Duloxetine: Drug Whys


Generic Name: Duloxetine (no generic available, U.S. patent expires June, 2013)
Common U.S. Brand Names: Cymbalta (Eli Lilly and Company, USA)
Popularity: 39th most commonly prescribed drug between 2002 — 2009 (U.S.)
Class: Antidepressant, Serotonin/Norepinephrine Reuptake Inhibitor (SNRI)

Treatment Uses — For treatment of major depressive disorder. Treatment of pain associated with diabetic peripheral neuropathies, management of fibromyalgia, and for management of chronic musculoskeletal pain (i.e., chronic low back pain or osteoarthritis).

Effective for treatment of generalized anxiety disorder. Has been trialed in treatment of stress incontinence although patient discontinuation due to side effects (typically nausea associated with the higher doses required) was common.

Duloxetine is a SNRI which, as a class of antidepressants along with selective serotonin reuptake inhibitors (SSRIs), has all but replaced the much older class called tricyclic antidepressants (TCAs).

The major advantage is that SSRIs and SNRIs have a far less lethal overdose profile than TCAs. SNRIs, the more recent entrants to the market, claim to be more effective than SSRIs but in practice are indicated only for patients who have responded poorly to tricyclics or SSRIs.

The FDA added a Black Box warning (their highest level advisory) to duloxetine, stating, "Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders." Prescribers are cautioned to consider this risk.

Duloxetine is not approved for use in children; however it is often prescribed for adolescents and young adults. In the U.S., outpatient dispensing of any new or refill antidepressant prescriptions to children, adolescents and young adults must be accompanied by an FDA approved medication guide (see: www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/UCM096273).

Dosing and Administration — The recommended initial dose of duloxetine for adults with major depressive disorder is 40 to 60 milligrams daily, taken orally. This may be divided into twice daily doses (20 or 30 milligrams) or given in a single daily dose of 60 milligrams.

While daily doses exceeding 60 milligrams do not usually provide greater effectiveness, upwards titration can be done weekly by increasing the daily dose by 30 milligrams up to a maximum of 120 milligrams daily. For diabetic neuropathy, 60 milligrams daily is the starting and maintenance dose with consideration to smaller initial doses in patients with renal insufficiency.

For fibromyalgia, duloxetine should be started at 30 milligrams once daily for one week, and then increased to 60 milligrams once daily as tolerated. For generalized anxiety disorder, initial dosing is recommended at 30 to 60 milligrams as a single daily dose.

Patients who start at 30 milligrams daily can be increased to 60 milligrams once daily after the first week. For chronic musculoskeletal pain, initial dosing is recommended to start at 30 milligrams once daily for one week then increased to 60 milligrams once daily, if tolerated.

Daily doses exceeding 60 milligrams offer no additional benefits in diabetic neuropathy, fibromyalgia, and generalized anxiety disorder and tend to be less well tolerated. When used off label for treatment of stress incontinence, 40 milligrams twice daily dosing is typically employed.

There are no pediatric dosing recommendations for duloxetine; it should not be used in children.

Taking duloxetine with food delays time to peak levels and reduces absorption by 10 percent. Evening doses are also absorbed more slowly and less completely than morning doses. None of these food or time variables have clinical significance; in other words, duloxetine can be taken without regard to meals.

Duloxetine capsules should be swallowed whole. Do not chew, crush, or open capsules to sprinkle on food or mix with liquids.

No dose reductions are recommended by the manufacturer for geriatric patients, by gender, or in smokers. In patients with renal impairment, duloxetine should be started at lower than usual doses and titrated upwards more gradually.

The manufacturer recommends against prescribing duloxetine to patients in renal failure (those on dialysis) or with significant renal insufficiency (creatinine clearance less than 30 mL/min).  Duloxetine is also not recommended for patients with any degree of liver (hepatic) insufficiency, liver disease or heavy alcohol consumption.

Fatal overdoses of duloxetine have been reported with as little as 1,000 milligrams. Overdoses generally manifest with sleepiness, coma, serotonin syndrome, seizures, tachycardia, hyper or hypotension, and vomiting.

Treatment should be supportive. Activated charcoal may be useful in reducing absorption. Hemodialysis is unlikely to be helpful. As in all overdoses, the possibility of multidrug ingestion should be considered.

Pharmacology/Pharmacokinetics/Stability — Following oral administration, duloxetine achieves levels in the bloodstream with 4 to 6 hours, peaking between 6 and 10 hours, depending on whether the dose was taken on an empty stomach or with food.

Relief of symptoms can usually be seen within seven days to two weeks. Duloxetine is metabolized extensively in the liver, 70 percent is excreted by the kidneys and 20 percent in feces. 

Adverse events have been observed in fetal animal studies of duloxetine, especially during the later third trimester. No well controlled human studies are yet available.

Use during pregnancy must be carefully balanced against risks and benefits. Women treated for major depression are likely to relapse if medication is discontinued during pregnancy. Therapy should be individualized. Duloxetine is excreted in breast milk.

