These Highlights Do Not Include All The Information Needed To Use Daliresp Safely And Effectively. See Full Prescribing Information For Daliresp.

Risk Summary

There are no randomized clinical studies of DALIRESP in pregnant women. In animal reproductive toxicity studies, DALIRESP administered to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest DALIRESP dose in these studies was approximately 30 and 26 times, respectively, the maximum recommended human dose (MRHD). DALIRESP induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD. DALIRESP induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the MRHD. DALIRESP has been shown to adversely affect pup post-natal development when dams were treated with the drug during pregnancy and lactation periods in mice at doses corresponding to 49 times the MRHD (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Labor and delivery

DALIRESP should not be used during labor and delivery. There are no human studies that have investigated effects of DALIRESP on preterm labor or labor at term; however, animal studies showed that DALIRESP disrupted the labor and delivery process in mice.

Data

Animal data

In an embryo-fetal development study, pregnant rats were dosed orally during the period of organogenesis with up to 1.8 mg/kg/day DALIRESP (approximately 30 times the MRHD on an AUC basis). No evidence of structural abnormalities or effects on survival rates were observed. DALIRESP did not affect embryo-fetal development at approximately 3 times the MRHD (on a mg/m² basis at a maternal oral dose of 0.2 mg/kg/day).

In a fertility and embryo-fetal development study, male rats were dosed orally with up to 1.8 mg/kg/day DALIRESP for 10 weeks and females for two weeks prior to pairing and throughout the organogenesis period. DALIRESP induced pre- and post-implantation loss at doses greater than or equal to approximately 10 times the MRHD (on a mg/m2 basis at maternal oral doses greater than or equal to 0.6 mg/kg/day). DALIRESP did not cause fetal structural abnormalities at exposures up to approximately 29 times the MRHD (on an AUC basis at maternal oral doses up to 1.8 mg/kg/day).

In an embryo-fetal development study in rabbits, pregnant does were dosed orally with 0.8 mg/kg/day DALIRESP during the period of organogenesis. DALIRESP did not cause fetal structural abnormalities at exposures approximately 26 times the MRHD (on a mg/m² basis at maternal oral doses of 0.8 mg/kg/day).

In pre- and post-natal developmental studies in mice, dams were dosed orally with up to 12 mg/kg/day

DALIRESP during the period of organogenesis and lactation. DALIRESP induced stillbirth and decreased pup

viability at doses corresponding to approximately 16 and 49 times, respectively, the MRHD (on a mg/m²

basis at maternal doses >2 mg/kg/day and 6 mg/kg/day, respectively). DALIRESP induced delivery retardation in pregnant mice at doses greater or equal to approximately 16 times the MRHD (on a mg/m² basis at maternal doses >2 mg/kg/day). DALIRESP decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/m² basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. DALIRESP also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on a mg/m² basis at a maternal dose of 12 mg/kg/day).

Limitations of Use

DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.

DALIRESP 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose.

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.

• 1.
  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
• 2.
  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 1-800-236-9933.

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. 04/2017

Distributed by:

AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850

Risk Summary

There is no information regarding the presence of DALIRESP in human milk, the effects on the breastfed infant, or the effects on milk production.

Roflumilast and/or its metabolites are excreted into the milk of lactating rats. Excretion of roflumilast and/or its metabolites into human milk is probable. DALIRESP should not be used by women who are nursing.

Data

Animal data

Roflumilast and/or its metabolite concentrations measured 8 hours after an oral dose of 1 mg/kg given to lactating rats were 0.32 and 0.02 mcg/g in the milk and pup liver, respectively.

The active ingredient in DALIRESP tablets is roflumilast. Roflumilast and its active metabolite (roflumilast N-oxide) are selective phosphodiesterase 4 (PDE4) inhibitors. The chemical name of roflumilast is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide. Its empirical formula is C₁₇H₁₄Cl₂F₂N₂O₃ and the molecular weight is 403.22.

The chemical structure is:

The drug substance is a white to off-white non-hygroscopic powder with a melting point of 160°C. It is practically insoluble in water and hexane, sparingly soluble in ethanol, and freely soluble in acetone.

