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ROFLUMILAST

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4) (a major cyclic-3',5'-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung tissue) that can lead to accumulation of intracellular cyclic AMP in lung cells.

Specific Substances

    1) CAS 162401-32-3
    1.2.1) MOLECULAR FORMULA
    1) C17-H14-Cl2-F2-N2-O3 (Prod Info DALIRESP(TM) oral tablets, 2011).

Available Forms Sources

    A) FORMS
    1) Roflumilast is available in the US as 500 microgram tablets (Prod Info DALIRESP(TM) oral tablets, 2011).
    B) USES
    1) Roflumilast is indicated for use as a treatment to reduce to the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Roflumilast has no acute bronchodilator characteristics and should not be used in the treatment of acute bronchospasm (Prod Info DALIRESP(TM) oral tablets, 2011).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Roflumilast is indicated to reduce to the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.
    B) PHARMACOLOGY: 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.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Weight decrease, diarrhea, nausea, headache and back pain. LESS COMMON: Insomnia, dizziness and influenza. INFREQUENT: Anxiety, depression. RARE: Suicidal thoughts.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: During clinical studies, single doses of 2500 mcg and 5000 mcg produced an increased incidence of headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess and hypotension. SEVERE TOXICITY: Limited data. Symptomatic hypotension may develop.
    0.2.20) REPRODUCTIVE
    A) Roflumilast is classified as FDA pregnancy category C. In animal studies, roflumilast was not teratogenic in mice, rats or rabbits; however, increased post-implantation loss and decreased survival/viability was observed in mice and rats.

Laboratory Monitoring

    A) Monitor vital signs and liver enzymes in all symptomatic patients.
    B) Assess neurologic status.
    C) Monitor fluid and electrolyte levels in patients with severe vomiting.
    D) Serum roflumilast levels are not readily available and are not clinically useful.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV fluids and vasopressors, if necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: Serious toxicity is not expected after ingestion of roflumilast alone, and prehospital gastrointestinal decontamination is not routinely required.
    2) HOSPITAL: Significant toxicity is not expected after overdose; gastrointestinal decontamination is generally not necessary. Activated charcoal should be considered after extremely large ingestions or if more toxic coingestants are involved.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with serious toxicity or severe allergic reactions.
    E) ANTIDOTE
    1) None.
    F) HYPOTENSION
    1) Initially treat with IV NS 10 to 20 ml/kg, if unresponsive to fluid bolus administer dopamine, norepinephrine, as necessary.
    G) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with a minor unintentional exposure who are asymptomatic or have mild symptoms can likely be managed at home.
    2) OBSERVATION CRITERIA: Patients with an inadvertent overdose who have more than mild symptoms and patients with deliberate self-harm ingestions should be sent to a health care facility for evaluation and treated until symptoms resolve.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) Failure to recognize the possible involvement of coingestants.
    J) PHARMACOKINETICS
    1) Tmax occurs approximately one hour after dosing, with a range of 0.5 to 2 hours. Plasma protein binding for roflumilast and the N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for roflumilast 500 mcg single dose is 2.9 L/kg. 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. The median half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other medications or conditions that can cause hypotension (beta-blockers, calcium channel blockers, vasodilators).

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. During Phase I trials, single doses of 2500 mcg and 5000 mcg caused headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess and hypotension.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose of roflumilast is 500 mcg once daily. PEDIATRIC: Roflumilast is not indicated for use in the pediatric population.

Clinical Effects

Summary Of Exposure

    A) USES: Roflumilast is indicated to reduce to the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.
    B) PHARMACOLOGY: 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.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Weight decrease, diarrhea, nausea, headache and back pain. LESS COMMON: Insomnia, dizziness and influenza. INFREQUENT: Anxiety, depression. RARE: Suicidal thoughts.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: During clinical studies, single doses of 2500 mcg and 5000 mcg produced an increased incidence of headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess and hypotension. SEVERE TOXICITY: Limited data. Symptomatic hypotension may develop.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PALPITATIONS
    1) WITH POISONING/EXPOSURE
    a) During Phase I clinical studies, single doses of 2500 mcg and 5000 mcg produced an increased incidence of palpitations (Prod Info DALIRESP(TM) oral tablets, 2011).
    B) LOW BLOOD PRESSURE
    1) WITH POISONING/EXPOSURE
    a) During Phase I clinical studies, single doses of 2500 mcg and 5000 mcg produced an increased incidence of clamminess and hypotension (Prod Info DALIRESP(TM) oral tablets, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In clinical trials of COPD patients, dizziness was reported in 2.1% (92 of 4438) of patients who received roflumilast 500 mcg once daily compared with 1.1% (45 of 4192) of patients who received placebo for up to 1 year (Prod Info DALIRESP(TM) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) During Phase I clinical studies, single doses of 2500 mcg and 5000 mcg produced an increased incidence of dizziness (Prod Info DALIRESP(TM) oral tablets, 2011).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In clinical trials of COPD patients, headache was reported in 4.4% (195 of 4438) of patients who received roflumilast 500 mcg once daily compared with 2.1% (87 of 4192) of patients who received placebo for up to 1 year (Prod Info DALIRESP(TM) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) During Phase I clinical studies, single doses of 2500 mcg and 5000 mcg produced an increased incidence of headache (Prod Info DALIRESP(TM) oral tablets, 2011).
    C) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials of COPD patients, insomnia was reported in 2.4% (105 of 4438) of patients who received roflumilast 500 mcg once daily compared with 1% (41 of 4192) of patients who received placebo for up to 1 year (Prod Info DALIRESP(TM) oral tablets, 2011).
    D) ANXIETY
    1) WITH THERAPEUTIC USE
    a) In clinical trials of COPD patients, anxiety was reported in 1.4% of patients who received roflumilast 500 mcg once daily (n=4438) compared with 0.9% of patients who received placebo (n=4192) for up to 1 year (Prod Info DALIRESP(TM) oral tablets, 2011).
    E) DEPRESSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) In clinical trials of COPD patients, depression was reported in 1.2% of patients who received roflumilast 500 mcg once daily (n=4438) compared with 0.9% of patients who received placebo (n=4192) for up to 1 year (Prod Info DALIRESP(TM) oral tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In clinical trials of COPD patients, diarrhea was reported in 9.5% (420 of 4438) of patients who received roflumilast 500 mcg once daily compared with 2.7% (113 of 4192) of patients who received placebo for up to 1 year. Diarrhea led to treatment discontinuation in 2.4% of patients (Prod Info DALIRESP(TM) oral tablets, 2011).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In clinical trials of COPD patients, nausea was reported in 4.7% (209 of 4438) of patients who received roflumilast 500 mcg once daily compared with 1.4% (60 of 4192) of patients who received placebo for up to 1 year. Nausea led to treatment discontinuation in 1.6% of patients (Prod Info DALIRESP(TM) oral tablets, 2011).
    C) VOMITING
    1) WITH THERAPEUTIC USE
    a) In clinical trials of COPD patients, vomiting was reported in 1% to 2% of patients who received roflumilast 500 mcg once daily (n=4438) and was reported more frequently compared with the placebo group (n=4192) (Prod Info DALIRESP(TM) oral tablets, 2011).
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In clinical trials of COPD patients, abdominal pain was reported in 1% to 2% of patients who received roflumilast 500 mcg once daily (n=4438) and was reported more frequently compared with the placebo group (n=4192) (Prod Info DALIRESP(TM) oral tablets, 2011).
    E) DISORDER OF GASTROINTESTINAL TRACT
    1) WITH POISONING/EXPOSURE
    a) During Phase I clinical studies, single doses of 2500 mcg and 5000 mcg produced an increased incidence of non-specified gastrointestinal disorders (Prod Info DALIRESP(TM) oral tablets, 2011).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In clinical trials of COPD patients, back pain was reported in 3.2% (142 of 4438) of patients who received roflumilast 500 mcg once daily compared with 2.2% (92 of 4192) of patients who received placebo for up to 1 year (Prod Info DALIRESP(TM) oral tablets, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Roflumilast is classified as FDA pregnancy category C. In animal studies, roflumilast was not teratogenic in mice, rats or rabbits; however, increased post-implantation loss and decreased survival/viability was observed in mice and rats.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) MICE, RABBITS, RATS: No effects on embryo-fetal development were observed in mice, rats, or rabbits administered doses approximately 12, 3, or 26 times the maximum recommended human dose, (on an mg/m(2) basis at maternal doses of 1.5, 0.2, and 0.8 mg/kg/day), respectively (Prod Info DALIRESP(R) oral tablets, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified roflumilast as FDA pregnancy category C (Prod Info DALIRESP(R) oral tablets, 2013).
    2) Roflumilast should only be used during pregnancy if the potential maternal benefit outweighs the fetal risk (Prod Info DALIRESP(R) oral tablets, 2013).
    B) ANIMAL STUDIES
    1) MICE: Stillbirth and decreased pup viability were observed in mice at doses approximately 16 and 49 times the maximum recommended human dose (MRHD) (on an mg/m(2) basis at maternal doses greater than 2 mg/kg/day and 6 mg/kg/day), respectively. Decreased pup rearing frequencies were observed in mice administered doses approximately 49 times the MRHD (on an mg/m(2) basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. Decreased survival and forelimb grip reflex and delayed pinna detachment were observed in mice at approximately 97 times the MRHD (on an mg/mg(2) basis at a maternal dose of 12 mg/kg/day) during pregnancy and lactation (Prod Info DALIRESP(R) oral tablets, 2013).
    2) RATS: Post-implantation loss was observed in rats administered doses greater than or equal to approximately 10 times the maximum recommended human dose (on an mg/mg(2) basis at maternal doses greater than or equal to 0.6 mg/kg/day) (Prod Info DALIRESP(R) oral tablets, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Excretion of roflumilast and/or its metabolites into human milk is probable. This drug should not be used by women who are breastfeeding (Prod Info DALIRESP(R) oral tablets, 2013).
    B) ANIMAL STUDIES
    1) RATS: Roflumilast and/or its metabolites are excreted into the milk of lactating rats (Prod Info DALIRESP(R) oral tablets, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Decreased fertility rates, increased incidence of tubular atrophy, degeneration in the testis, and spermatogenic granuloma in the epididymides were observed in male rats administered 1.8 mg/kg/day (approximately 29 times the maximum recommended human dose (MRHD), based on mg/m(2)); no effect on fertility rate or reproductive organ morphology was observed at the 0.8 mg/kg/day dose (approximately 13 times the MRHD, based on mg/m(2)). No effect on female fertility was observed in rats administered doses up to 1.5 mg/kg/day (approximately 24 times the MRHD, based on mg/m(2)) (Prod Info DALIRESP(R) oral tablets, 2013).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) UNDIFFERENTIATED CARCINOMAS
    1) Two-year carcinogenicity studies in hamsters revealed an increased incidence of undifferentiated carcinomas of the nasal epithelium at greater than or equal to 8 mg/kg/day (approximately 11 times the MRHD based on summed AUCs of roflumilast and its metabolites). The tumorigenicity of roflumilast seems to be attributed to the metabolite, 4-amino-3,5-dichloro-pyridine N-Oxide (ADCP N-oxide) (Prod Info DALIRESP(TM) oral tablets, 2011).
    B) LACK OF EFFECT
    1) Two-year carcinogenicity studies found no evidence of tumorigenicity with doses of roflumilast at 12 mg/kg/day in female mice and 18 mg/kg/day in male mice (approximately 10 and 15 times the MRHD, respectively, based on summed AUCs of roflumilast and its metabolites) (Prod Info DALIRESP(TM) oral tablets, 2011).

Genotoxicity

    A) Roflumilast tested positive in the 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 HRPT 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 the in vitro micronucleus test with V79 cells (Prod Info DALIRESP(TM) oral tablets, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and liver enzymes in all symptomatic patients.
    B) Assess neurologic status.
    C) Monitor fluid and electrolyte levels in patients with severe vomiting.
    D) Serum roflumilast levels are not readily available and are not clinically useful.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with a minor unintentional exposure who are asymptomatic or have mild symptoms can likely be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with an inadvertent overdose who have more than mild symptoms and patients with deliberate self-harm ingestions should be sent to a health care facility for evaluation and treated until symptoms resolve.

Monitoring

    A) Monitor vital signs and liver enzymes in all symptomatic patients.
    B) Assess neurologic status.
    C) Monitor fluid and electrolyte levels in patients with severe vomiting.
    D) Serum roflumilast levels are not readily available and are not clinically useful.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Serious toxicity is not expected after ingestion of roflumilast alone, and prehospital gastrointestinal decontamination is not routinely required.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and liver enzymes in all symptomatic patients.
    2) Asses neurologic status.
    3) Monitor fluid and electrolyte levels in patients with severe vomiting.
    4) Serum roflumilast levels are not readily available and are not clinically useful.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. During Phase I trials, single doses of 2500 mcg and 5000 mcg caused headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess and hypotension.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose of roflumilast is 500 mcg once daily. PEDIATRIC: Roflumilast is not indicated for use in the pediatric population.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose of roflumilast is 500 mcg once daily (Prod Info DALIRESP(R) oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of roflumilast use in the pediatric population have not been established (Prod Info DALIRESP(R) oral tablets, 2013).

Maximum Tolerated Exposure

    A) During Phase I trials, single doses of 2500 mcg and 5000 mcg caused headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess and hypotension (Prod Info DALIRESP(TM) oral tablets, 2011).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) 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 is unknown, the clinical effects of roflumilast are thought to be related to the effects of increased intracellular cyclic AMP in lung cells (Prod Info DALIRESP(TM) oral tablets, 2011).

Physicochemical

Physical Characteristics

    A) Roflumilast is a white to off-white non-hygroscopic powder with a melting point of 160 degrees Celsius. It is insoluble in water and hexane, sparingly soluble in ethanol and freely soluble in acetone (Prod Info DALIRESP(TM) oral tablets, 2011).

Molecular Weight

    A) 403.22 (Prod Info DALIRESP(TM) oral tablets, 2011).

References

General Bibliography

    1) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    2) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    3) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    4) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    5) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    6) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    7) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    8) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    9) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    10) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    11) Product Information: DALIRESP(R) oral tablets, roflumilast oral tablets. Forest Pharmaceuticals, Inc. (per FDA), St. Louis, MO, 2013.
    12) Product Information: DALIRESP(TM) oral tablets, roflumilast oral tablets. Forest Laboratories, Inc., St. Louis, MO, 2011.
    13) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    14) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    15) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.