Daliresp

Figure 1. Effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide. Note that the dashed lines indicate the lower and higher bounds (0.8-1.25) of the 90% confidence interval of the geometric mean ratio of C_max or AUC for roflumilast or roflumilast N-oxide for Treatment (DALIRESP+Coadministered Drug) vs. Reference (DALIRESP). The dosing regimens of coadministered drugs was: Midazolam:2mg po SD; Erythromycin:500mg po TID; Ketoconazole:200mg po BID; Rifampicin:600mg po QD; Fluvoxamine:50mg po QD; Digoxin:250ug po SD; Maalox:30mL po SD; Salbutamol:0.2mg pi TID; Cimetidine:400mg po BID; Formoterol:40ug po BID; Budesonide:400ug po BID; Theophylline:375mg po BID; Warfarin:250mg po SD; Enoxacin:400mg po BID; Sildenafil:100mg SD; Minulet (combination oral contraceptive):0.075mg gestodene/0.03mg ethinylestradiol po QD; Montelukast:10mg po QD

Drug interactions considered to be significant are described in more detail below [also see Drug Interactions (5.4) and Drug Interactions (7)].

Inhibitors of CYP3A4 and CYP1A2:

Erythromycin: In an open-label crossover study in 16 healthy volunteers, the coadministration of CYP 3A4 inhibitor erythromycin (500 mg three times daily for 13 days) with a single oral dose of 500 mcg DALIRESP resulted in 40% and 70% increase in C_max and AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in C_max and AUC for roflumilast N-oxide, respectively.

Ketoconazole: In an open-label crossover study in 16 healthy volunteers, the coadministration of a strong CYP 3A4 inhibitor ketoconazole (200 mg twice daily for 13 days) with a single oral dose of 500 mcg DALIRESP resulted in 23% and 99% increase in C_max and AUC for roflumilast, respectively, and a 38% reduction and 3% increase in C_max and AUC for roflumilast N-oxide, respectively.

Fluvoxamine: In an open-label crossover study in 16 healthy volunteers, the coadministration of dual CYP 3A4/1A2 inhibitor fluvoxamine (50 mg daily for 14 days) with a single oral dose of 500 mcg DALIRESP showed a 12% and 156% increase in roflumilast C_max and AUC along with a 210% decrease and 52% increase in roflumilast N-oxide C_max and AUC, respectively.

Enoxacin: In an open-label crossover study in 16 healthy volunteers, the coadministration of dual CYP 3A4/1A2 inhibitor enoxacin (400 mg twice daily for 12 days) with a single oral dose of 500 mcg DALIRESP resulted in an increased C_max and AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide C_max was decreased by 14% while roflumilast N-oxide AUC was increased by 23%.

Cimetidine: In an open-label crossover study in 16 healthy volunteers, the coadministration of a dual CYP 3A4/1A2 inhibitor cimetidine (400 mg twice daily for 7 days) with a single dose of 500 mcg oral DALIRESP resulted in a 46% and 85% increase in roflumilast C_max and AUC; and a 4% decrease in C_max and 27% increase in AUC for roflumilast N-oxide, respectively.

Oral Contraceptives containing Gestodene and Ethinyl Estradiol:

In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single oral dose of 500 mcg DALIRESP with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state caused a 38% increase and 12% decrease in C_max of roflumilast and roflumilast N-oxide, respectively. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively.

Inducers of CYP enzymes:

Rifampicin: In an open-label, three-period, fixed-sequence study in 15 healthy volunteers, coadministration of the strong CYP3A4 inducer rifampicin (600 mg once daily for 11 days) with a single oral dose of 500 mcg DALIRESP resulted in reduction of roflumilast C_max and AUC by 68% and 79%, respectively; and an increase of roflumilast N-oxide C_max by 30% and reduced roflumilast N-oxide AUC by 56%.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies were conducted in hamsters and mice with roflumilast to evaluate its carcinogenic potential. In 2-year oral gavage carcinogenicity studies, roflumilast treatment resulted in dose-related, statistically significant increases in the incidence of undifferentiated carcinomas of nasal epithelium in hamsters at ≥ 8 mg/kg/day (approximately 11 times the MRHD based on summed AUCs of roflumilast and its metabolites). The tumorigenicity of roflumilast appears to be attributed to a reactive metabolite of 4-amino-3,5-dichloro-pyridine N-oxide (ADCP N-oxide). No evidence of tumorigenicity was observed in mice at roflumilast oral doses up to 12 and 18 mg/kg/day in females and males, respectively (approximately 10 and 15 times the MRHD, respectively, based on summed AUCs of roflumilast and its metabolites).