DALIRESP is supplied as white to off-white, round tablets, embossed with “D” on one side and “250” or “500” on the other side. Each tablet contains 250 mcg or 500 mcg of roflumilast.

Each tablet of DALIRESP for oral administration contains the following inactive ingredients: lactose monohydrate, corn starch, povidone, and magnesium stearate.

DALIRESP 250 mcg is supplied as white to off-white, round tablets, embossed with “D” on one side and “250” on the other side.

DALIRESP 250 mcg tablets are available:

        Blister pack 28:                    NDC 0310-0088-28

        2X10 Unit Dose:                  NDC 0310-0088-39

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

DALIRESP 500 mcg tablets are available:

        Bottles of 30:                         NDC 0310-0095-30

        Bottles of 90:                         NDC 0310-0095-90

COPD does not normally occur in children. The safety and effectiveness of DALIRESP in pediatric patients have not been established.

Of the 4438 COPD subjects exposed to DALIRESP for up to 12 months in 8 controlled clinical trials, 2022 were >65 years of age and 471 were >75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for roflumilast, no adjustment of dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].

The use of DALIRESP is contraindicated in the following condition:

Moderate to severe liver impairment (Child-Pugh B or C) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6) ].

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 [see Adverse Reactions (6.1)]. In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In these studies, 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. In addition, 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.

The following adverse reactions are described in greater detail in other sections:

• •
  Psychiatric Events Including Suicidality [see Warnings and Precautions (5.2)]
• •
  Weight Decrease [see Warnings and Precautions (5.3)]

A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 [see Clinical Pharmacology (12.3)].

In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, the AUCs of roflumilast and roflumilast N-oxide were decreased by 21% and 7%, respectively and C_max were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment [see Clinical Pharmacology (12.3) ].

No case of overdose has been reported in clinical studies with DALIRESP. During the Phase I studies of DALIRESP, the following symptoms were observed at an increased rate after a single oral dose of 2500 mcg and a single dose of 5000 mcg: headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess, and arterial hypotension.

In COPD patients, 4‑week treatment with DALIRESP 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, and 42%, respectively. In a pharmacodynamic study in healthy volunteers, DALIRESP 500 mcg once daily reduced the number of total cells, neutrophils and eosinophils found in bronchoalveolar lavage fluid following segmental pulmonary lipopolysaccharide (LPS) challenge by 35%, 38% and 73%, respectively. The clinical significance of these findings is unknown.

A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. 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 Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUCs of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively, in Child-Pugh A subjects and by 92% and 41%, respectively, in Child-Pugh B subjects, as compared to age-, weight-, and gender-matched healthy subjects. The C_max of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. DALIRESP 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering DALIRESP to patients who have mild liver impairment (Child-Pugh A). DALIRESP is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C) [see Contraindications (4) and Clinical Pharmacology (12.3)].

DALIRESP^® is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which DALIRESP exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells.

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

• •
  Acute Bronchospasm: Do not use for the relief of acute bronchospasm. (5.1)
• •
  Psychiatric Events including Suicidality: Advise patients, their caregivers, and families 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. Carefully weigh the risks and benefits of treatment with DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior. (5.2)
• •
  Weight Decrease: Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of DALIRESP. (5.3)
• •
  Drug Interactions: Use with strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended. (5.4)

In case of overdose, patients should seek immediate medical help. Appropriate supportive medical care should be provided. Since roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of drug removal. It is not known whether roflumilast is dialyzable by peritoneal dialysis.

The maintenance dose of DALIRESP is one 500 micrograms (mcg) tablet per day, with or without food.

Starting treatment with a dose of DALIRESP 250 mcg once daily for 4 weeks and increasing to DALIRESP 500 mcg once daily thereafter may reduce the rate of treatment discontinuation in some patients [see Clinical Studies (14.1)] . However, 250 mcg per day is not the effective (therapeutic) dose.

