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Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10% to 20% 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 (34.7%), dry mouth (22.7%), headache (20.0%) and dizziness (18.7%), and except for headache, these were reported significantly more often than in the placebo group:

Other side-effects include:

Orthostatic hypotension
Fatigue
Vivid nightmares
Increased sweating
Decreased appetite and weight loss
Blurred vision
Paresthesia
Disturbances of the gastrointestinal tract, such as nausea, constipation, diarrhea, indigestion, vomiting and profuse bleeding
Tremor
Anxiety, nervousness, agitation
Palpitations
Decreased sex drive or difficulty achieving orgasm
Impotence or delayed ejaculation
Hot flashes
Taste disturbances
Difficulty passing urine
Increase in blood pressure or heart rate
Cold hands or feet
Jaundice
Inflammation of the liver or hepatitis leading to cirrhosis if left unchecked.
Depersonalization
Hypomania
Weight gain or loss

Duloxetine and 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these sexual side effects can sometimes last for months, years, or longer, even after the drug has been completely withdrawn. This disorder is known as post-SSRI sexual dysfunction.

Postmarketing spontaneous reports

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.

A number of more serious complications, in which duloxetine may have played a role, has been published in the form of case reports:

The Los Angeles County Department of Coroner released a report of the first post mortem studies of duloxetine; they identified twelve cases in which duloxetine was present on toxicologic analysis, but in no case was it deemed to be the ultimate cause of death. Five cases were declared multiple drug intoxication, and two were declared suicide.
A case of hyponatremia induced by duloxetine was reported by doctors at Weill Cornell Medical College in New York. This is common to all SSRIs.
A case of dyskinesia during treatment with duloxetine was reported in Germany.
Two episodes of serotonin syndrome have been documented in the use of duloxetine in conjunction with other medications.
A case of fulminant hepatic failure involving duloxetine which resulted in death was reported by the Department of Internal Medicine, Ohio State University, Columbus, Ohio.
An attack of acute porphyria in a patient with known variegate porphyria who had been commenced on duloxetine.

Discontinuation syndrome

Further information: SSRI discontinuation syndrome

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.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. The withdrawal syndrome from duloxetine resembles the SSRI discontinuation syndrome.

When discontinuing treatment with Cymbalta, the manufacturer recommends a gradual reduction in the dose, rather than abrupt cessation, 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." This tapering process may be ineffective for some patients.

In MDD placebo-controlled clinical trials of up to nine weeks' duration, systematically evaluating discontinuation symptoms in patients taking duloxetine following abrupt discontinuation found the following symptoms occurring at a rate greater than or equal to 2% and at a significantly higher rate in Cymbalta-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, vomiting, irritability, and nightmare.

Suicidality

The FDA requires all antidepressants, including duloxetine, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the FDA experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group.

To obtain statistically significant results the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications. As suicidal ideation and behavior in clinical trials are rare, the results for any drug taken separately usually do not reach statistical significance. In line with the general results, duloxetine use in depressed adults insignificantly decreased the odds of suicidality by 12% or 20% depending of the statistical technique used. However, in the subgroup of young adults (18–24 years old) duloxetine increased the odds of suicidality 5-fold, close to statistical significance. There have been no trials of duloxetine in minors.

Several commentators noted that the data FDA used in their analysis of duloxetine-associated suicidality may have been incomplete. According to Arif Khan, the Summary Basis of Approval used by the FDA to approve duloxetine for depression contained only the mention of two completed suicides out of 3490 patients, and the rest of the data was not sufficient to "conduct any meaningful analysis." Jeanne Lenzer wrote in The Independent and Slate Magazine, and this fact was also confirmed by a Lilly spokesman, that another two completed suicides, which occurred in the depression studies ran by the Lilly's Japanese partner Shionogi, have not been reported to the FDA. According to Lenzer, four completed suicides also occurred in the trials of duloxetine for stress urinary incontinence (SUI). As these trials failed, the FDA initially insisted that any information about them is a commercial secret and cannot be released. Later, in a short statement the FDA acknowledged that in SUI trials eleven suicide attempts occurred in persons taking duloxetine vs none in the placebo group.

A series of four cases of duloxetine-associated suicidality has been reported. In all four cases depressed patients began having suicidal thoughts after starting on duloxetine or increasing its dose. These thoughts stopped, and the patients returned to normal after duloxetine was discontinued, and they were switched to another antidepressant.

A suicide of 19-year-old Traci Johnson, a healthy volunteer in a duloxetine clinical pharmacology study, was highly publicized. For about a month she had been given high doses of duloxetine, and then she was switched to placebo. Four days after the switch, she hanged herself with her scarf from a shower rod in the bathroom of Lilly Laboratory for Clinical Research. The New York Times article mentioned a withdrawal syndrome as a possible reason for this suicide.

Pharmacology

Pharmacodynamics

Although the exact mechanisms of the antidepressant and central pain inhibitory action of duloxetine in humans are unknown, they are believed to be related to its potentiation of serotonergic and noradrenergic activity in the central nervous system. Preclinical studies demonstrate that duloxetine potently inhibits neuronal serotonin and norepinephrine reuptake , and it has been demonstrated that this inhibition is balanced throughout the dosing range (when compared to venlafaxine in which the inhibition of noradrenaline is low at low doses and raises as the dose escalates).

It is also considered a less potent inhibitor of dopamine reuptake. However, duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors and can therefore be considered to be a selective reuptake inhibitor at the 5-HT and NA receptors. Duloxetine undergoes extensive metabolism, but the major circulating metabolites do not contribute significantly to the pharmacologic activity.

Pharmacokinetics

Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state is usually achieved after 3 days.

Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2.

When orally administered it is well absorbed. There is an average 2-hour lag until absorption begins with maximal plasma concentrations occurring about 6 hours post dose. Food does not affect the C_max of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours. Duloxetine is highly

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