What is Duloxetine

Duloxetine (brand name: Cymbalta) is an antidepressant - selective serotonin reuptake and norepinephrine inhibitor. It is used in the treatment of depression and peripheral neuropathic pain in adults.

Mechanism of action

Duloxetine is a reuptake inhibitor of serotonin (5-HT) and noradrenaline (NA). It weakly inhibits dopamine reuptake, but shows no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors. Duloxetine increases dose-dependently extra cellular levels of serotonin and noradrenaline in various brain areas of animals. Duloxetine normalizes pain thresholds in several preclinical models of neuropathic and inflammatory pain and attenuated pain behavior in a model of persistent pain. This effect is explained by the inhibitory action on pain of duloxetine as a result of potentiation of descending inhibitory pain tracts in the central nervous system.


Pharmacokinetics

After administration of an oral dose, duloxetine is well absorbed, reaching peak plasma concentration at 6 hours after dosing. The absolute oral bioavailability of duloxetine ranges between 32% and 80%. The presence of food in the digestive tract delays the time to peak concentration of 6-10 hours and slightly (11%) reduces the degree of absorption. These changes have no clinical significance.

Duloxetine is approximately 96% bound to plasma proteins, including albumin and alpha-1 acid glycoprotein. Protein binding is not affected by hepatic or renal impairment. Duloxetine is extensively metabolised by the hepatic cytochrome P450 enzymes and metabolites are primarily excreted in the urine. Both CYP2D6 and CYP1A2 catalyze the formation of the two major inactive metabolites glucuronide conjugate of 4-hydroxy duloxetine and sulphate conjugate of 5-hydroxy-6-methoxy duloxetine.

The elimination half-life of duloxetine after an oral dose ranges from 8 to 17 hours (mean 12 hours). After an intravenous dose the plasma clearance of duloxetine ranges from 22 l / hr to 46 l / hr (mean of 36 l / hr). After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l / hr (mean 101 l / hr).

Although pharmacokinetic differences have been identified between males and females (apparent plasma clearance is approximately 50% lower in females), from the point of view clinical this difference does not justify the need for dose reduction in women.

Renal impairment:

patients with end-stage renal disease (ESRD) patients receiving dialysis had Cmax and AUC twice higher than healthy subjects duloxetine. Pharmacokinetic data on duloxetine is limited in patients with renal impairment from mild to moderate.

Hepatic impairment:

moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of duloxetine. Compared with healthy subjects, the apparent plasma clearance of duloxetine was 79% lower, the apparent terminal half-life was 2.3 times higher and the AUC was 3.7 times higher in patients with moderate hepatic impairment.

Toxicity:

Duloxetine is not genotoxic, mutagenic or carcinogenic according to the standard tests. In the carcinogenicity study in rats multinucleated cells in the liver with no other histopathologic changes were observed. The underlying mechanism and the clinical relevance is unknown. Female mice receiving duloxetine for 2 years had an increased incidence of hepatocellular adenomas and only the highest dose (144 mg / kg / day) carcinomas, but were considered secondary to the induction of hepatic microsomal enzymes. The relevance of these findings in mice may have on humans is unknown.

In studies of peri- and postnatal toxicity, female rats treated with duloxetine (45 mg / kg / day) before and during mating and in the first stage of gestation showed a decrease in food consumption and in the maternal body weight, oestrous cycle disruption, decreased number of live births decreased offspring survival and growth retardation of the offspring. In a developmental toxicity study in rabbits, a higher incidence of cardiovascular and skeletal malformations at lower doses than usual at maximum clinical, but other studies they gave negative results are observed.


Indications and dosing

Diabetic peripheral neuropathic pain

Oral administration:

Adults: the initial dose and recommended maintenance dose is 60 mg once a day with or without food. However they have been used in dosages up to maximum 120 mg per day. Plasma concentrations of duloxetine show great interindividual variability so some patients that respond insufficiently to 60 mg may benefit from a higher dose.

The response to treatment should be evaluated after two months. In patients with inadequate initial response, it is unlikely that additional response after this period of time occurs.

The therapeutic benefit should be reassessed regularly (at least every 3 months). Duloxetine treatment should not be withdrawn abruptly but the dose should be reduced gradually.

Elderly: No adjustments are recommended dosage for elderly patients solely on the basis of age, only caution is recommended when treating these patients

Children: The safety and efficacy of duloxetine has not been evaluated in this group.