Roflumilast tested positive in an in vivo mouse micronucleus test, but negative in the following assays: Ames test for bacterial gene mutation, in vitro chromosome aberration assay in human lymphocytes, in vitro HPRT test with V79 cells, an in vitro micronucleus test with V79 cells, DNA adduct formation assay in rat nasal mucosa, liver and testes, and in vivo mouse bone marrow chromosome aberration assay. Roflumilast N-oxide was negative in the Ames test and in vitro micronucleus test with V79 cells.

In a human spermatogenesis study, roflumilast 500 mcg had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3-month off-treatment period. In a fertility study, roflumilast decreased fertility rates in male rats at 1.8-mg/kg/day (approximately 29 times the MRHD on a mg/m² basis). These rats also showed increases in the incidence of tubular atrophy, degeneration in the testis and spermiogenic granuloma in the epididymides. No effect on male rat fertility rate or reproductive organ morphology was observed at 0.8 mg/kg/day (approximately 13 times the MRHD on a mg/m² basis). No effect on female fertility was observed up to the highest roflumilast dose of 1.5 mg/kg/day in rats (approximately 24 times the MRHD on a mg/m² basis).

14 CLINICAL STUDIES

14.1 Chronic Obstructive Pulmonary Disease (COPD)

The efficacy and safety of DALIRESP (roflumilast) in COPD was evaluated in 8 randomized double-blind, controlled, parallel group clinical trials in 9394 adult patients (4425 receiving DALIRESP 500 mcg) 40 years of age and older with COPD. Of the 8 trials, two were placebo-controlled dose selection trials (Trials 1 and 2) of 6 months duration that evaluated the efficacy of DALIRESP 250 mcg and 500 mcg once daily, four were placebo-controlled 1-year trials (Trials 3, 4, 5, and 6) primarily designed to evaluate the efficacy of DALIRESP on COPD exacerbations, and two were 6-month efficacy trials (Trials 7 and 8) which assessed the effect of DALIRESP as add-on therapy to a long-acting beta agonist or long-acting anti-muscarinic. The 8 trials enrolled patients with nonreversible obstructive lung disease (FEV₁/FVC ≤ 70% and ≤ 12% or 200 mL improvement in FEV₁ in response to 4 puffs of albuterol/salbutamol) but the severity of airflow obstruction at baseline was different among the trials. Patients enrolled in the dose selection trials had the full range of COPD severity (FEV1 30-80% predicted); median age of 63 years, 73% male, and 99% Caucasian. Patients enrolled in the four exacerbation trials had severe COPD (FEV₁ ≤ 50% predicted); median age of 64 years, 74% male, and 90% Caucasian. Patients enrolled in the two 6-month efficacy trials had moderate to severe COPD (FEV₁ 40-70% predicted); median age of 65 years, 68% male, and 97% Caucasian. COPD exacerbations and lung function (FEV₁) were co-primary efficacy outcome measures in the four 1-year trials. In the two 6-month supportive efficacy trials, lung function (FEV₁) alone was the primary efficacy outcome measure.

The two 6-month dose-selection efficacy trials (Trials 1 and 2) explored doses of 250 mcg and 500 mcg once daily in a total of 1929 patients (751 and 724 on DALIRESP 250 and 500 mcg, respectively). The selection of the 500 mcg dose was primarily based on nominal improvements in lung function (FEV₁) over the 250 mcg dose. The once daily dosing regimen was primarily based on the determination of a plasma half-life of 17 hours for roflumilast and 30 hours for its active metabolite roflumilast N-oxide [see Clinical Pharmacology (12.3)].

Effect on Exacerbations

The effect of DALIRESP 500 mcg once daily on COPD exacerbations was evaluated in four 1-year trials (Trials 3, 4, 5, and 6).

Two of the trials (Trials 3 and 4) conducted initially enrolled a population of patients with severe COPD (FEV₁ ≤ 50% of predicted) inclusive of those with chronic bronchitis and/or emphysema who had a history of smoking of at least 10 pack years. Inhaled corticosteroids were allowed as concomitant medications and used in 61% of both DALIRESP and placebo-treated patients and short-acting beta agonists were allowed as rescue therapy. The use of long-acting beta agonists, long-acting anti-muscarinics, and theophylline were prohibited. The rate of moderate or severe COPD exacerbations was a co-primary endpoint in both trials. There was not a symptomatic definition of exacerbation in these 2 trials. Exacerbations were defined in terms of severity requiring treatment with a moderate exacerbation defined as treatment with systemic glucocorticosteroids in Trial 3 or systemic glucocorticosteroids and/or antibiotics in Trial 4 and a severe exacerbation defined as requiring hospitalizations and/or leading to death in Trial 3 or requiring hospitalization in Trial 4. The trials randomized 1176 patients (567 on DALIRESP) in Trial 3 and 1514 patients (760 on DALIRESP) in Trial 4. Both trials failed to demonstrate a significant reduction in the rate of COPD exacerbations.

