DULOXETINE HYDROCHLORIDE (Page 4 of 14)

5.11 Increases in Blood Pressure

In adult placebo-controlled clinical trials across the approved adult populations from baseline to endpoint, duloxetine delayed-release capsules treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of duloxetine delayed-release capsules on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily(approximately 3.3 times the maximum recommended dosage). At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing.Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment [see Adverse Reactions (6.1)].

5.12 Clinically Important Drug Interactions

Both CYP1A2 and CYP2D6 are responsible for duloxetine delayed-release capsules metabolism.
Potential for Other Drugs to Affect Duloxetine Delayed-Release Capsules

CYP1A2 Inhibitors — Co-administration of duloxetine delayed-release capsules with potent CYP1A2 inhibitors should be avoided [see Drug Interactions (7.1)].
CYP2D6 Inhibitors — Because CYP2D6 is involved in duloxetine delayed-release capsules metabolism, concomitant use of duloxetine delayed-release capsules with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine delayed-release capsules [see Drug Interactions (7.2)].
Potential for Duloxetine Delayed-Release Capsules to Affect Other Drugs

Drugs Metabolized by CYP2D6 — Co-administration of duloxetine delayed-release capsules with drugs that are extensively metabolized by CYP2D6 and that 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 duloxetine delayed-release capsules. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, duloxetine delayed-release capsules and thioridazine should not be co-administered [see Drug Interactions (7.9)].
Other Clinically Important Drug Interactions

Alcohol — Use of duloxetine delayed-release capsules concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, duloxetine delayed-release capsules should not be prescribed for patients with substantial alcohol use [see Warnings and Precautions (5.2) and Drug Interactions (7.15)]. CNS Acting Drugs — Given the primary CNS effects of duloxetine delayed-release capsules, 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 [see Warnings and Precautions (5.12) and Drug Interactions (7.16)].

5.13 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including duloxetine delayed-release capsules. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported with duloxetine delayed-release capsules use and appeared to be reversible when duloxetine delayed-release capsules were discontinued. Geriatric patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of duloxetine delayed-release capsules should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.14 Use in Patients with Concomitant Illness

Clinical experience with duloxetine delayed-release capsules in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of duloxetine delayed-release capsules’s enteric coating. In extremely acidic conditions, duloxetine delayed-release capsules, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using duloxetine delayed-release capsules in patients with conditions that may slow gastric emptying (e.g., some diabetics).
Duloxetine delayed-release capsules have not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing.
Hepatic impairment
Avoid use in patients with chronic liver disease or cirrhosis [see Dosage and Administration (2.7), Warnings and Precautions (5.2), and Use in Specific Populations (8.9)].
Severe Renal Impairment

Avoid use in patients with severe renal impairment, GFR <30 mL/minute.Increased plasma concentration of duloxetine delayed-release capsules, and especially of its metabolites, occurred in patients with end-stage renal disease (requiring dialysis) [see Dosage and Administration (2.7) and Use in Specific Populations (8.10)].
Glycemic Control in Patients with Diabetes

As observed in DPNP trials, duloxetine delayed-release capsules treatment worsened glycemic control in some patients with diabetes. In three clinical trials of duloxetine delayed-release capsules for the management of neuropathic pain associated with diabetic peripheral neuropathy [see Clinical Studies (14.4)], the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c ) was 7.8%. In the 12-week acute treatment phase of these studies, duloxetine delayed-release capsules were associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the duloxetine delayed-release capsules group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the duloxetine delayed-release capsules group and by 0.2% in the routine care group.

5.15 Urinary Hesitation and Retention


Duloxetine delayed-release capsules are in a class of drugs known to affect urethral resistance.If symptoms of urinary hesitation develop during treatment with duloxetine delayed-release capsules, consideration should be given to the possibility that they might be drug-related. In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine delayed-release capsules use, hospitalization and/or catheterization has been needed.

6 ADVERSE REACTIONS

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

  • Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)]
  • Hepatotoxicity [see Warnings and Precautions (5.2)]
  • Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions (5.3)]
  • Serotonin Syndrome [see Warnings and Precautions (5.4)]
  • Increased Risk of Bleeding [see Warnings and Precautions (5.5)]
  • Severe Skin Reactions [see Warnings and Precautions (5.6)]
  • Discontinuation Syndrome [see Warnings and Precautions (5.7)]
  • Activation of Mania/Hypomania [see Warnings and Precautions (5.8)]
  • Angle-Closure Glaucoma [see Warnings and Precautions (5.9)]
  • Seizures [see Warnings and Precautions (5.10)]
  • Increases in Blood Pressure [see Warnings and Precautions (5.11)]
  • Clinically Important Drug Interactions [see Warnings and Precautions (5.12)]
  • Hyponatremia [see Warnings and Precautions (5.13)]
  • Urinary Hesitation and Retention [see Warnings and Precautions (5.15)]

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