• •
  DALIRESP 250 mcg tablets are white to off-white, round, embossed with “D” on one side and “250” on the other side
• •
  DALIRESP 500 mcg tablets are white to off-white, round, embossed with “D” on one side and “500” on the other side

The following adverse reactions have been identified from spontaneous reports of DALIRESP received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to DALIRESP. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to DALIRESP exposure:  hypersensitivity reactions (including angioedema, urticaria, and rash), gynecomastia.

Nursing Mothers: DALIRESP should not be used by women who are nursing as excretion of roflumilast and/or its metabolites into human milk is probable and there are no human studies that have investigated effects of DALIRESP on breast-fed infants. (8.2)

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

DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm.

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 safety data described below reflect exposure of 4438 patients to DALIRESP 500 mcg once daily in four 1-year placebo-controlled trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials [see Clinical Studies (14.1)]. In these trials, 3136 and 1232 COPD patients were exposed to DALIRESP 500 mcg once daily for 6 months and 1 year, respectively.

The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV₁) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with DALIRESP reported an adverse reaction compared with 65.3% treated with placebo.

The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for DALIRESP-treated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of DALIRESP were diarrhea (2.4%) and nausea (1.6%).

Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in DALIRESP-treated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure.

Table 1 summarizes the adverse reactions reported by ≥2% of patients in the DALIRESP group in 8 controlled COPD clinical trials.

Adverse reactions that occurred in the DALIRESP group at a frequency of 1 to 2% where rates exceeded that in the placebo group include:

Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting

Infections and infestations - rhinitis, sinusitis, urinary tract infection

Musculoskeletal and connective tissue disorders - muscle spasms

Nervous system disorders - tremor

Psychiatric disorders - anxiety, depression

The safety profile of roflumilast reported during Trial 9 was consistent with the key pivotal studies.

Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In 8 controlled 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 reactions were insomnia, anxiety, and depression which were reported at higher rates in those treated with DALIRESP 500 mcg daily (2.4%, 1.4%, and 1.2% for DALIRESP versus 1.0%, 0.9%, and 0.9% for placebo, respectively) [see Adverse Reactions (6.1)]. 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. One patient completed suicide while receiving DALIRESP in Trial 9 [see Clinical Studies (14.1)], which assessed the effect of adding roflumilast to a fixed-dose combination (FDC) of ICS/LABA on rates of exacerbations in COPD patients over 1 year of treatment. 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.

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)].

An additional placebo-controlled 1-year trial (Trial 9) evaluated the effect of DALIRESP 500 mcg on COPD exacerbations when added to a fixed-dose combination (FDC) product containing an inhaled corticosteroid and long-acting beta agonist (ICS/LABA). At screening, patients were required to have two or more exacerbations in the previous year. This trial randomized a total of 2354 patients (1178 randomized to DALIRESP, 1176 to placebo). Approximately 60% of the patients enrolled had severe COPD (postbronchodilator FEV₁ 30%-50% of predicted) associated with chronic bronchitis and 39% had very severe COPD (postbronchodilator FEV₁ ≤ 30% of predicted) associated with chronic bronchitis; mean age of 64 years, 69% male, and 80% Caucasian. The use of long-acting muscarinic antagonists was allowed.

Rx Only              28 Tablets                NDC 0310-0088-28

Daliresp ^®

(roflumilast) tablets          250 mcg

28 Day Pack

CONTENTS: One Child-Resistant Package containing 28 tablets

AstraZeneca

Rx Only                              NDC 0310-0095-30

Daliresp ^®

(roflumilast) tablets

500 mcg per tablet

Dispense the accompanying

Medication Guide to each patient

30 Tablets

AstraZeneca

Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of DALIRESP. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with DALIRESP is not recommended [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

The co-administration of DALIRESP (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit [see Clinical Pharmacology (12.3)].

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). The male rats also showed increases in the incidence of tubular atrophy, degeneration in the testis and spermiogenic granuloma in the epididymides. No effect on rat fertility rate or male reproductive organ morphology was observed at 0.6 mg/kg/day (approximately 10 times the MRHD on a mg/m² basis). In a female fertility study, no effect on 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).

