Depression Symptoms Treatment

Drug Approvals

(British Approved Name Modified, US Adopted Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Adverse Effects and Treatment

Adverse effects reported most frequently with duloxetine include nausea, headache, insomnia, fatigue, somnolence, dry mouth, dizziness, and constipation. Other common adverse effects include anorexia, diarrhoea, dyspepsia, vomiting, anxiety, visual disturbances, tremor, weight gain or loss, sexual dysfunction, nervousness, lethargy, yawning, hot flushes, increased sweating, and pruritus. Dose-related increases in blood pressure have also been observed in some patients. Reports of reversible increases in liver enzymes, tachycardia, ecchymosis, urinary hesitation, skin rashes, and photosensitivity reactions are less common, and hepatitis, cholestaticjaundice, convulsions and activation of mania or hypomania have occurred rarely. Cases of orthostatic hypotension and syncope, serotonin syndrome, and akathisia have also been reported. Suicidal ideation may occur in some patients. Hyponatraemia, possibly due to inappropriate secretion of antidiuretic hormone, has been associated with the use of antidepressants, particularly in the elderly.

In the treatment of overdosage oral activated charcoal should be considered if more than 7.5 mg/kg of duloxetine has been ingested and the patient presents within 1 hour of ingestion this should be followed by symptomatic and supportive therapy. Dialysis, haemoperfusion, exchange perfusion, and measures to increase urine production are considered unlikely to be ofbenefit.

Precautions

Duloxetine should not be used in patients with hepatic or severe renal impairment and is contra-indicated in patients with uncontrolled narrow-angle glaucoma or hypertension. Patients with raised intra-ocular pressure or at risk of angle-closure glaucoma should be monitored closely. Blood pressure should also be monitored because of the risk of hypertension. Increases in fasting blood glucose and in total cholesterol have been reported in diabetic patients. It should be used with caution in patients with a history of seizures, of bleeding disorders, or of hypomania or mania.

Patients should be closely monitored during early anti-depressant therapy until significant improvement in depression is observed because suicide is an inherent risk in depressed patients. For further details, see under Depression. Suicidal thoughts and behaviour may also develop during early treatment with antidepressants for other disorders the same precautions observed when treating patients with depression should therefore be observed when treating patients with other disorders.

As with other antidepressants, duloxetine may impair performance of skilled tasks and, if affected, patients should not drive or operate machinery.

Symptoms reported when duloxetine therapy was stopped abruptly include headache, nausea, vomiting, dizziness, insomnia, anxiety, and paraesthesia. It is therefore recommended that duloxetine should be withdrawn gradually over at least 2 weeks after more than one week of therapy and the patient monitored to minimise the risk of withdrawal reactions.

Children. Duloxetine has not been studied for the treatment of depression in adolescents and children consequently its use in patients under 18 years of age is not generally recommended. In addition, other antidepressants have been shown to increase the risk of suicidal thoughts and behaviour in such patients (see Effects on the Mental State, under Fluoxetine).

Interactions

Duloxetine should not be used with MAOIs and at least 14 days should elapse between stopping an MAOI and starting treatment with duloxetine. At least 5 days should elapse between stopping duloxetine and starting any drug liable to provoke a serious reaction (e.g. phenelzine). The use of duloxetine with other antidepressants including the SSRIs, other serotonin and no-radrenaline reuptake inhibitors, and the reversible inhibitors of monoamine oxidase is not recommended. For further details, see Antidepressants under Interactions of Phenelzine.

Caution is advised when using duloxetine with other centrally acting drugs including alcohol and those with sedative properties.

Duloxetine is metabolised by the cytochrome P450 isoenzymes CYP1A2 and CYP2D6. It should not be given with potent inhibitors of CYP1A2 such as flu-voxamine, ciprofloxacin, and enoxacin as such combinations are likely to result in increased duloxetine concentrations. Similarly, caution is recommended when duloxetine is given with potent CYP2D6 inhibitors such as paroxetine. Duloxetine itself is also a moderate inhibitor of CYP2D6 and, consequently, licensed drug information recommends that it should be used cautiously with drugs that have a narrow therapeutic index and are extensively metabolised by this isoenzyme. In particular, use with thioridazine is contra-indicated because of the risk of serious ventricular arrhythmias and sudden death associated with raised thioridazine concentrations.

Duloxetine is highly protein bound and adverse effects may occur if given with other highly protein-bound drugs.

Antimigraine drugs. There have been rare reports of serotonin syndrome associated with the use of serotonin and noradrena-line reuptake inhibitors (SNRIs) with serotonin (5-HT1) agonists such as sumatriptan.

