Lilly has focused on hurrying as many new compounds as it can into its drug-development pipeline.
It's brimming now with a dozen potential medicines awaiting regulatory approval or in the final stage of clinical studies, plus 26 more in phase 2 human testing. The nearly 40 compounds are five times more than Lilly had in mid- or late-stage development in Longtime Goldman Sachs drug stock analyst Jami Rubin is less optimistic. Goldman downgraded Lilly stock this fall to sell from neutral, writing, "We don't think Lilly has gone far enough to address its upcoming challenges from patent expirations.
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