Duloren

The active ingredient in Duloren is Duloren.

Each Duloren 30 mg & 60 mg capsule contains 30 mg & 60 mg of Duloren as Duloren hydrochloride respectively.

Excipients/Inactive Ingredients: Capsule Content: Hypromellose, hypromellose acetate succinate, sucrose, sugar spheres, talc, titanium dioxide (E171), triethyl citrate.

Capsule Shell:

60 mg: Gelatin, sodium lauryl sulfate, titanium dioxide (E171), indigo carmine (E132), yellow iron oxide (E172), edible white ink.

Edible Green Ink Contains: Black Iron Oxide-Synthetic (E172), yellow iron oxide-synthetic (E172), propylene glycol, shellac.

Edible White Ink Contains: Titanium Dioxide (E171), propylene glycol, shellac, povidone.

Duloren® is indicated for the treatment of:

• Major Depressive Disorder
• Generalized Anxiety Disorder
• Diabetic Peripheral Neuropathy
• Fibromyalgia
• Chronic Musculoskeletal Pain

Duloren is a selective serotonin and norepinephrine reuptake inhibitor antidepressant (SSNRI). Duloren affects chemicals in the brain that may become unbalanced and cause depression.

Duloren is used to treat major depressive disorder in adults. Duloren is also used to treat general anxiety disorder in adults and children who are at least 7 years old.

Duloren is also used in adults to treat fibromyalgia (a chronic pain disorder), or chronic muscle or joint pain (such as low back pain and osteoarthritis pain).

Duloren is also used to treat pain caused by nerve damage in adults with diabetes (diabetic neuropathy).

Duloren may also be used for purposes not listed in this medication guide.

Swallow Duloren whole. Do not chew or crush. Do not open the capsule and sprinkle its contents on food or mix with liquids. All of these might affect the enteric coating. Duloren can be given without regard to meals. If a dose of Duloren is missed, take the missed dose as soon as it is remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take two doses of Duloren at the same time.

Dosage For Treatment Of Major Depressive Disorder

Administer Duloren at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated. Periodically reassess to determine the need for maintenance treatment and the appropriate dose for such treatment.

Dosage For Treatment Of Generalized Anxiety Disorder

Adults

For most patients, initiate Duloren 60 mg once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dose for such treatment.

Elderly

Initiate Duloren at a dose of 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg. Thereafter, patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. Safety of doses above 120 mg once daily has not been adequately evaluated.

Children And Adolescents (7 to 17 years of age)

Initiate Duloren at a dose of 30 mg once daily for 2 weeks before considering an increase to 60 mg. The recommended dose range is 30 to 60 mg once daily. Some patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. The safety of doses above 120 mg once daily has not been evaluated.

Dosage For Treatment of Diabetic Peripheral Neuropathic Pain

Administer Duloren 60 mg once daily. 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, consider a lower starting dose and gradual increase in dose for patients with renal impairment.

Dosage For Treatment of Fibromyalgia

Administer Duloren 60 mg once daily. Begin treatment at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions.

Dosage For Treatment Of Chronic Musculoskeletal Pain

Administer Duloren 60 mg once daily. Begin treatment at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions.

Dosing In Special Populations

Hepatic Impairment

Avoid use in patients with chronic liver disease or cirrhosis.

Severe Renal Impairment

Avoid use in patients with severe renal impairment, GFR < 30 mL/min.

Discontinuing Duloren

Adverse reactions after discontinuation of Duloren, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible.

Switching A Patient To Or From A Monoamine Oxidase Inhibitor (MAOI) Intended To Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Duloren. Conversely, at least 5 days should be allowed after stopping Duloren before starting an MAOI intended to treat psychiatric disorders.

Use Of Duloren With Other MAOIs Such As Linezolid Or Methylene Blue

Do not start Duloren in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.

In some cases, a patient already receiving Duloren therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Duloren should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Duloren may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Duloren is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.

How supplied

Dosage Forms And Strengths

Duloren is available as delayed release capsules:

20 mg opaque green capsules imprinted with “Lilly 3235 20mg”

30 mg opaque white and blue capsules imprinted with “Lilly 3240 30mg”

60 mg opaque green and blue capsules imprinted with “Lilly 3270 60mg”

Storage And Handling

Duloren is available as delayed release capsules in the following strengths, colors, imprints, and presentations:

Storage And Handling

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA. Revised: Sep 2016.