Hepatic impairment: Administration of duloxetine in patients with liver disease is not recommended.

Renal impairment:

Mild or moderate (creatinine clearance of 30-80 ml / min) renal impairment are not required dose reductions.

Severe renal impairment (creatinine clearance <30 ml / min): administration of duloxetine is not recommended.

General anxiety disorder

Oral administration:

Adults: Duloxetine should be administered at a total dose of 40 mg / day (20 mg twice daily) to 60 mg / day (once a day or 30 mg twice daily) with or without food. There is no evidence that the above 60 mg / day confer additional benefit.

Acute episodes of major depression require several months or more of continuous drug treatment. There is no sufficient evidence to indicate how long a patient should continue treatment with duloxetine. Patients should be periodically evaluated to determine the need for maintenance treatment and the appropriate dose for the same.

Elderly: The same dose as adults, although caution is recommended.

Treatment of fibromyalgia

Oral administration:

Adults: the doses used in several clinical studies have been 60 mg 2 times a day, although there have come to use 40 mg four times a day. Although still insufficient, the data support the conclusion that duloxetine at doses of 60 and 120 mg / day are effective in the treatment of fibromyalgia.

Treatment of stress incontinence:

Oral administration:

Adults: The recommended dose of 40 mg twice daily and 60 mg twice daily.


Contraindications and Precautions

Duloxetine is contraindicated in patients with hypersensitivity to the active substance or any of the components of the formulation.

There have been reported symptoms associated with abrupt discontinuation of duloxetine (and other inhibitors of serotonin reuptake). Whenever possible, it is recommended that a gradual reduction in the dose rather than an abrupt interruption. If intolerable symptoms occur after dose reduction or discontinuation of treatment, consider resuming the previously prescribed dose. Then, the physician may continue decreasing the dose at a more gradual pace.

Must be at least 14 days elapse between discontinuation of an MAOI and initiation of treatment with duloxetine. They must spend at least five days after stopping Cymbalta before starting an MAOI.

Duloxetine is contraindicated in patients with liver disease resulting in hepatic impairment.

Duloxetine should not be used in combination with CYP1A2 inhibitors, like fluvoxamine, ciprofloxacin or enoxacin since the combination results in elevated plasma concentrations of duloxetine.

The initiation of treatment with duloxetine is contraindicated in patients with uncontrolled hypertension because this could cause a hypertensive crisis patients.

Duloxetine should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and / or seizures.

There have been reports of mydriasis in association with duloxetine, therefore, caution should be used when prescribing duloxetine in patients with high or patients at risk of acute narrow-angle glaucoma intraocular pressure.

There have been reports of suicidal ideation and behavior during treatment with duloxetine or shortly after discontinuation, particularly when used in the treatment of anxiety. Physicians should advise patients to report their thoughts or feelings of anxiety or depressive symptoms at any time.

There are no adequate data on the use of duloxetine in pregnant women. Studies in some species of animals have shown reproductive toxicity at systemic exposure levels (AUC) of lower than the maximum clinical exposure levels of duloxetine.

The potential risk for humans is unknown. As with other serotoninergic drugs, discontinuation symptoms may occur in the neonate after maternal duloxetine shortly before delivery. Duloxetine should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Women should inform their physician if they become pregnant or intend to become pregnant during treatment.

Duloxetine is very weakly excreted into human breast milk. The estimated infant in mg / kg daily dose is approximately 0.14% of the dose consumed by the mother. As the safety of duloxetine in infants is not known, the use of this drug during breast feeding is not recommended.

Although there have been no studies on the effects on the ability to drive and use machines, administration of duloxetine may be associated with sedation and dizziness. Therefore, patients should be instructed that if they experience sedation or dizziness they should avoid the performance of potentially hazardous tasks such as driving or operating machinery.


Drug interaction

Using Duloxetine in combination with other antidepressants, especially with inhibitors of serotonin reuptake and selective reversible monoamine oxidase inhibitors (MAOIs) is not recommended.

Caution should be exercised when Duloxetine is co-administered with drugs that inhibit CYP1A2.

Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered at a dose of 60 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the area under the curve (AUC) of desipramine increased three times. Co-administration of duloxetine (40 mg twice daily) increases the area under the curve (AUC) in the equilibrium state of tolterodine (2 mg twice daily) by 71% but does not affect the pharmacokinetics of its active metabolite 5-hydroxy and dose adjustment is not recommended.

