Drug Name

Cymbalta (Duloxetine)

Generic Name

Duloxetine (du LOX e teen)

Looks like

Duloxetine is available with a prescription generically and under the brand name Cymbalta. Other brand or generic formulations may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

• Cymbalta 20 mg - green capsules
• Cymbalta 30 mg - white/blue capsules
• Cymbalta 60 mg - green/blue capsules

Dosage Form

Capsule

Route Of Administration

ORAL

Imprint Code

LILLY;3235;20;mg / LILLY;3240;30;mg / LILLY;3237;60;mg

Size

15mm / 16mm / 20mm

Alternatives

Pain
Tramadol, Naprosyn (Naproxen), Aleve (Naproxen)
Anxiety
Lexapro (Escitalopram), Tenormin (Atenolol)
Depression
Lexapro (Escitalopram), Zoloft (Sertraline), Prozac (Fluoxetine), Celexa (Citalopram)

Drug Uses

Duloxetine is used to treat major depressive disorder and general anxiety disorder. It is also used to treat pain caused by nerve damage in people with diabetes (diabetic neuropathy).

Drug class

Duloxetine is an antidepressant in a group of drugs called selective serotonin and norepinephrine reuptake inhibitors (SSNRIs). Duloxetine affects chemicals in the brain that may become unbalanced and cause depression.

Contains

Each capsule contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients include FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow.

Chemical formula

Cymbalta (duloxetine hydrochloride) is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+) - (S) - N - methyl - y - (1 - naphthyloxy) - 2 - thiophenepropylamine hydrochloride. The empirical formula is C18H19NOS*HCl, which corresponds to a molecular weight of 333.88. Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water.

Mechanism of Action

Although the exact mechanisms of the antidepressant and central pain inhibitory action of duloxetine in humans are unknown, the antidepressant and pain inhibitory actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO). Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.

How Taken

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Your doctor may occasionally change your dose to make sure you get the best results from the medication.

Try to take the medicine at the same time each day. Follow the directions on your prescription label.

Do not crush, chew, break, or open a delayed-release capsule. Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking or opening the pill would cause too much of the drug to be released at one time. It may take 4 weeks or longer for your symptoms to improve. For best results, keep using the medication as directed. Do not stop using Cymbalta without first talking to your doctor. You may have unpleasant side effects if you stop taking this medication suddenly. Store Cymbalta at room temperature away from moisture and heat.

Dosage and Administration

Initial Treatment
Major Depressive Disorder
Cymbalta should be administered at a total dose of 40 mg/day (given as 20 mg BID) to 60 mg/day (given either once a day or as 30 mg BID) without regard to meals.

There is no evidence that doses greater than 60 mg/day confer any additional benefits.

Diabetic Peripheral Neuropathic Pain
Cymbalta should be administered at a total dose of 60 mg/day given once a day, without regard to meals.

While a 120 mg/day dose was shown to be safe and effective, there is no evidence that doses higher than 60 mg confer additional significant benefit, and the higher dose is clearly less well tolerated. For patients for whom tolerability is a concern, a lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment.

Maintenance/Continuation/Extended Treatment
Major Depressive Disorder
It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. There is insufficient evidence available to answer the question of how long a patient should continue to be treated with Cymbalta. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.

Diabetic Peripheral Neuropathic Pain
As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Cymbalta must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials, but a one-year open-label safety study was conducted.

Special Populations
Dosage for Renally Impaired Patients- Cymbalta is not recommended for patients with end-stage renal disease (requiring dialysis) or in severe renal impairment (estimated creatinine clearance <30 mL/min).

Dosage for Hepatically Impaired Patients- It is recommended that Cymbalta not be administered to patients with any hepatic insufficiency.

Dosage for Elderly Patients- No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose.

Treatment of Pregnant Women During the Third Trimester- Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. When treating pregnant women with Cymbalta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Cymbalta in the third trimester.

Dosage for Nursing Mothers- Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics.

Discontinuing Cymbalta
Symptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended 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.