Use Duloren delayed-release capsules as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Duloren delayed-release capsules comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Duloren delayed-release capsules refilled.
• Take Duloren delayed-release capsules by mouth with or without food. Taking it with food may help to decrease the chance of nausea or stomach upset.
• Swallow Duloren delayed-release capsules whole. Do not break, crush, or chew before swallowing. Do not open the capsule and sprinkle the contents on food or in liquid.
• Take Duloren delayed-release capsules on a regular schedule to get the most benefit from it. Taking Duloren delayed-release capsules at the same time each day will help you remember to take it.
• Continue to take Duloren delayed-release capsules even if you feel well. Do not miss any doses.
• Do not suddenly stop taking Duloren delayed-release capsules without checking with your doctor. Side effects may occur. They may include anxiety, numbness or tingling of the skin, diarrhea, dizziness, headache, increased sweating, irritability, nausea, trouble sleeping, unusual tiredness, or vomiting. If you need to stop Duloren delayed-release capsules, your doctor may need to gradually lower your dose.
• If you miss a dose of Duloren delayed-release capsules, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Duloren delayed-release capsules.

Use: Labeled Indications

Fibromyalgia (delayed-release particles capsule only): Management of fibromyalgia.

Generalized anxiety disorder: Treatment of generalized anxiety disorder.

Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder.

Musculoskeletal pain, chronic: Management of chronic musculoskeletal pain including osteoarthritis of the knee and low back pain.

Neuropathic pain associated with diabetes mellitus: Management of pain associated with diabetic peripheral neuropathy.

Off Label Uses

Chemotherapy-induced peripheral neuropathy

Data from a randomized, double-blind, placebo-controlled study support the use of Duloren in the treatment of pain, numbness, and tingling associated with chemotherapy-induced peripheral neuropathy. Subgroup analyses suggest efficacy may be greater for oxaliplatin-induced neuropathy as opposed to paclitaxel-induced neuropathy

American College of Physicians (ACP) guidelines on nonsurgical management of urinary incontinence recommend against pharmacologic therapy in women with stress urinary incontinence and note that although low-quality, placebo-controlled studies of Duloren demonstrate beneficial effects, these effects have not been confirmed by data from high-quality studies.

National Institute for Health and Care Excellence (NICE) evidence-based guidelines on the management of urinary incontinence and pelvic organ prolapse in women state that Duloren should not be considered as first-line treatment for women with predominant stress urinary incontinence nor routinely used as second-line treatment for women with stress urinary incontinence. However, Duloren may be considered as second-line therapy for women who decline surgical treatment or who are not suitable candidates for surgical treatment.

See also:
What other drugs will affect Duloren?

Potential for Other Drugs to Affect Duloren

Both CYP1A2 and CYP2D6 are responsible for Duloren metabolism

Inhibitors of CYP1A2 Concomitant use of Duloren with fluvoxamine, an inhibitor of CYP1A2, results in approximately a 6-fold increase in AUC and about a 2.5-fold increase in Cmax of Duloren. Some quinolone antibiotics would be expected to have similar effects and these combinations should be avoided

Inhibitors of CYP2D6 Because CYP2D6 is involved in Duloren metabolism, concomitant use of Duloren with potent inhibitors of CYP2D6 may result in higher concentrations of Duloren. Paroxetine (20 mg QD) increased the concentration of Duloren (40 mg QD) by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine).

Potential for Duloren to Affect Other Drugs

Drugs Metabolized by CYP1A2 In vitro drug interaction studies demonstrate that Duloren does not induce CYP1A2 activity, and it is unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates.

Drugs Metabolized by CYP2D6 Duloren is a moderate inhibitor of CYP2D6. When Duloren was administered (at a dose of 60 mg BID) in conjunction with a single 50-mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. Therefore, co-administration of Duloren with other drugs that are extensively metabolized by this isozyme and which have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Duloren. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Duloren and thioridazine should not be co-administered.

Drugs Metabolized by CYP3A Results of in vitro studies demonstrate that Duloren does not inhibit or induce CYP3A activity.

Duloren May Have a Clinically Important Interaction with the Following Other Drugs:

Alcohol When Duloren and ethanol were administered several hours apart so that peak concentrations of each would coincide, Duloren did not increase the impairment of mental and motor skills caused by alcohol.

In the Duloren clinical trials database, three Duloren-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen

CNS Acting Drugs Given the primary CNS effects of Duloren, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action.

