Duloxetine Hydrochloride

Pronunciation

Pronunciation: doo-LOX-e-teen HYE-droe-KLOR-ide
Class: SNRI

Trade Names

Cymbalta
- Capsules, delayed-release, oral 20 mg
- Capsules, delayed-release, oral 30 mg
- Capsules, delayed-release, oral 60 mg

Pharmacology

Unknown; however, potentiation of serotonergic and noradrenergic activity in the CNS is suspected.

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Pharmacokinetics

Absorption

Well absorbed. C max occurs 6 h postdose. Steady state reached after 3 days. Food delays T max from 6 to 10 h and decreases AUC 10%.

Distribution

Vd is approximately 1,640 L. Protein binding is more than 90%.

Metabolism

Extensive hepatic metabolism by CYP1A2 and CYP2D6 to numerous metabolites.

Elimination

Elimination half-life is approximately 12 h. Less than 1% is excreted unchanged in urine. Of the administered dose, 70% appears in urine as metabolites and 20% in feces.

Special Populations

Renal Function Impairment

C max and AUC were approximately 100% greater in patients with ESRD receiving intermittent hemodialysis than in subjects with healthy renal function. Mild to moderate renal impairment has no significant effect on duloxetine Cl.

Hepatic Function Impairment

Metabolism and elimination of duloxetine were decreased in patients with clinically evident hepatic impairment.

Elderly

AUC was 25% higher and half-life was 4 h longer in elderly women; dosage adjustment not necessary.

Gender

Half-life of duloxetine is similar in men and women; no dosage adjustment based on gender is needed.

Smoking status

Duloxetine bioavailability is reduced by approximately 33% in smokers; dosage adjustments are not recommended.

Indications and Usage

Chronic musculoskeletal pain; diabetic peripheral neuropathic pain; fibromyalgia; generalized anxiety disorder; major depressive disorder (MDD).

Unlabeled Uses

Stress urinary incontinence.

Contraindications

Uncontrolled narrow-angle glaucoma; MAOI therapy.

Dosage and Administration

Chronic Musculoskeletal Pain
Adults

PO Start with 30 mg daily for 1 wk. The dosage may be increased to 60 mg once daily after 1 wk. There is no evidence that dosages of more than 60 mg daily confer additional benefit.

Diabetic Peripheral Neuropathic Pain
Adults

PO 60 mg once daily. A lower starting dose may be considered for patients in whom tolerability is a concern.

Fibromyalgia
Adults

PO Start with 30 mg once daily for 1 wk. The dosage may be increased to 60 mg once daily after 1 wk. Some patients may respond to the starting dose.

Generalized Anxiety Disorder
Adults

PO Start with 30 or 60 mg once daily. If the starting dosage is 30 mg once daily, the dosage may be increased to 60 mg once daily after 1 wk. Additional dosage increases should be in increments of 30 mg once daily. There is no evidence that dosages of more than 60 mg once daily confer additional benefit. The safety of dosages greater than 120 mg once daily have not been adequately evaluated.

Major Depressive Disorder
Adults

PO 40 mg daily (given as 20 mg twice daily) to 60 mg daily (given once daily or as 30 mg twice daily). It may be desirable to start at 30 mg once daily for 1 wk before increasing to 60 mg once daily.

Renal Function Impairment

Use a lower starting dose and increase gradually; not recommended in patients with ESRD or CrCl less than 30 mL/min.

Hepatic Function Impairment

Do not administer.

Pregnancy

Consider tapering duloxetine in the third trimester.

General Advice

  • Advise patient to take duloxetine without regard to meals.
  • Advise patient to swallow capsule whole and not to crush, chew, or open capsule.
  • Assess patients with MDD periodically to determine the need for maintenance treatment and appropriateness of dose.
  • Efficacy of duloxetine in the treatment of generalized anxiety disorder beyond 10 wk has not been studied. Periodically evaluate patients for long-term usefulness of the drug.
  • Efficacy of duloxetine in the management of diabetic peripheral neuropathic pain has not been evaluated beyond 12 wk.
  • Efficacy of duloxetine in the management of fibromyalgia has not been evaluated beyond 3 mo.
  • A gradual reduction in dose, rather than abrupt discontinuation of therapy, is recommended in order to minimize discontinuation symptoms (eg, dizziness, headache, nightmares, paresthesia).

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Alcohol

Not recommended with substantial alcohol use.

Aspirin, NSAIDs, warfarin

Risk of bleeding may be increased. Caution patients of the increased risk of bleeding. Closely monitor warfarin therapy and adjust the dose as needed.

Beta-blockers (eg, metoprolol, propranolol)

Increased risk of excessive beta-blockade (eg, bradycardia). Monitor cardiac function.

