Duloxetine: Package Insert and Label Information (Page 7 of 8)

14.4 Diabetic Peripheral Neuropathic Pain in Adults

The efficacy of duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy in adults was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose trials in adult patients having diabetic peripheral neuropathic pain (DPNP) for at least 6 months (Study DPNP-1 and Study DPNP-2). These trials enrolled a total of 791 patients of whom 592 (75%) completed the trials. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to duloxetine. Patients recorded their pain daily in a diary.

Both trails compared duloxetine 60 mg once daily or 60 mg twice daily with placebo. Study DPNP-1 additionally compared duloxetine 20 mg with placebo. A total of 457 patients (342 duloxetine, 115 placebo) were enrolled in Study DPNP-1 and a total of 334 patients (226 duloxetine, 108 placebo) were enrolled in Study DPNP-2.

Treatment with duloxetine 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain scores from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 3 and 4 show the fraction of patients achieving that degree of improvement in Studies DPNP-1 and DPNP-2, respectively. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the trial were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the trial.

Figure 3: Percentage of DPNP Adult Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study DPNP-1)

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Figure 4: Percentage of DPNP Adult Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study DPNP-2)

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14.5 Fibromyalgia

Adult Trials in Fibromyalgia

The efficacy of duloxetine for the management of fibromyalgia in adults was established in two randomized, double-blind, placebo-controlled, fixed-dose trials in adult patients meeting the American College of Rheumatology criteria for fibromyalgia (a history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). Study FM-1 was three months in duration and enrolled female patients only. Study FM-2 was six months in duration and enrolled male and female patients. Approximately 25% of participants had a comorbid diagnosis of MDD. Studies FM-1 and FM-2 enrolled a total of 874 patients of whom 541 (62%) completed the trials. A total of 354 patients (234 duloxetine, 120 placebo) were enrolled in Study FM-1 and a total of 520 patients (376 duloxetine, 144 placebo) were enrolled in Study FM-2 (5% male, 95% female). The patients had a baseline pain score of 6.5 on an 11-point scale ranging from 0 (no pain) to 10 (worse possible pain).

Studies FM-1 and FM-2 compared duloxetine 60 mg once daily or 120 mg daily (given in divided doses in Study FM-1 and as a single daily dose in Study FM-2) with placebo. Study FM-2 additionally compared duloxetine 20 mg with placebo during the initial three months of a six-month trial.

Treatment with duloxetine 60 mg or 120 mg daily statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Pain reduction was observed in patients both with and without comorbid MDD. However, the degree of pain reduction may be greater in patients with comorbid MDD. For various degrees of improvement in pain from baseline to study endpoint, Figures 5 and 6 show the fraction of patients achieving that degree of improvement in Studies FM-1 and FM-2, respectively. The figures are cumulative so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the trial were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the trial. Improvement was also demonstrated on measures of function (Fibromyalgia Impact Questionnaires) and patient global impression of change (PGI). Neither trial demonstrated a benefit of 120 mg compared to 60 mg, and a higher dosage was associated with more adverse reactions and premature discontinuations of treatment.

Figure 5: Percentage of Adult Fibromyalgia Patients Achieving Various Levels of Pain Relief at Study Endpoint as Measured by 24-Hour Average Pain Severity (Study FM-1)

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Figure 6: Percentage of Adult Fibromyalgia Patients Achieving Various Levels of Pain Relief at Study Endpoint as Measured by 24-Hour Average Pain Severity (Study FM-2)

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Additionally, the benefit of up-titration in non-responders to duloxetine delayed-release capsules at 60 mg/day was evaluated in a separate trial (Study FM-3). Adult patients were initially treated with duloxetine delayed-release capsules 60 mg once daily for eight weeks in open-label fashion. Subsequently, completers of this phase were randomized to double-blind treatment with duloxetine delayed-release capsules at either 60 mg once daily or 120 mg once daily. Responders were defined as patients who had at least a 30% reduction in pain score from baseline at the end of the 8 week treatment. Patients who were non-responders at 8 week were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly titrated to duloxetine delayed-release capsules 120 mg as compared to those who were blindly continued on duloxetine delayed-release capsules 60 mg.

Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine) delayed-release capsules. However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

14.6 Chronic Musculoskeletal Pain in Adults

Duloxetine delayed-release capsules are indicated for the treatment of chronic musculoskeletal pain in adults. This has been established in trials in adult patients with chronic low back pain and chronic pain due to osteoarthritis.

Trials in Chronic Low Back Pain in Adults

The efficacy of duloxetine delayed-release capsules in chronic low back pain (CLBP) in adults was assessed in two double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Studies CLBP-1 and CLBP-2), and one of 12-weeks duration (CLBP-3). Studies CLBP-1 and CLBP-3 demonstrated efficacy of duloxetine delayed-release capsules in the treatment of CLBP. Patients in all trials had no signs of radiculopathy or spinal stenosis.