The co-administration of DALIRESP (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully against benefit [see Clinical Pharmacology (12.3)].

Risk Summary

There are no randomized clinical studies of DALIRESP in pregnant women. In animal reproductive toxicity studies, DALIRESP administered to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest DALIRESP dose in these studies was approximately 30 and 26 times, respectively, the maximum recommended human dose (MRHD). DALIRESP induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD. DALIRESP induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the MRHD. DALIRESP has been shown to adversely affect pup post-natal development when dams were treated with the drug during pregnancy and lactation periods in mice at doses corresponding to 49 times the MRHD (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Labor and delivery

DALIRESP should not be used during labor and delivery. There are no human studies that have investigated effects of DALIRESP on preterm labor or labor at term; however, animal studies showed that DALIRESP disrupted the labor and delivery process in mice.

Data

Animal data

In an embryo-fetal development study, pregnant rats were dosed orally during the period of organogenesis with up to 1.8 mg/kg/day DALIRESP (approximately 30 times the MRHD on an AUC basis). No evidence of structural abnormalities or effects on survival rates were observed. DALIRESP did not affect embryo-fetal development at approximately 3 times the MRHD (on a mg/m² basis at a maternal oral dose of 0.2 mg/kg/day).

In a fertility and embryo-fetal development study, male rats were dosed orally with up to 1.8 mg/kg/day DALIRESP for 10 weeks and females for two weeks prior to pairing and throughout the organogenesis period. DALIRESP induced pre- and post-implantation loss at doses greater than or equal to approximately 10 times the MRHD (on a mg/m2 basis at maternal oral doses greater than or equal to 0.6 mg/kg/day). DALIRESP did not cause fetal structural abnormalities at exposures up to approximately 29 times the MRHD (on an AUC basis at maternal oral doses up to 1.8 mg/kg/day).

In an embryo-fetal development study in rabbits, pregnant does were dosed orally with 0.8 mg/kg/day DALIRESP during the period of organogenesis. DALIRESP did not cause fetal structural abnormalities at exposures approximately 26 times the MRHD (on a mg/m² basis at maternal oral doses of 0.8 mg/kg/day).

In pre- and post-natal developmental studies in mice, dams were dosed orally with up to 12 mg/kg/day

DALIRESP during the period of organogenesis and lactation. DALIRESP induced stillbirth and decreased pup

viability at doses corresponding to approximately 16 and 49 times, respectively, the MRHD (on a mg/m²

basis at maternal doses >2 mg/kg/day and 6 mg/kg/day, respectively). DALIRESP induced delivery retardation in pregnant mice at doses greater or equal to approximately 16 times the MRHD (on a mg/m² basis at maternal doses >2 mg/kg/day). DALIRESP decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/m² basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. DALIRESP also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on a mg/m² basis at a maternal dose of 12 mg/kg/day).

Limitations of Use

DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.

DALIRESP 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose.

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.

• 1.
  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
• 2.
  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 1-800-236-9933.

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. 04/2017

Distributed by:

AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850

Risk Summary

There is no information regarding the presence of DALIRESP in human milk, the effects on the breastfed infant, or the effects on milk production.

Roflumilast and/or its metabolites are excreted into the milk of lactating rats. Excretion of roflumilast and/or its metabolites into human milk is probable. DALIRESP should not be used by women who are nursing.

Data

Animal data

Roflumilast and/or its metabolite concentrations measured 8 hours after an oral dose of 1 mg/kg given to lactating rats were 0.32 and 0.02 mcg/g in the milk and pup liver, respectively.

The active ingredient in DALIRESP tablets is roflumilast. Roflumilast and its active metabolite (roflumilast N-oxide) are selective phosphodiesterase 4 (PDE4) inhibitors. The chemical name of roflumilast is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide. Its empirical formula is C₁₇H₁₄Cl₂F₂N₂O₃ and the molecular weight is 403.22.

The chemical structure is:

The drug substance is a white to off-white non-hygroscopic powder with a melting point of 160°C. It is practically insoluble in water and hexane, sparingly soluble in ethanol, and freely soluble in acetone.