CNS-active drugs (eg, narcotic analgesics)

Use with caution because of possible additive effects.

Drugs affecting gastric acidity

Use with caution. Because duloxetine is enteric-coated, drugs that raise GI pH may lead to earlier release of duloxetine; however, aluminum- and magnesium-containing antacids and famotidine have no clinically important effect on the rate or extent of duloxetine absorption.

Drugs highly bound to plasma proteins (eg, phenytoin)

Plasma concentrations of these drugs may be increased, potentially resulting in adverse reactions. Closely monitor the patient response and adjust treatment as needed.

Drugs with a narrow therapeutic index and extensively metabolized by CYP2D6 (eg, flecainide, phenothiazines [eg, thioridazine], propafenone, tricyclic antidepressants [eg, desipramine])

Plasma concentrations of these agents may be elevated, increasing the risk of adverse reactions. Coadminister with caution. Avoid thioridazine because of possible serious ventricular arrhythmias and sudden death resulting from elevated plasma levels.

Inhibitors of CYP1A2 (eg, cimetidine, fluvoxamine, some quinolone antibiotics [eg, ciprofloxacin])

Duloxetine plasma levels may be elevated, increasing the risk of adverse reactions. Avoid coadministration.

Inhibitors of CYP2D6 (eg, fluoxetine, paroxetine, quinidine, terbinafine)

Duloxetine plasma levels may be elevated, increasing the risk of adverse reactions. Monitor the clinical response and adjust the duloxetine dose as needed.

Linezolid

Coadministration may result in serotonin syndrome. Because linezolid has MAOI activity, allow at least 2 wk between stopping linezolid and starting duloxetine.

MAOIs (eg, isocarboxazid, rasagiline, selegiline)

Concurrent use with duloxetine is contraindicated. It is recommended that duloxetine not be used with an MAOI or within 14 days of discontinuing treatment with an MAOI. Allow at least 5 days after stopping duloxetine before starting an MAOI.

Methylene blue

Risk of neurologic adverse reactions, including serotonin syndrome, may be increased. Avoid concurrent use.

Serotonergic drugs (eg, cyclobenzaprine, lithium, other SNRIs, SSRIs, St. John's wort, sympathomimetics [eg, amphetamine], tramadol, tryptophan)

Risk of serotonin syndrome may be increased. Coadministration is not recommended.

Triptans (eg, sumatriptan)

Risk of serotonin syndrome may be increased. Closely monitor the clinical response, particularly during initiation and dose increases. Serotonin syndrome requires immediate medical attention, including supportive care and withdrawal of the serotonergic agent. Administration of an antiserotonergic agent (eg, cyproheptadine) may be helpful.

Adverse Reactions

Cardiovascular

Flushing (3%); hot flush, palpitations (2%); MI, orthostatic hypotension, peripheral coldness, tachycardia (0.1% to 1%); hypertensive crisis, supraventricular arrhythmia (postmarketing).

CNS

Headache (14%); somnolence (12%); fatigue (11%); dizziness, insomnia (10%); agitation (5%); decreased libido (4%); anxiety, tremor (3%); abnormal dreams, paresthesia (2%); chills/rigors, dysgeusia, lethargy, parathesia/hypesthesia, sleep disorder (at least 1%); aggression, anger, extrapyramidal disorder, hallucinations, restless leg syndrome, seizures upon treatment discontinuation, trismus (postmarketing).

Dermatologic

Hyperhidrosis (7%); rash (4%); pruritus (3%); erythema multiforme, Stevens-Johnson syndrome, urticaria (postmarketing).

EENT

Nasopharyngitis (5%); blurred vision (3%); oropharyngeal pain (2%); vertigo (at least 1%); glaucoma (postmarketing).

GI

Nausea (25%); dry mouth (15%); constipation, diarrhea (10%); decreased appetite (9%); abdominal pain (6%); vomiting (5%); dyspepsia (2%); flatulence (at least 1%).

Genitourinary

Erectile dysfunction (5%) abnormal orgasm, delayed ejaculation (3%); ejaculation disorder (2%); anorgasmia (at least 1%); gynecological bleeding (postmarketing).

Hypersensitivity

Anaphylactic reaction, angioneurotic edema, hypersensitivity (postmarketing).

Metabolic-Nutritional

Decreased weight (2%); weight increased (at least 1%); hyperglycemia (postmarketing).

Musculoskeletal

Musculoskeletal pain (4%); muscle spasm (3%).

Respiratory

Upper respiratory tract infection (4%); cough, influenza (3%); yawning (2%).

