A-Z Drug Facts > Duloxetine Hydrochloride

Duloxetine Hydrochloride

Pronunciation: (doo-LOX-e-teen HYE-droe-KLOR-ide)
Class: Serotonin and norepinephrine reuptake inhibitor

Trade Names:
Cymbalta
- Capsules, delayed-release 20 mg
- Capsules, delayed-release 30 mg
- Capsules, delayed-release 60 mg

Pharmacology

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

Pharmacokinetics

Absorption

Well absorbed. C _max occurs 6 h postdose. Steady state reached after 3 days.

Distribution

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

Metabolism

Hepatic metabolism by CYP1A2 and CYP2D6 to numerous metabolites.

Elimination

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

Special Populations

Smoking status

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

Indications and Usage

Diabetic peripheral neuropathic pain; fibromyalgia; generalized anxiety disorder; major depressive disorder.

Unlabeled Uses

Stress urinary incontinence.

Contraindications

Uncontrolled narrow-angle glaucoma; MAOI therapy; hypersensitivity to any component of product.

Dosage and Administration

Diabetic Peripheral Neuropathic Pain
Adults

PO 60 mg once daily without regard to meals.

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.

Generalized Anxiety Disorder
Adults

PO Start with 30 or 60 mg once daily without regard to meals. 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 (max, 120 mg once daily). There is no evidence that dosages of more than 60 mg once daily confer additional benefit.

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) without regard to meals.

General Advice

• Advise patient to swallow capsule whole and not to crush, chew, or open capsule.
• Assess patients with major depressive disorder 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 months.

Storage/Stability

Store at controlled room temperature (59° to 86°F).

Drug Interactions

Alcohol

Not recommended with substantial alcohol use.

Aspirin, NSAIDs, warfarin

Risk of bleeding may be increased.

Beta-blockers (eg, metoprolol, propranolol)

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

CNS-active drugs

Use with caution because of possible additive effects.

Drugs affecting gastric acidity

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 significant effect on the rate or extent of duloxetine absorption.

Drugs highly bound to plasma proteins

Plasma concentrations of these drugs may be increased, potentially resulting in adverse reactions.

Drugs with a narrow therapeutic index and extensively metabolized by CYP2D6 (eg, amitriptyline, desipramine, flecainide, imipramine, nortriptyline, phenothiazines, propafenone)

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

Food

Food delays the T _max from 6 to 10 h and decreases the extent of absorption 10%. The C _max is not affected. However, duloxetine may be taken without regard to meal.

Inhibitors of CYP1A2 (eg, cimetidine, fluvoxamine, some quinolone antibiotics), inhibitors of CYP2D6 (eg, fluoxetine, paroxetine, quinidine)

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

MAOIs (eg, isocarboxazid)

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.

Serotonergic drugs (eg, 5-HT ₁ agonists [eg, sumatriptan], linezolid, lithium, St. John's wort, sympathomimetics [eg, amphetamine], tramadol, tryptophan)

Risk of serotonin syndrome may be increased.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hot flush (3%); palpitations (2%); MI (0.1% to 1%); hypertensive crisis, supraventricular arrhythmia (postmarketing).

CNS

Somnolence (21%); headache (20%); dizziness (17%); insomnia (16%); fatigue (15%); decreased appetite (11%); asthenia (8%); agitation (6%); tremor (5%); decreased libido (4%); abnormal dreams, anxiety, dysgeusia, migraine, pyrexia, sleep disorder (3%); yawning (2%); hypoesthesia, lethargy, vertigo (at least 1%); aggression, anger, extrapyramidal disorder, hallucinations, trismus (postmarketing).

Dermatologic

Hyperhidrosis (8%); rash (4%); pruritus (3%); erythema multiforme, Stevens-Johnson syndrome, urticaria (postmarketing).

EENT

Nasopharyngitis (9%); pharyngolaryngeal pain (6%); blurred vision (3%); glaucoma, tinnitus (postmarketing).

GI

Nausea (30%); dry mouth (18%); constipation (15%); diarrhea (13%); vomiting (6%); dyspepsia (5%); loose stools (3%); flatulence (at least 1%).

Genitourinary

Erectile dysfunction, pollakiuria (5%); ejaculation disorder (4%); abnormal orgasm, delayed ejaculation (3%); penis disorder (2%); anorgasmia (at least 1%).

Hypersensitivity

Anaphylactic reaction, angioneurotic edema, hypersensitivity (postmarketing).

Metabolic-Nutritional

Anorexia (5%); decreased weight, increased weight (2%); hyperglycemia (postmarketing).

Musculoskeletal

Muscle cramps, musculoskeletal pain (5%); muscle spasm, myalgia (4%); trismus (postmarketing).

Respiratory

Upper respiratory tract infection (7%); cough (6%).

Miscellaneous

Seasonal allergy (3%); chill/fever (at least 1%).

Precautions

Warnings Antidepressants increased the risk of suicidal thinking and behavior in short-term studies in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders. Closely observe 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 for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of therapy and when increasing or decreasing the dose. 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.

Elderly

No dosage adjustment is recommended for elderly patients; use with caution.

Renal Function

Not recommend for patients with end-stage renal disease or severe renal function impairment (CrCl less than 30 mL/min).

Hepatic Function

Significantly increased exposure to duloxetine occurs in patients with hepatic function impairment; 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.

Abnormal bleeding

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

Blood pressure

Elevations in BP may occur.

Discontinuation of therapy

A gradual reduction in dose, rather than abrupt discontinuation of therapy, is recommended in order to minimize discontinuation symptoms (eg, dizziness, headache, nightmares, paresthesia).

Glycemic control

May worsen glycemic control in some patients with diabetes.

Hepatotoxicity

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

Hyponatremia

Hyponatremia and SIADH have been reported and appear to be reversible when duloxetine is discontinued. Cholestatic jaundice and elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis.

Mania/Hypomania

May be activated.

Orthostatic hypotension and syncope

May occur with therapeutic doses.

Seizures

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

Serotonin syndrome

Life-threatening serotonin syndrome may occur, particularly with coadministration of serotonergic drugs.

Suicide

Monitor depressed patients at risk 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 patient information leaflet 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 being treated for depression, 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 take 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 depressants 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.
• Advise 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.

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