Exploratory analyses of the results of Trials 3 and 4 identified a subpopulation of patients with severe COPD associated with chronic bronchitis and COPD exacerbations within the previous year that appeared to demonstrate a better response in the reduction of the rate of COPD exacerbations compared to the overall population. As a result, two subsequent trials (Trial 5 and Trial 6) were conducted that enrolled patients with severe COPD but associated with chronic bronchitis, at least one COPD exacerbation in the previous year, and at least a 20 pack-year smoking history. In these trials, long-acting beta agonists and short-acting anti-muscarinics were allowed and were used by 44% and 35% of patients treated with DALIRESP and 45% and 37% of patients treated with placebo, respectively. The use of inhaled corticosteroids was prohibited. As in trials 3 and 4, the rate of moderate exacerbations (defined as requiring intervention with systemic glucocorticosteroids) or severe exacerbations (defined as leading to hospitalization and/or to death) was a co-primary endpoint.

Trial 5 randomized a total of 1525 patients (765 on DALIRESP) and Trial 6 randomized a total of 1571 patients (772 on DALIRESP). In both trials, DALIRESP 500 mcg once daily demonstrated a significant reduction in the rate of moderate or severe exacerbations compared to placebo (Table 2). These two trials provide the evidence to support the use of DALIRESP for the reduction of COPD exacerbations.

For patients in Trials 5 and 6 who received concomitant long-acting beta agonists or short-acting anti-muscarinics, reduction of moderate or severe exacerbations with DALIRESP was similar to that observed for the overall populations of the two trials.

Effect on Lung Function

While DALIRESP is not a bronchodilator, all 1-year trials (Trials 3, 4, 5, and 6) evaluated the effect of DALIRESP on lung function as determined by the difference in FEV₁ between DALIRESP and placebo-treated patients (pre-bronchodilator FEV₁ measured prior to study drug administration in three of the trials and post-bronchodilator FEV₁ measured 30 minutes after administration of 4 puffs of albuterol/salbutamol in one trial) as a co-primary endpoint. In each of these trials DALIRESP 500 mcg once daily demonstrated a statistically significant improvement in FEV₁ which averaged approximately 50 mL across the four trials. Table 3 shows FEV₁ results from Trials 5 and 6 which had demonstrated a significant reduction in COPD exacerbations.

Lung function was also evaluated in two 6-month trials (Trials 7 and 8) to assess the effect of DALIRESP when administered as add-on therapy to treatment with a long-acting beta agonist or a long-acting anti-muscarinic. These trials were conducted in a different population of COPD patients [moderate to severe COPD (FEV₁ 40 to 70% of predicted) without a requirement for chronic bronchitis or frequent history of exacerbations] from that for which efficacy in reduction of exacerbations has been demonstrated and provide safety support to the DALIRESP COPD program.

No trials have been conducted to assess the effects of DALIRESP on COPD exacerbations when added to a fixed-dose combination product containing a long-acting beta agonist and inhaled corticosteroid.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

DALIRESP is supplied as white to off-white, round tablets, embossed with “D” on one side and “500” on the other side. Each tablet contains 500 mcg of roflumilast.

DALIRESP tablets are available:

•   Bottles of 30:                     NDC 0456-0095-30
•   Bottles of 90:                     NDC 0456-0095-90
•   10X10 Unit Dose:            NDC 0456-0095-63

16.2 Storage and Handling

Store DALIRESP 500 mcg tablets at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F). [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

• Bronchospasm

DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm. [see Warnings and Precautions (5.1)].

• Psychiatric Events including Suicidality

Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In clinical trials, 5.9% (263) of patients treated with DALIRESP 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse events were insomnia, anxiety, and depression which were reported at higher rates in those treated with DALIRESP 500 mcg (2.4%, 1.4%, and 1.2% for DALIRESP versus 1.0%, 0.9%, and 0.9% for placebo, respectively). Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving DALIRESP compared to one patient (suicidal ideation) who received placebo. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression.

Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with DALIRESP in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with DALIRESP if such events occur [see Warnings and Precautions (5.2)].

• Weight Decrease

Weight loss was a common adverse reaction in DALIRESP clinical trials and was reported in 7.5% (331) of patients treated with DALIRESP 500 mcg once daily compared to 2.1% (89) treated with placebo. In two placebo-controlled clinical trials of one year duration in which weight was prospectively assessed, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo and 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe (>10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving DALIRESP. Patients treated with DALIRESP should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of DALIRESP should be considered [see Warnings and Precautions (5.3)].