DALIRESP is supplied as white to off-white, round tablets, embossed with “D” on one side and “250” or “500” on the other side. Each tablet contains 250 mcg or 500 mcg of roflumilast.

Each tablet of DALIRESP for oral administration contains the following inactive ingredients: lactose monohydrate, corn starch, povidone, and magnesium stearate.

DALIRESP 250 mcg is supplied as white to off-white, round tablets, embossed with “D” on one side and “250” on the other side.

DALIRESP 250 mcg tablets are available:

        Blister pack 28:                    NDC 0310-0088-28

        2X10 Unit Dose:                  NDC 0310-0088-39

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

DALIRESP 500 mcg tablets are available:

        Bottles of 30:                         NDC 0310-0095-30

        Bottles of 90:                         NDC 0310-0095-90

COPD does not normally occur in children. The safety and effectiveness of DALIRESP in pediatric patients have not been established.

Of the 4438 COPD subjects exposed to DALIRESP for up to 12 months in 8 controlled clinical trials, 2022 were >65 years of age and 471 were >75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for roflumilast, no adjustment of dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].

The use of DALIRESP is contraindicated in the following condition:

Moderate to severe liver impairment (Child-Pugh B or C) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6) ].

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 [see Adverse Reactions (6.1)]. In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In these studies, 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. In addition, 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.

The following adverse reactions are described in greater detail in other sections:

• •
  Psychiatric Events Including Suicidality [see Warnings and Precautions (5.2)]
• •
  Weight Decrease [see Warnings and Precautions (5.3)]

A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 [see Clinical Pharmacology (12.3)].

In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, the AUCs of roflumilast and roflumilast N-oxide were decreased by 21% and 7%, respectively and C_max were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment [see Clinical Pharmacology (12.3) ].

No case of overdose has been reported in clinical studies with DALIRESP. During the Phase I studies of DALIRESP, the following symptoms were observed at an increased rate after a single oral dose of 2500 mcg and a single dose of 5000 mcg: headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess, and arterial hypotension.

In COPD patients, 4‑week treatment with DALIRESP 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, and 42%, respectively. In a pharmacodynamic study in healthy volunteers, DALIRESP 500 mcg once daily reduced the number of total cells, neutrophils and eosinophils found in bronchoalveolar lavage fluid following segmental pulmonary lipopolysaccharide (LPS) challenge by 35%, 38% and 73%, respectively. The clinical significance of these findings is unknown.

A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. 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 Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUCs of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively, in Child-Pugh A subjects and by 92% and 41%, respectively, in Child-Pugh B subjects, as compared to age-, weight-, and gender-matched healthy subjects. The C_max of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. DALIRESP 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering DALIRESP to patients who have mild liver impairment (Child-Pugh A). DALIRESP is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C) [see Contraindications (4) and Clinical Pharmacology (12.3)].

DALIRESP^® is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which DALIRESP exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells.

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

• •
  Acute Bronchospasm: Do not use for the relief of acute bronchospasm. (5.1)
• •
  Psychiatric Events including Suicidality: Advise patients, their caregivers, and families 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. Carefully weigh the risks and benefits of treatment with DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior. (5.2)
• •
  Weight Decrease: Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of DALIRESP. (5.3)
• •
  Drug Interactions: Use with strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended. (5.4)

In case of overdose, patients should seek immediate medical help. Appropriate supportive medical care should be provided. Since roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of drug removal. It is not known whether roflumilast is dialyzable by peritoneal dialysis.

The maintenance dose of DALIRESP is one 500 micrograms (mcg) tablet per day, with or without food.

Starting treatment with a dose of DALIRESP 250 mcg once daily for 4 weeks and increasing to DALIRESP 500 mcg once daily thereafter may reduce the rate of treatment discontinuation in some patients [see Clinical Studies (14.1)] . However, 250 mcg per day is not the effective (therapeutic) dose.