The manufacturer does not recommend breast feeding although duloxetine is not stable at an acidic pH; hence drug reaching a breast fed infant’s stomach would likely degrade significantly.

Studies demonstrate breast fed infants receive an average of 0.14 percent of the maternal dose of duloxetine. Use in breast feeding mothers should carefully weigh risks versus benefits.

Duloxetine’s mechanism of action in the body is believed to be associated with potentiation of neurotransmitter activity in the central nervous system.

Duloxetine (Cymbalta) comes in 20, 30 and 60 milligram delayed release capsules imprinted with the dosage strength on the side of the capsule.

Strengths are colored differently. Capsules should be stored at room temperature between 68 to 77 F with occasional variations to between 59 to 86 F permitted.

Cautions and Warnings — Aside from the FDA Black Box warnings on worsening of depression and risk of suicide, common sense is necessary with any patient being treated with antidepressants.

Regardless of age, monitoring for clinical worsening, risk of suicide and unusual behaviors is mandatory. Family, friends and caregivers should be made aware of this and instructed to monitor the patient daily. Duloxetine cannot be used in patients taking monoamine oxidase inhibitors (MAOIs).  

Once a widely prescribed antidepressant, MAOIs are now rarely used, and tend to be reserved for patients who don’t respond to newer and safer agents.  Use of duloxetine in patients taking or who have taken an MAOI within the past 14 days can lead to a fatal serotonin syndrome.

This syndrome looks very similar to malignant hyperthermia with rigidity, extremely high fevers, and a constellation of other physical effects resulting from excessive levels of serotonin in the brain. A minimum of two weeks separation between use of duloxetine and MAOIs is imperative.

Discontinue duloxetine at least five days prior to starting an MAOI. Abruptly stopping duloxetine may lead to another distressing constellation of symptoms including abnormal movements and sensations.

Taper doses gradually when discontinuing therapy. If a patient has been taking duloxetine for six weeks or longer, it should be tapered over at least two weeks.

Increased blood pressure has been reported with duloxetine; periodic monitoring of blood pressure is recommended. Dose related increases in heart rate have also been observed. Neither was very dramatic in study patients.

In practice, orthostatic hypotension is more commonly seen, especially following initiation of therapy (during the first week) and with dose increases. Duloxetine has also been reported to worsen glycemic control in patients with diabetes although increases in serum glucose were also not very dramatic.

Caution is recommended when using duloxetine in patients with known seizure disorders. Seizure patients were excluded from clinical trials of the drug. Despite this, a slight increase in seizure as a reported side effect was seen when compared to placebo.

Abnormal bleeding has occurred with duloxetine, including major hemorrhage. Bleeding is more common when used in combination with NSAIDs, aspirin, warfarin or other anticoagulants. Duloxetine can exacerbate narrow angle glaucoma and should not be given to patients whose glaucoma is not controlled.

Important Side Effects and Interactions — Headache is reported by 13 to 14 percent of patients taking duloxetine, as is nausea (23 to 25 percent), dose related somnolence (10 to 12 percent), xerostomia (dry mouth, by 11 to 15 percent), dizziness (10 percent), dose related insomnia (10 percent), anorexia (loss of appetite, by 7 to 9 percent), dose related constipation (10 percent), and diarrhea (9 to 10 percent).

Only 3 percent of (male) patients report delayed ejaculation with duloxetine. SSRIs are often prescribed to treat premature ejaculation; duloxetine would not be very effective for this purpose, especially when compared to SSRIs.
 
There are 174 drugs and drug classes specifically reported to interact with duloxetine. Several are worth noting.

Cimetidine, an H2 antagonist available over-the-counter (OTC) for treatment of gastrointestinal reflux disease (GERD) and the entire prescription family of quinolone antibiotics (ciprofloxacin, etc) can dramatically decrease duloxetine metabolism, significantly raising blood levels of the drug.

Use of these drugs with duloxetine should be avoided. Combination therapy with duloxetine and the SSRI paroxetine (Paxil) increased levels of duloxetine by 60 percent. Similar adverse effects would likely occur in combination with fluoxetine (Prozac) or quinidine.

Patients taking certain drugs with a narrow therapeutic window can become toxic when also given duloxetine. These include some of the TCAs such as nortriptyline, amitriptyline and imipramine as well as phenothiazines and either of the Class 1C antiarrhythmics (flecainide and propafenone). The risk of death from toxic levels of these drugs strongly suggests patients taking them not be given duloxetine.

Average Costs — U.S.

  • 20, 30 and 60 milligram capsules

Patient cost: $5.48, $5.63, and $5.70 each*

Large Hospital cost: $4.45, $4.98 and $4.98 each

*(Wal Mart® and Target don’t include this med in their $4/month programs)

References:

  • MICROMEDEXÒ Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed November, 2011).
  • Albany Medical Center Pharmacy, Albany, New York.

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