• Drug Interactions

The administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure which may result in a decrease in the therapeutic effectiveness of DALIRESP. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) with DALIRESP is not recommended [see Drugs That Induce Cytochrome P450 (CYP) Enzymes (7.1) and Clinical Pharmacology (12.3)].

Manufactured by:
Takeda GmbH
Production Site Oranienburg
Lehnitzstrasse 70 – 98
16515 Oranienburg
Germany

Manufactured for:
Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045, USA

Daliresp^® is a registered trademark of Takeda GmbH.

© 2010-2013 Forest Laboratories, Inc.

MEDICATION GUIDE

DALIRESP^® (da'-li-resp)

(roflumilast)

Tablets

Read this Medication Guide before you start taking DALIRESP^® and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is the most important information I should know about DALIRESP?

DALIRESP can cause serious side effects. Tell your healthcare provider right away if you have any of the symptoms listed below while taking DALIRESP.

• DALIRESP may cause mental health problems including suicidal thoughts and behavior. Some people taking DALIRESP may develop mood or behavior problems including:
  • thoughts of suicide or dying
  • attempt to commit suicide
  • trouble sleeping (insomnia)
  • new or worse anxiety
  • new or worse depression
  • acting on dangerous impulses
  • other unusual changes in your behavior or mood
• Weight loss. DALIRESP can cause weight loss. You should check your weight on a regular basis. You will also need to see your healthcare provider regularly to have your weight checked. If you notice that you are losing weight, call your healthcare provider. Your healthcare provider may ask you to stop taking DALIRESP if you lose too much weight.

DALIRESP may affect the way other medicines work, and other medicines may affect how DALIRESP works. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

What is DALIRESP?

DALIRESP is a prescription medicine used in adults with severe Chronic Obstructive Pulmonary Disease (COPD) to decrease the number of flare-ups or the worsening of COPD symptoms (exacerbations).

DALIRESP is not a bronchodilator and should not be used for treating sudden breathing problems. Your healthcare provider may give you other medicine to use for sudden breathing problems.

It is not known if DALIRESP is safe and effective in children.

Who should not take DALIRESP?

Do not take DALIRESP if you:

• have certain liver problems. Talk with your healthcare provider before you take DALIRESP if you have liver problems.

What should I tell my healthcare provider before taking DALIRESP?

Before you take DALIRESP, tell your healthcare provider if you:

• have or have had a history of mental health problems including depression and suicidal behavior.
• have liver problems
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if DALIRESP will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. It is not known if DALIRESP passes into your breast milk. You and your healthcare provider should decide if you will take DALIRESP or breastfeed. You should not do both.

How should I take DALIRESP?

• Take DALIRESP exactly as your healthcare provider tells you to take it.
• DALIRESP can be taken with or without food.
• If you take more than your prescribed dose of DALIRESP, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of DALIRESP?

DALIRESP can cause serious side effects, including:

See “ What is the most important information I should know about DALIRESP? ”

The most common side effects of DALIRESP include:

• diarrhea
• weight loss
• nausea
• headache
• back pain
• flu like symptoms
• problems sleeping (insomnia)
• dizziness
• decreased appetite

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of DALIRESP.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store DALIRESP Tablets?

• Store DALIRESP at 68°F to 77°F (20°C to 25°C); excursions permitted to 15° - 30°C (59° - 86°F). [See USP Controlled Room Temperature].

Keep DALIRESP Tablets and all medicines out of the reach of children.

General information about DALIRESP

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DALIRESP for a condition for which it was not prescribed. Do not give DALIRESP to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about DALIRESP. For more information about DALIRESP, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DALIRESP that is written for health professionals.

For more information about DALIRESP call 1-800-678-1605.

What are the ingredients in DALIRESP?

Active ingredient: roflumilast
Inactive ingredients: lactose monohydrate, corn starch, povidone and magnesium stearate.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Rev. 08/2013

Manufactured by:
Takeda GmbH
Production Site Oranienburg
Lehnitzstrasse 70 – 98
16515 Oranienburg
Germany

Manufactured for:
Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045, USA

Principal Display Panel – 30 Tablets Bottle Label

Rx Only NDC 0456-0095-30

Daliresp ^®

(roflumilast) tablets

500 mcg per tablet

Dispense the accompanying Medication Guide to each patient

30 Tablets

FOREST PHARMACEUTICALS, INC.

Subsidiary of Forest Laboratories, Inc.

St. Louis, Missouri 63045