Caution is advised if duloxetine is administered with drugs that are predominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants such as nortriptyline, amitriptyline and imipramine) particularly if they have a narrow therapeutic index (such as flecainide, propafenone and metoprolol).

Inducing drugs reduce the CYP12Ade the plasma concentrations of duloxetine. Pharmacokinetic studies in smokers have shown that these subjects are lower than nonsmokers plasma concentrations of duloxetine almost 50%.

Although not systematically evaluated Duloxetine combinations with other drugs acting on the CNS, caution is advised when the drug is administered with other drugs or centrally acting substances including alcohol and sedative drugs (benzodiazepines, morphinomimetics, antipsychotics, phenobarbital and sedating) antihistamines.

Caution should be exercised when duloxetine is combined with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction.

There are also reports that Duloxetine increases in INR values when Duloxetine is co-administered to patients treated with warfarin.

Rarely, there have been reports of serotonin syndrome in patients treated concomitantly with SSRIs (eg paroxetine, fluoxetine) concomitantly with serotonergic drugs. Caution is advised if duloxetine is used concomitantly with serotonergic antidepressants like SSRIs, tricyclics like clomipramine or amitriptyline.

Adverse reactions may be more frequent if Duloxetine is used in combination with herbal preparations containing St. John's wort or St. John's Wort (Hypericum perforatum).


Side effects

Approximately 10% of the 1139 patients who were given duloxetine in placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% of the 777 patients who received placebo. Nausea (duloxetine 1.4%, placebo 0.1%) was the only adverse event considered related to the drug that caused discontinuation. Other adverse reactions were:

Gastrointestinal disorders:
  • nausea 20%
  • dry mouth 15%
  • constipation 11%
  • diarrhea 8%
  • vomiting 5%
Metabolism and nutrition disorders:
  • appetite decreased 8%
  • weight loss 2%
General disorders:
  • fatigue 8%
Nervous system disorders:
  • dizziness 9%
  • drowsiness 7%
  • tremors 3%
Disorders of the skin and subcutaneous tissue:
  • increased perspiration 6%
Vascular disorders:
  • heat stroke (hot flushes) 2%
Eye disorders:
  • blurred Vision 4%
Psychiatric disorders:
  • insomnia 11%
  • anxiety 3%
Cardiovascular disorders:
  • increases in blood pressure by an average of 2 mm Hg systolic and diastolic 0.5 mm Hg compared with the placebo group, and an increase in the incidence of at least one measurement greater than 140 mm Hg systolic blood pressure. Alterations testing laboratory have been reported small increases in mean values with respect to the baseline in ALT, AST, alkaline phosphatase, CPK and liver enzymes.
Disorders related to sexuality have been reported:
  • abnormal orgasm (men 4%, women 2%)
  • ejaculatory dysfunction: men 3%
  • eecreased libido: men 6%, women 1%
  • ED (Erectile Dysfunction): men 4%
  • delayed ejaculation: men 3%

Duloxetine is in a class of drugs with a known effect on the resistance of the urethra. If symptoms of urinary retention develop during treatment with duloxetine, consider who might be drug-related.

There have been fatal cases of acute overdoses, particularly overdoses with mixed but also duloxetine alone, with as low as 1.000 mg. Signs and symptoms of overdose (duloxetine alone or with other drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.

There is no specific antidote for Duloxetine but if serotonin syndrome ensues, it can be considered a specific treatment (such cyproheptadine and / or temperature control). In case of acute overdose, treatment should consist of those general measures employed in the treatment of any drug overdose.

Should ensure adequate airway, oxygenation and ventilation and vital signs and cardiac rhythm should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate protection of air, may be indicated if performed soon after ingestion or in symptomatic patients.

Activated charcoal may be useful in limiting duloxetine absorption in the gastrointestinal tract. The administration of activated charcoal decreases the AUC and Cmax third, although in some subjects activated carbon had a limited effect. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be beneficial.

In the management of overdose, the possibility of multiple drugs should be considered. particulate whether the subject has eaten a tricyclic antidepressant. In this case, decreased clearance of antidepressant and / or its active metabolite may increase the possibility of clinically significant sequelae whichever extend the time needed medical observation.