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Medications: Cymbalta® – duloxetine

MEDICATIONS

Cymbalta® – duloxetine (View the FDA label)

Cymbalta® is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for:

  • Major Depressive Disorder (MDD) (1.1)
  • Generalized Anxiety Disorder (GAD) (1.2)
  • Diabetic Peripheral Neuropathic Pain (DPNP) (1.3)
  • Fibromyalgia (FM) (1.4)
  • Chronic Musculoskeletal Pain (1.5)

Most common adverse reactions (≥5% and at least twice the incidence of placebo patients): nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis (6.3).

Suicidality: Monitor for clinical worsening and suicide risk (5.1)

Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in patients treated with Cymbalta. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Cymbalta should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease (5.2)

Orthostatic Hypotension and Syncope: Cases have been reported with duloxetine therapy (5.3)

Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including with Cymbalta, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John’s Wort). If such symptoms occur, discontinue Cymbalta and initiate supportive treatment. If concomitant use of Cymbalta with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.4)

Abnormal Bleeding: Cymbalta may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation (5.5, 7.4)

Severe Skin Reactions: Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with Cymbalta. Cymbalta should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified. (5.6)

Discontinuation: May result in symptoms, including dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue (5.7)

Activation of mania or hypomania has occurred (5.8)

Seizures: Prescribe with care in patients with a history of seizure disorder (5.9)

Blood Pressure: Monitor blood pressure prior to initiating treatment and periodically throughout treatment (5.10)

Inhibitors of CYP1A2 or Thioridazine: Should not administer with Cymbalta (5.11)

Hyponatremia: Cases of hyponatremia have been reported (5.12)

Hepatic Insufficiency and Severe Renal Impairment: Should ordinarily not be administered to these patients (5.13) • Controlled Narrow-Angle Glaucoma: Use cautiously in these patients (5.13)

Glucose Control in Diabetes: In diabetic peripheral neuropathic pain patients, small increases in fasting blood glucose, and HbA1c have been observed (5.13)

Conditions that Slow Gastric Emptying: Use cautiously in these patients (5.13)

Urinary Hesitation and Retention (5.14)

Potent inhibitors of CYP1A2 should be avoided (7.1).

Potent inhibitors of CYP2D6 may increase duloxetine concentrations (7.2).

Duloxetine is a moderate inhibitor of CYP2D6 (7.9).

Signs and Symptoms
In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.

Management of Overdose
There is no specific antidote to Cymbalta, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken Cymbalta and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Warnings and Precautions (5.4) and Drug Interactions (7)]. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

Uses

Cymbalta® is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for:

  • Major Depressive Disorder (MDD) (1.1)
  • Generalized Anxiety Disorder (GAD) (1.2)
  • Diabetic Peripheral Neuropathic Pain (DPNP) (1.3)
  • Fibromyalgia (FM) (1.4)
  • Chronic Musculoskeletal Pain (1.5)
Side Effects

Most common adverse reactions (≥5% and at least twice the incidence of placebo patients): nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis (6.3).

Precautions

Suicidality: Monitor for clinical worsening and suicide risk (5.1)

Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in patients treated with Cymbalta. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Cymbalta should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease (5.2)

Orthostatic Hypotension and Syncope: Cases have been reported with duloxetine therapy (5.3)

Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including with Cymbalta, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John’s Wort). If such symptoms occur, discontinue Cymbalta and initiate supportive treatment. If concomitant use of Cymbalta with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.4)

Abnormal Bleeding: Cymbalta may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation (5.5, 7.4)

Severe Skin Reactions: Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with Cymbalta. Cymbalta should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified. (5.6)

Discontinuation: May result in symptoms, including dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue (5.7)

Activation of mania or hypomania has occurred (5.8)

Seizures: Prescribe with care in patients with a history of seizure disorder (5.9)

Blood Pressure: Monitor blood pressure prior to initiating treatment and periodically throughout treatment (5.10)

Inhibitors of CYP1A2 or Thioridazine: Should not administer with Cymbalta (5.11)

Hyponatremia: Cases of hyponatremia have been reported (5.12)

Hepatic Insufficiency and Severe Renal Impairment: Should ordinarily not be administered to these patients (5.13) • Controlled Narrow-Angle Glaucoma: Use cautiously in these patients (5.13)

Glucose Control in Diabetes: In diabetic peripheral neuropathic pain patients, small increases in fasting blood glucose, and HbA1c have been observed (5.13)

Conditions that Slow Gastric Emptying: Use cautiously in these patients (5.13)

Urinary Hesitation and Retention (5.14)

Interactions

Potent inhibitors of CYP1A2 should be avoided (7.1).

Potent inhibitors of CYP2D6 may increase duloxetine concentrations (7.2).

Duloxetine is a moderate inhibitor of CYP2D6 (7.9).

Overdose

Signs and Symptoms
In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.

Management of Overdose
There is no specific antidote to Cymbalta, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken Cymbalta and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Warnings and Precautions (5.4) and Drug Interactions (7)]. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

Interpreting the GeneSight® Test:
Gene-Drug Interaction Chart

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