Precautions

Warnings

Antidepressants increased the risk of suicidal thinking and behavior in short-term studies in children, adolescents, and young adults with MDD and other psychiatric disorders. Closely observe all patients who are started on therapy for clinical worsening, suicidality, or unusual changes in behavior.


Monitor

Monitor BP before starting therapy and periodically during prolonged treatment. Monitor all patients for the emergence of agitation, clinical worsening, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of therapy and when increasing or decreasing the dose. Monitor for the emergence of serotonin syndrome or NMS-like signs and symptoms. Monitor for possible sexual adverse reactions.


Pregnancy

Category C . Neonates exposed to duloxetine late in the third trimester may develop complications requiring prolonged hospitalization, respiratory support, and tube feeding.

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established. Duloxetine is not approved for use in children.

Elderly

Use with caution; duloxetine has been associated with cases of clinically significant hyponatremia in elderly patients.

Renal Function

Not recommend for patients with ESRD or severe renal impairment (CrCl less than 30 mL/min).

Hepatic Function

Do not administer duloxetine to these patients.

Special Risk Patients

Use with caution in patients with controlled narrow-angle glaucoma or conditions that may slow gastric emptying (eg, diabetes).

Hazardous Tasks

May impair judgement, motor skills, or thinking.

Abnormal bleeding

Bleeding events, ranging from ecchymosis, epistaxis, hematoma, life-threatening hemorrhage, and petechiae, have been reported. Aspirin, NSAIDs, and warfarin may add to this risk.

Blood pressure

Elevations in BP may occur.

Glycemic control

May worsen glycemic control in some patients with diabetes.

Hepatotoxicity

Hepatic failure, sometimes fatal, presenting as hepatitis with abdominal pain, elevated transaminase levels with or without jaundice, and hepatomegaly, has been reported.

Hyponatremia

Use with caution in elderly patients, volume-depleted patients, and patients taking diuretics. Hyponatremia and SIADH have been reported and appear to be reversible when duloxetine is discontinued.

Mania/Hypomania

May be activated.

Orthostatic hypotension and syncope

May occur with therapeutic doses.

Screening for bipolar disorder

Screen patients with depression for risk of bipolar disorder prior to initiating therapy.

Seizures

Seizures have been reported in a small number of patients; use with caution in patients with history of seizures.

Serotonin syndrome/NMS-like reaction

Life-threatening serotonin syndrome or NMS-like reactions may occur, particularly with coadministration of serotonergic drugs.

Suicide

Monitor depressed patients at risk of suicide during initial therapy. Prescribe smallest quantity consistent with good patient management in order to reduce risk of overdose.

Urinary hesitation and retention

May occur.

Overdosage

Symptoms

Coma, death, hypertension, hypotension, seizures, serotonin syndrome, somnolence, syncope, tachycardia, vomiting.

Patient Information

  • Advise patient to read the Medication Guide before starting therapy and with each refill.
  • Advise patient to take prescribed dose without regard to meals, but to take with food if stomach upset occurs.
  • Advise patient to swallow capsule whole, and not to crush or chew the capsule. Caution patient not to open capsule and sprinkle contents on food or mix with liquids.
  • Inform patient that it may take 1 to 4 wk to note improvement in symptoms and to continue with prescribed therapy once improvement has been noted.
  • Instruct patient to notify health care provider if symptoms do not appear to be getting better or are getting worse, or if bothersome adverse reactions (eg, changes in sexual function, diarrhea, drowsiness, headache, insomnia, nausea, nervousness, unusual sweating) occur.
  • Advise patient and family or caregiver of patient to be alert for abnormal changes in mood or thinking and to immediately report any of the following symptoms to health care provider: agitation, anxiety, hostility or aggressiveness, impulsivity, irritability, panic attacks, or suicidal thoughts or behavior.
  • Instruct patient in BP and pulse measurement skills.
  • Advise patient to periodically monitor and record BP and pulse at home and to inform health care provider if abnormal measurements are noted. Also, advise patient to bring record of BP and pulse to each follow-up visit.
  • Advise patient that if medication needs to be discontinued, it will be slowly withdrawn unless safety concerns (eg, rash) require a more rapid withdrawal.
  • Advise patient to take frequent sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
  • Advise patient to avoid other antidepressants while taking duloxetine.
  • Advise patient that drug may impair judgment, thinking, or motor skills, or cause drowsiness or dizziness, and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.
  • Caution patient about the concomitant use of duloxetine and NSAIDs, aspirin, or warfarin because this combination is associated with an increased risk of bleeding.
  • Advise patient to avoid alcoholic beverages because of increased risk of severe liver injury.

Copyright © 2009 Wolters Kluwer Health.

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