• •
  DALIRESP 250 mcg tablets are white to off-white, round, embossed with “D” on one side and “250” on the other side
• •
  DALIRESP 500 mcg tablets are white to off-white, round, embossed with “D” on one side and “500” on the other side

The following adverse reactions have been identified from spontaneous reports of DALIRESP received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to DALIRESP. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to DALIRESP exposure:  hypersensitivity reactions (including angioedema, urticaria, and rash), gynecomastia.

Nursing Mothers: DALIRESP should not be used by women who are nursing as excretion of roflumilast and/or its metabolites into human milk is probable and there are no human studies that have investigated effects of DALIRESP on breast-fed infants. (8.2)

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

DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm.

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 safety data described below reflect exposure of 4438 patients to DALIRESP 500 mcg once daily in four 1-year placebo-controlled trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials [see Clinical Studies (14.1)]. In these trials, 3136 and 1232 COPD patients were exposed to DALIRESP 500 mcg once daily for 6 months and 1 year, respectively.

The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV₁) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with DALIRESP reported an adverse reaction compared with 65.3% treated with placebo.

The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for DALIRESP-treated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of DALIRESP were diarrhea (2.4%) and nausea (1.6%).

Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in DALIRESP-treated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure.

Table 1 summarizes the adverse reactions reported by ≥2% of patients in the DALIRESP group in 8 controlled COPD clinical trials.

Adverse reactions that occurred in the DALIRESP group at a frequency of 1 to 2% where rates exceeded that in the placebo group include:

Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting

Infections and infestations - rhinitis, sinusitis, urinary tract infection

Musculoskeletal and connective tissue disorders - muscle spasms

Nervous system disorders - tremor

Psychiatric disorders - anxiety, depression

The safety profile of roflumilast reported during Trial 9 was consistent with the key pivotal studies.

Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In 8 controlled 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 reactions were insomnia, anxiety, and depression which were reported at higher rates in those treated with DALIRESP 500 mcg daily (2.4%, 1.4%, and 1.2% for DALIRESP versus 1.0%, 0.9%, and 0.9% for placebo, respectively) [see Adverse Reactions (6.1)]. 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. One patient completed suicide while receiving DALIRESP in Trial 9 [see Clinical Studies (14.1)], which assessed the effect of adding roflumilast to a fixed-dose combination (FDC) of ICS/LABA on rates of exacerbations in COPD patients over 1 year of treatment. 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.

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)].

An additional placebo-controlled 1-year trial (Trial 9) evaluated the effect of DALIRESP 500 mcg on COPD exacerbations when added to a fixed-dose combination (FDC) product containing an inhaled corticosteroid and long-acting beta agonist (ICS/LABA). At screening, patients were required to have two or more exacerbations in the previous year. This trial randomized a total of 2354 patients (1178 randomized to DALIRESP, 1176 to placebo). Approximately 60% of the patients enrolled had severe COPD (postbronchodilator FEV₁ 30%-50% of predicted) associated with chronic bronchitis and 39% had very severe COPD (postbronchodilator FEV₁ ≤ 30% of predicted) associated with chronic bronchitis; mean age of 64 years, 69% male, and 80% Caucasian. The use of long-acting muscarinic antagonists was allowed.

Rx Only              28 Tablets                NDC 0310-0088-28

Daliresp ^®

(roflumilast) tablets          250 mcg

28 Day Pack

CONTENTS: One Child-Resistant Package containing 28 tablets

AstraZeneca

Rx Only                              NDC 0310-0095-30

Daliresp ^®

(roflumilast) tablets

500 mcg per tablet

Dispense the accompanying

Medication Guide to each patient

30 Tablets

AstraZeneca

Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of DALIRESP. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with DALIRESP is not recommended [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

The co-administration of DALIRESP (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit [see Clinical Pharmacology (12.3)].

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). The male rats also showed increases in the incidence of tubular atrophy, degeneration in the testis and spermiogenic granuloma in the epididymides. No effect on rat fertility rate or male reproductive organ morphology was observed at 0.6 mg/kg/day (approximately 10 times the MRHD on a mg/m² basis). In a female fertility study, no effect on 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).

The co-administration of DALIRESP (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully against benefit [see Clinical Pharmacology (12.3)].