Study CLBP-1: Two hundred thirty-six adult patients (N=115 on duloxetine delayed-release capsules, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase. After 7 weeks of treatment, duloxetine-treated patients with less than 30% reduction in average daily pain and who were able to tolerate 60 mg once daily had their duloxetine delayed-release capsules dosage, in a double-blinded fashion, increased to 120 mg once daily for the remainder of the trial. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking duloxetine delayed-release capsules 60-120 mg daily had a significantly greater pain reduction compared to patients taking placebo. Randomization was stratified by the patients’ baseline NSAIDs use status. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.

Study CLBP-2: Four hundred and four patients were randomized to receive fixed dosages of duloxetine delayed-release capsules daily or a matching placebo (N=59 on duloxetine delayed-release capsules 20 mg, N=116 on duloxetine delayed-release capsules 60 mg, N=112 on duloxetine delayed-release capsules 120 mg, N=117 on placebo) and 267 (66%) completed the entire 13-week trial. After 13 weeks of treatment, none of the three duloxetine delayed-release capsules dosages showed a statistically significant difference in pain reduction compared to placebo.

Study CLBP-3: Four hundred and one patients were randomized to receive fixed doses of duloxetine delayed-release capsules 60 mg daily or placebo (N=198 on duloxetine delayed-release capsules, N=203 on placebo), and 303 (76%) completed the trial. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 12 weeks of treatment, patients taking duloxetine delayed-release capsules 60 mg daily had significantly greater pain reduction compared to patients taking placebo.

For various degrees of improvement in pain from baseline to study endpoint, Figures 8 and 9 show the fraction of patients in Studies CLBP-1 and CLBP-3 achieving that degree of improvement, respectively. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the trial were assigned the value of 0% improvement.

Figure 8: Percentage of Adult Patients with CLBP Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study CLBP-1)

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Figure 9: Percentage of Adult Patients with CLBP Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study CLBP-3)

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Trials in Chronic Pain Due to Osteoarthritis in Adults

The efficacy of duloxetine delayed-release capsules in chronic pain due to osteoarthritis (OA) in adults was assessed in 2 double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study OA-1 and Study OA-2). All patients in both trials fulfilled the ACR clinical and radiographic criteria for classification of idiopathic OA of the knee. Randomization was stratified by the patients’ baseline NSAIDs-use status.

Patients assigned to duloxetine delayed-release capsules started treatment in both trials at a dose of 30 mg once daily for one week. After the first week, the dose of duloxetine delayed-release capsules was increased to 60 mg once daily. After 7 weeks of treatment with duloxetine delayed-release capsules 60 mg once daily, in Study OA-1 patients with sub-optimal response to treatment (<30% pain reduction) and tolerated duloxetine delayed-release capsules 60 mg once daily had their doseincreased to 120 mg. However, in Study OA-2, all patients, regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving duloxetine delayed-release capsules 60 mg once daily or have their dosage increased to 120 mg once daily for the remainder of the trial. Patients in the placebo treatment groups in both trials received a matching placebo for the entire duration of trials. For both trails, efficacy analyses were conducted using 13-week data from the combined duloxetine delayed-release capsules 60 mg and 120 mg once daily treatment groups compared to the placebo group.

Study OA-1: Two hundred fifty-six patients (N=128 on duloxetine delayed-release capsules, N=128 on placebo) enrolled and 204 (80%) completed the trial. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking duloxetine delayed-release capsules had significantly greater pain reduction than patients taking placebo. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.

Study OA-2: Two hundred thirty-one patients (N=111 on duloxetine delayed-release capsules, N=120 on placebo) enrolled and 173 (75%) completed the trial. Patients had a mean baseline pain of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking duloxetine delayed-release capsules did not show a significantly greater pain reduction than patients taking placebo.

In Study OA-1, for various degrees of improvement in pain from baseline to study endpoint, Figure 10 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the trail were assigned the value of 0% improvement.

Figure 10: Percentage of Adult Patients with OA Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study OA-1)

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16 HOW SUPPLIED/STORAGE AND HANDLING

Duloxetine delayed-release capsules are available in the following strengths, colors, imprints, and presentations:

Body color: blue, Cap color: blue, Cap imprint: ap, Body imprint: DLX30

NDC: 70518-1054-00

NDC: 70518-1054-01

NDC: 70518-1054-02

NDC: 70518-1054-03

NDC: 70518-1054-04

NDC: 70518-1054-05

NDC: 70518-1054-06

PACKAGING: 30 in 1 BLISTER PACK

PACKAGING: 90 in 1 BOTTLE PLASTIC

PACKAGING: 30 in 1 BOTTLE PLASTIC

PACKAGING: 60 in 1 BOTTLE PLASTIC

PACKAGING: 30 in 1 BOX

PACKAGING: 1 in 1 POUCH

PACKAGING: 30 in 1 BOTTLE PLASTIC

a equivalent to duloxetine base

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Repackaged and Distributed By:

Remedy Repack, Inc.