Pharmacokinetics

Duloxetine is well absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 6 hours after an oral dose. Food delays the time to reach peak concentrations to 10 hours. Protein binding is about 96%, primarily to albumin and alpha1-acid glycoprotein. Duloxetine is extensively metabolised by the cytochrome P450 isoenzymes CYP1A2 and CYP2D6 two major, but inactive, metabolites are formed, 4-hy-droxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. These and other metabolites are principally excreted in the urine about 20% is excreted in the faeces. Less than 1% of a dose is excreted in the urine as unchanged duloxetine. The elimination half-life of duloxetine is 8 to 17 hours with an average of about 12 hours. Duloxetine is distributed into breast milk.

Uses and Administration

Duloxetine hydrochloride is a serotonin and noradrenaline reuptake inhibitor (SNRI) (see Venlafaxine). It is given orally as the hydrochloride although doses are expressed in terms of the base duloxetine hydrochloride 22.5 mg is equivalent to about 20 mg of duloxetine.

Duloxetine is used in the treatment of depression in usual initial doses of 20 or 30 mg twice daily, or 60 mg once daily. A lower starting dose of 30 mg once daily for the first week may be suitable for some patients, to allow them to adjust to the effects of duloxetine before increasing the dose. A dose of 60 mg once daily may be used for maintenance therapy.

Duloxetine is also used in the treatment of generalised anxiety disorder, in a usual dose of 60 mg once daily. A lower starting dose of 30 mg daily for the first week may be considered in some patients, before increasing to 60 mg daily.

In the treatment of diabetic peripheral neuropathic pain the usual dose is 60 mg once daily. Some patients who respond insufficiently to this dose may benefit from up to 120 mg daily in divided doses. Response to therapy should be evaluated after 2 months and every 3 months thereafter.

Duloxetine is also used in the treatment of moderate to severe stress urinary incontinence in women. Usual initial doses are 40 mg twice daily however, some patients may benefit from an initial dose of 20 mg twice daily for 2 weeks before increasing to 40 mg twice daily.

For dosage in hepatic or renal impairment, see below.

Duloxetine should be withdrawn gradually to reduce the risk of withdrawal symptoms (see Precautions, above).

Administration in hepatic or renal impairment. Duloxetine should not be used in patients with hepatic impairment.

UK licensed product information for duloxetine states that no dosage adjustment is necessary in mild to moderate renal impairment (creatinine clearance 30 mL/minute or above). However, US information suggests that a lower starting dose and gradual dose increase may be warranted for patients, such as diabetics, with renal impairment. Both UK and US information recommend that duloxetine should not be used in more severe renal impairment (creatinine clearance less than 30 mL/minute).

Anxiety disorders. Duloxetine is used in the treatment of generalised anxiety disorder (see under Phobic Disorders). References.

Depression. As discussed, there is very little difference in efficacy between the different groups of antidepressant drugs, and choice is often made on the basis of adverse effect profile. SSRIs are widely used as an alternative to the older tricyclics as they have fewer adverse effects and are safer in overdos-age. Similar properties may also favour the use of serotonin and noradrenaline reuptake inhibitors such as duloxetine.

Micturition disorders. Duloxetine is used to increase urethral tone in the treatment of women with moderate to severe stress urinary incontinence. A systematic review concluded that duloxetine treatment reduced the frequency of incontinence episodes and significantly improved the patient’s quality of life however, it was unclear if these benefits were sustained. In addition, the review showed that adverse effects, particularly nausea, were common with duloxetine and led some patients to stop treatment.

Pain. Duloxetine is used in the treatment of diabetic peripheral neuropathic pain. It has also been tried with some success in fibromyalgia (see Soft-tissue Rheumatism), a condition that responds poorly to analgesics and anti-inflammatory drugs.

Proprietary Preparations

Argentina: Cymbalta Duxetin

Australia:: Cymbalta

Belgium: Cymbalta Yentreve

Brazil: Cymbalta

Chile: Cymbalta Yentreve

Czech Republic: Ariclaim Cymbalta Xeristar Yentreve

Denmark: Cymbalta Yentreve

Finland: Cymbalta Yentreve

France: Cymbalta Yentreve

Germany: Cymbalta Yentreve

Greece: Ariciaim Cymbalta Xeristar Yentreve

Hong Kong: Cymbalta

Hungary: Cymbalta

India: Delok

Indonesia: Cymbalta

Ireland: Cymbalta Yentreve

Israel: Cymbalta

Italy: Ariciaim Cymbalta Xeristar Yentreve

Malaysia: Cymbalta

Mexico: Cymbalta Yentreve

The Netherlands: Ariciaim Cymbalta Xeristar Yentreve

Norway: Cymbalta Yentreve

Philippines: Cymbalta

Portugal: Ariciaim Cymbalta Xeristar Yentreve

Russia: Cymbalta

South Africa: Cymbalta

Singapore Cymbalta

Spain: Cymbalta Xeristar

Sweden: Cymbalta Yentreve

UK: Cymbalta Yentreve

USA: Cymbalta