Potential for Interaction with Drugs that Affect Gastric Acidity Duloren has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Duloren, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Duloren in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of Duloren. However, co-administration of Duloren with aluminum- and magnesium-containing antacids (51 mEq) or Duloren with famotidine, had no significant effect on the rate or extent of Duloren absorption after administration of a 40-mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects Duloren absorption.

See also:
What are the possible side effects of Duloren?

The following serious adverse reactions are described below and elsewhere in the labeling:

• Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults
• Hepatotoxicity
• Orthostatic Hypotension, Falls and Syncope
• Serotonin Syndrome
• Abnormal Bleeding
• Severe Skin Reactions
• Discontinuation of Treatment with Duloren
• Activation of Mania/Hypomania
• Angle-Closure Glaucoma
• Seizures
• Effect on Blood Pressure
• Clinically Important Drug Interactions
• Hyponatremia
• Urinary Hesitation and Retention

Clinical Trial Data Sources

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.

Adults

The data described below reflect exposure to Duloren in placebo-controlled trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The population studied was 17 to 89 years of age; 65.7%, 60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and CLBP, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day. The data below do not include results of the trial examining the efficacy of Duloren in patients ≥ 65 years old for the treatment of generalized anxiety disorder; however, the adverse reactions observed in this geriatric sample were generally similar to adverse reactions in the overall adult population.

Children And Adolescents

The data described below reflect exposure to Duloren in pediatric, 10-week, placebo-controlled trials for MDD (N=341) and GAD (N=135). The population studied (N=476) was 7 to 17 years of age with 42.4% children age 7 to 11 years of age, 50.6% female, and 68.6% white. Patients received 30-120 mg per day during placebo-controlled acute treatment studies. Additional data come from the overall total of 822 pediatric patients (age 7 to 17 years of age) with 41.7% children age 7 to 11 years of age and 51.8% female exposed to Duloren in MDD and GAD clinical trials up to 36-weeks in length, in which most patients received 30-120 mg per day.

Adverse Reactions Reported As Reasons For Discontinuation Of Treatment In Adult Placebo-Controlled Trials

Major Depressive Disorder

Approximately 8.4% (319/3779) of the patients who received Duloren in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of the patients receiving placebo. Nausea (Duloren 1.1%, placebo 0.4%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Duloren-treated patients and at a rate of at least twice that of placebo).

Generalized Anxiety Disorder

Approximately 13.7% (139/1018) of the patients who received Duloren in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloren 3.3%, placebo 0.4%), and dizziness (Duloren 1.3%, placebo 0.4%).

Diabetic Peripheral Neuropathic Pain

Approximately 12.9% (117/906) of the patients who received Duloren in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloren 3.5%, placebo 0.7%), dizziness (Duloren 1.2%, placebo 0.4%), and somnolence (Duloren 1.1%, placebo 0.0%).

Fibromyalgia

Approximately 17.5% (227/1294) of the patients who received Duloren in 3 to 6 month placebo-controlled trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloren 2.0%, placebo 0.5%), headache (Duloren 1.2%, placebo 0.3%), somnolence (Duloren 1.1%, placebo 0.0%), and fatigue (Duloren 1.1%, placebo 0.1%).

Chronic Pain Due To Osteoarthritis

Approximately 15.7% (79/503) of the patients who received Duloren in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloren 2.2%, placebo 1.0%).

Chronic Low Back Pain

Approximately 16.5% (99/600) of the patients who received Duloren in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloren 3.0%, placebo 0.7%), and somnolence (Duloren 1.0%, placebo 0.0%).

Most Common Adult Adverse Reactions

Pooled Trials For All Approved Indications

The most commonly observed adverse reactions in Duloren-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.

Diabetic Peripheral Neuropathic Pain

The most commonly observed adverse reactions in Duloren-treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.

Fibromyalgia

The most commonly observed adverse reactions in Duloren-treated patients (as defined above) were nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.

Chronic Pain Due To Osteoarthritis

The most commonly observed adverse reactions in Duloren-treated patients (as defined above) were nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness.

Chronic Low Back Pain

The most commonly observed adverse reactions in Duloren-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.

Adverse Reactions Occurring At An Incidence Of 5% Or More Among Duloren-Treated Patients In Adult Placebo-Controlled Trials

Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with Duloren and with an incidence greater than placebo.

Table 2: Treatment-Emergent Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Indications Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia.