Даксас

Даксас® 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.

Limitations Of Use

Даксас is not a bronchodilator and is not indicated for the relief of acute bronchospasm. Даксас 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose.

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

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

The use of Даксас is contraindicated in the following condition:

Moderate to severe liver impairment (Child-Pugh B or C).

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Treatment Of Acute Bronchospasm

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

Psychiatric Events Including Suicidality

Treatment with Даксас is associated with an increase in psychiatric adverse reactions. In 8 controlled clinical trials 5.9% (263) of patients treated with Даксас 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 Даксас 500 mcg daily (2.4%, 1.4%, and 1.2% for Даксас 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 Даксас compared to one patient (suicidal ideation) who received placebo. One patient completed suicide while receiving Даксас in Trial 9 , 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 Даксас in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with Даксас 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 Даксас if such events occur.

Weight Decrease

Weight loss was a common adverse reaction in Даксас clinical trials and was reported in 7.5% (331) of patients treated with Даксас 500 mcg once daily compared to 2.1% (89) treated with placebo. 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 Даксас. Patients treated with Даксас should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of Даксас should be considered.

Drug Interactions

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 Даксас. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) with Даксас is not recommended.

Patient Counseling Information

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

Bronchospasm

Даксас is not a bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).

Psychiatric Events Including Suicidality

Treatment with Даксас is associated with an increase in psychiatric adverse reactions. 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. The risks and benefits of treatment with Даксас in patients with a history of depression and/or suicidal thoughts or behavior should be carefully considered. Advise patients, 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 so that the risks and benefits of continuing treatment with Даксас may be considered.

Weight Decrease

Weight loss was a common adverse reaction in Даксас clinical trials. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving Даксас. Advise patients treated with Даксас to have their weight monitored regularly. If unexplained weight loss occurs, patients should inform their healthcare provider so that the weight loss can be evaluated, as discontinuation of Даксас may need to be considered.

Drug Interactions

The use of cytochrome P450 enzyme inducers resulted in a reduction in exposure which may result in decreased therapeutic effectiveness of Даксас. The use of strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) with Даксас is not recommended.

Nonclinical Toxicology

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-dichloropyridine 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).

Use In Specific Populations

Pregnancy

Risk Summary

There are no randomized clinical studies of Даксас in pregnant women. In animal reproductive toxicity studies, Даксас administered to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest Даксас dose in these studies was approximately 30 and 26 times, respectively, the maximum recommended human dose (MRHD). Даксас induced postimplantation loss in rats at doses greater than or equal to approximately 10 times the MRHD. Даксас induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the MRHD. Даксас 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

Даксас should not be used during labor and delivery. There are no human studies that have investigated effects of Даксас on preterm labor or labor at term; however, animal studies showed that Даксас 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 Даксас (approximately 30 times the MRHD on an AUC basis). No evidence of structural abnormalities or effects on survival rates were observed. Даксас 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 Даксас for 10 weeks and females for two weeks prior to pairing and throughout the organogenesis period. Даксас 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). Даксас 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 Даксас during the period of organogenesis. Даксас 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 Даксас during the period of organogenesis and lactation. Даксас 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). Даксас 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). Даксас 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. Даксас 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).

Lactation

Risk Summary

There is no information regarding the presence of Даксас 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. Даксас 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.

Pediatric Use

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

Geriatric Use

Of the 4438 COPD subjects exposed to Даксас 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.

Hepatic Impairment

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 Cmax 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. Даксас 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering Даксас to patients who have mild liver impairment (Child-Pugh A). Даксас is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C).

Renal Impairment

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 Cmax were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment.

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

• Psychiatric Events Including Suicidality
• Weight Decrease

Adverse Reactions In Clinical Studies

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 Даксас 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. In these trials, 3136 and 1232 COPD patients were exposed to Даксас 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 Даксас 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 Даксасtreated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of Даксас 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 Даксас-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 Даксас group in 8 controlled COPD clinical trials.

Table 1: Adverse Reactions Reported by ≥2% of Patients Treated with Даксас 500 mcg daily and Greater Than Placebo

Adverse reactions that occurred in the Даксас 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.

Postmarketing Experience

The following adverse reactions have been identified from spontaneous reports of Даксас 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 Даксас. 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 Даксас exposure: hypersensitivity reactions (including angioedema, urticaria, and rash), gynecomastia.

Human Experience

No case of overdose has been reported in clinical studies with Даксас. During the Phase I studies of Даксас, 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.

Management Of Overdose

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.

In COPD patients, 4-week treatment with Даксас 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, and 42%, respectively. In a pharmacodynamic study in healthy volunteers, Даксас 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.

Absorption

The absolute bioavailability of roflumilast following a 500 mcg oral dose is approximately 80%. Maximum plasma concentrations (Cmax) of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to 2 hours) in the fasted state while plateau-like maximum concentrations of the N-oxide metabolite are reached in approximately eight hours (ranging from 4 to 13 hours). Food has no effect on total drug absorption, but delays time to maximum concentration (Tmax) of roflumilast by one hour and reduces Cmax by approximately 40%, however, Cmax and Tmax of roflumilast N-oxide are unaffected. An in vitro study showed that roflumilast and roflumilast N-oxide did not inhibit P-gp transporter.

Distribution

Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for single-dose 500 mcg roflumilast is about 2.9 L/kg. Studies in rats with radiolabeled roflumilast indicate low penetration across the blood-brain barrier.

Metabolism

Roflumilast is extensively metabolized via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is the only major metabolite observed in the plasma of humans. Together, roflumilast and roflumilast N-oxide account for the majority (87.5%) of total dose administered in plasma. In urine, roflumilast was not detectable while roflumilast N-oxide was only a trace metabolite (less than 1%). Other conjugated metabolites such as roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N-oxide were detected in urine.

While roflumilast is three times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro, the plasma AUC of roflumilast N-oxide on average is about 10-fold greater than the plasma AUC of roflumilast.

In vitro studies and clinical drug-drug interaction studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is a low probability of relevant interactions with substances metabolized by these P450 enzymes. In addition, in vitro studies demonstrated no induction of the CYP 1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP2B6 by roflumilast.

Elimination

The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9.6 L/h. Following an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately 4 days for roflumilast and 6 days for roflumilast N-oxide following once-daily dosing. Following intravenous or oral administration of radiolabeled roflumilast, about 70% of the radioactivity was recovered in the urine.