Switching Patients to or from a Monoamine Oxidase Inhibitor
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI.

Missed Dose

Take the missed dose as soon as you remember. However, if it is almost time for the next regularly scheduled dose, skip the missed dose and take the next one as directed. Do not take extra medicine to make up the missed dose.

Overdose

Seek emergency medical attention if you think you have taken too much of this medication. Overdose symptoms may include nausea, vomiting, diarrhea, agitation, confusion, hallucinations, fast heart rate, feeling light-headed, or fainting.

Storage

Store Cymbalta at room temperature away from moisture and heat.

How Supplied

Cymbalta (duloxetine hydrochloride) Delayed-release Capsules are available in 20, 30, and 60 mg strengths.

The 20 mg capsule has an opaque green body and cap, and is imprinted with "20 mg" on the body and "LILLY 3235" on the cap:
NDC 0002-3235-60 (PU3235) - Bottles of 60
NDC 0002-3235-33 (PU3235) - (ID2100) Blisters

The 30 mg capsule has an opaque white body and opaque blue cap, and is imprinted with "30 mg" on the body and "LILLY 3240" on the cap:
NDC 0002-3240-30 (PU3240) - Bottles of 30
NDC 0002-3240-90 (PU3240) - Bottles of 90
NDC 0002-3240-04 (PU3240) - Bottles of 1000
NDC 0002-3240-33 (PU3240) - (ID2100) Blisters

The 60 mg capsule has an opaque green body and opaque blue cap, and is imprinted with "60 mg" on the body and "LILLY 3237" on the cap:
NDC 0002-3237-30 (PU3237) - Bottles of 30
NDC 0002-3237-90 (PU3237) - Bottles of 90
NDC 0002-3237-04 (PU3237) - Bottles of 1000
NDC 0002-3237-33 (PU3237) - (ID2100) Blisters

What is the most important information I should know about Cymbalta (Duloxetine)?

Do not take Cymbalta together with thioridazine (Mellaril), or a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate). You must wait at least 14 days after stopping an MAOI before you can take Cymbalta. After you stop taking Cymbalta, you must wait at least 5 days before you start taking an MAOI.
You may have thoughts about suicide when you first start taking an antidepressant, especially if you are younger than 24 years old. Your doctor will need to check you at regular visits for at least the first 12 weeks of treatment.

Call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself. Avoid drinking alcohol while taking Cymbalta. Alcohol may increase the risk of damage to your liver. Cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by Cymbalta. Tell your doctor if you regularly use any of these other medicines. Cymbalta can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

What should I discuss with my doctor before taking Cymbalta (Duloxetine)?

Do not use Cymbalta together with thioridazine (Mellaril), or an MAO inhibitor such as isocarboxazid (Marplan), tranylcypromine (Parnate), phenelzine (Nardil), rasagiline (Azilect), or selegiline (Eldepryl, Emsam). Serious and sometimes fatal reactions can occur when these medicines are taken with Cymbalta. You must wait at least 14 days after stopping an MAO inhibitor before you can take Cymbalta. After you stop taking Cymbalta, you must wait at least 5 days before you start taking an MAOI. Do not use this medication if you are allergic to duloxetine, or if you have untreated or uncontrolled glaucoma.
Before taking Cymbalta, tell your doctor if you are allergic to any drugs, or if you have:

• liver or kidney disease;
• seizures or epilepsy;
• bipolar disorder (manic depression); or
• a history of drug abuse or suicidal thoughts.

If you have any of these conditions, you may need a dose adjustment or special tests to safely take Cymbalta.

You may have thoughts about suicide when you first start taking an antidepressant, especially if you are younger than 24 years old. Tell your doctor if you have worsening symptoms of depression or suicidal thoughts during the first several weeks of treatment, or whenever your dose is changed.

Your family or other caregivers should also be alert to changes in your mood or symptoms. Your doctor will need to check you at regular visits for at least the first 12 weeks of treatment.