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

  • Suicidal Thoughts and Behaviors — Advise patients, their families, and their caregivers to look for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted up or down and instruct them to report such symptoms to their healthcare provider [see Boxed Warning and Warnings and Precautions ( 5.1)].
  • Administration — Advise patients to swallow duloxetine delayed-release capsules whole and to not chew, crush, or open the capsule (do not sprinkle contents on food or mixed with liquids) because these actions might affect the enteric coating.
  • Hepatotoxicity — Inform patients that severe liver problems, sometimes fatal, have been reported in patients treated with duloxetine delayed-release capsules. Instruct patients to talk to their healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow skin/eyes while taking duloxetine delayed-release capsules, which may be signs of liver problems. Instruct patients to talk to their healthcare provider about their alcohol consumption. Use of duloxetine delayed-release capsules with heavy alcohol intake may be associated with severe liver injury [see Warnings and Precautions ( 5.2)].
  • Alcohol — Although duloxetine does not increase the impairment of mental and motor skills caused by alcohol, use of duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury [see Warnings and Precautions ( 5.2) and Drug Interactions ( 7.15)].
    • Orthostatic Hypotension, Falls and Syncope — Advise patients of the risk of orthostatic hypotension, falls and syncope, especially during the period of initial use and subsequent dose escalation, and in association with the use of concomitant drugs that might potentiate the orthostatic effect of duloxetine [see Warnings and Precautions ( 5.3)].
    • Serotonin Syndrome — Caution patients about the risk of serotonin syndrome with the concomitant use of duloxetine delayed-release capsules and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort [see Contraindications ( 4), Warnings and Precautions ( 5.4), and Drug Interactions ( 7.14)]. Advise patients of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Caution patients to seek medical care immediately if they experience these symptoms.
      • Increased Risk of Bleeding — Caution patients about the concomitant use of duloxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [see Warnings and Precautions ( 5.5) and Use in Specific Populations ( 8.1)].
        • Severe Skin Reactions — Caution patients that duloxetine may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Counsel patients to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions [see Warnings and Precautions ( 5.6)].
          • Discontinuation of Treatment — Instruct patients that discontinuation of duloxetine delayed-release capsules may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue, and should be advised not to alter their dosing regimen, or stop taking duloxetine delayed-release capsules without consulting their healthcare provider [see Warnings and Precautions ( 5.7)].
          • Activation of Mania or Hypomania — Adequately screen patients with depressive symptoms for risk of bipolar disorder (e.g. family history of suicide, bipolar disorder, and depression) prior to initiating treatment with duloxetine delayed-release capsules. Advise patients to report any signs or symptoms of a manic reaction such as greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand ideas, and excessive happiness or irritability [see Warnings and Precautions ( 5.8)].
          • Angle-Closure Glaucoma — Advise patients that taking duloxetine delayed-release capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. [see Warnings and Precautions ( 5.9)].
            • Seizures — Advise patients to inform their healthcare provider if they have a history of seizure disorder [see Warnings and Precautions ( 5.10)].
              • Effects on Blood Pressure — Caution patients that duloxetine delayed-release capsules may cause an increase in blood pressure [see Warnings and Precautions ( 5.11)].
                • Concomitant Medications — Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions [see Dosage and Administration ( 2.9, 2.10), Contraindications ( 4), Warnings and Precautions ( 5.4, 5.12), and Drug Interactions ( 7)].

                  Repackaged By / Distributed By: RemedyRepack Inc.

                  625 Kolter Drive, Indiana, PA 15701

                  (724) 465-8762

                  • Hyponatremia — Advise patients that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including duloxetine delayed-release capsules. Advise patients of the signs and symptoms of hyponatremia [see Warnings and Precautions ( 5.13)].
                  • Concomitant Illnesses — Advise patients to inform their healthcare provider about all of their medical conditions [see Warnings and Precautions ( 5.14)].
                  • Urinary Hesitation and Retention — Duloxetine is in a class of medicines that may affect urination. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow [see Warnings and Precautions ( 5.15)].
                  • Pregnancy
                    • Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with duloxetine.
                    • Advise pregnant women or patients who intend to become pregnant that duloxetine use during the month before delivery may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.
                    • Advise pregnant women that there is a risk of relapse with discontinuation of antidepressants.
                  • Advise pregnant women that there is a risk of relapse with discontinuation of antidepressants.
                  • Lactation ― Advise breastfeeding women using duloxetine to monitor infants for sedation, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2)].
                  • Interference with Psychomotor Performance —duloxetine may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous machinery including automobiles, until they are reasonably certain that duloxetine therapy does not affect their ability to engage in such activities.

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