FDA pregnancy category C. Cymbalta may be harmful to an unborn baby, and may cause problems in a newborn baby if the mother takes the medication late in pregnancy (during the third trimester). Tell your doctor if you are pregnant or plan to become pregnant during treatment. Cymbalta can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Older adults may be more sensitive to the side effects of this medication.

Do not give Cymbalta to anyone younger than 18 years old without the advice of a doctor.

Absorption and Distribution

Orally administered duloxetine hydrochloride is well absorbed. There is a median 2-hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. There is a 3-hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.

The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and a1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.

Metabolism and Elimination

Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP2D6 and CYP1A2 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces.

Special Populations

Gender

Duloxetine's half-life is similar in men and women. Dosage adjustment based on gender is not necessary.

Age

The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the patient is not necessary.

Smoking Status

Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.

Race

No specific pharmacokinetic study was conducted to investigate the effects of race.

Renal Insufficiency

Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60-mg dose of duloxetine, Cmax and AUC values were approximately 100% greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. For this reason, Cymbalta is not recommended for patients with end-stage renal disease (requiring dialysis) or severe renal impairment (estimated creatinine clearance [CrCl]<30 mL/min). Population PK analyses suggest that mild to moderate degrees of renal dysfunction (estimated CrCl 30-80 mL/min) have no significant effect on duloxetine apparent clearance.

Hepatic Insufficiency

Patients with clinically evident hepatic insufficiency have decreased duloxetine metabolism and elimination. After a single 20-mg dose of Cymbalta, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer. It is recommended that duloxetine not be administered to patients with any hepatic insufficiency.

Nursing Mothers

The disposition of duloxetine was studied in 6 lactating women who were at least 12-weeks postpartum. Duloxetine 40 mg BID was given for 3.5 days. Like many other drugs, duloxetine is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 ug/day while on 40 mg BID dosing. Lactation did not influence duloxetine pharmacokinetics. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics.

Possible side effects

Get emergency medical help if you have any of these signs of an allergic reaction: skin rash or hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Call your doctor at once if you have any of these serious side effects:

• nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• restlessness, overactive reflexes, hallucinations, loss of coordination, fainting, coma; or
• nausea, vomiting, diarrhea, fever, and fast heartbeat.

Less serious side effects may include:

• constipation;
• drowsiness, dizziness, headache;
• sleep problems (insomnia);
• weight changes;
• feeling anxious or nervous, increased sweating;
• sore throat; or
• decreased sex drive, impotence, or difficulty having an orgasm.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect.

What other drugs will affect Cymbalta (Duloxetine)?

Before taking Cymbalta, tell your doctor if you are using any of the following medicines:

• cimetidine (Tagamet);
• linezolid (Zyvox);
• lithium (Lithobid, Eskalith);
• St. John's wort;
• tramadol (Ultram);
• tryptophan (sometimes called L-tryptophan);
• almotriptan (Axert), frovatriptan (Frova), sumatriptan (Imitrex), naratriptan (Amerge), rizatriptan (Maxalt), or zolmitriptan (Zomig); or
• any other antidepressants such as amitriptyline (Elavil), amoxapine (Ascendin), clomipramine (Anafranil), desipramine (Norpramin), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), imipramine (Janimine, Tofranil), nortriptyline (Pamelor), paroxetine (Paxil), protriptyline (Vivactil), sertraline (Zoloft), trimipramine (Surmontil), or venlafaxine (Effexor).

This list is not complete and there may be other drugs that can interact with Cymbalta. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

What should I avoid while taking Cymbalta (Duloxetine)?

Avoid drinking alcohol while taking Cymbalta. Alcohol may increase the risk of damage to your liver. Cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by Cymbalta. Tell your doctor if you regularly use any of these other medicines. Cymbalta can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Contraindications

Hypersensitivity
Cymbalta is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.

Monoamine Oxidase Inhibitors
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated.

Uncontrolled Narrow-Angle Glaucoma
n clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma.

Warnings

Clinical Worsening and Suicide Risk- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders.

Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults.

All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.

Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms.

Families and caregivers of pediatric