- ACRONYMS AND DEFINITIONS
- COPD - Chronic obstructive pulmonary disease
- GOLD - Global Initiative for Chronic Obstructive Lung Disease
- PDE4 - Phosphodiesterase 4
- DRUGS IN CLASS
- Phosphodiesterase 4 (PDE4) inhibitors
- Roflumilast (Daliresp®)
- MECHANISM OF ACTION
- Roflumilast inhibits PDE4 which leads to accumulation of intracellular cyclic AMP
- While the specific mechanism(s) by which roflumilast 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.
- FDA-APPROVED INDICATION
- Roflumilast 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
- PubMed abstract] [
- The REACT trial enrolled 1945 patients with severe COPD
- Main inclusion criteria: Smoking history at least 20 pack-year | Diagnosis of COPD | FEV1/FVC ratio < 0.70 | FEV1 ≤ 50% of predicted | History of ≥ 2 exacerbations in the previous year | Using ICS + LABA for 12 months prior to enrollment
- Main exclusion criteria: Diagnosis of asthma or other major lung disease
- Baseline characteristics: Average age 65 years | Using long-acting muscarinic antagonist - 70% | Average postbronchodilator FEV1/FVC - 40% | Current smoker - 43%
- Patients were randomized to one of two groups:
- Group 1 (969 patients) - Roflumilast 500 mcg once daily
- Group 2 (966 patients) - Placebo once daily
- All patients continued with ICS + LABA therapy. Patients already taking a LAMA (70%) were allowed to continue it.
- If a patient had an exacerbation that needed additional treatment during the study, the investigator could give them up to 40 mg prednisolone, administered systemically, per day for 7 – 14 days
- The following treatments were not allowed: oral and parenteral glucocorticosteroids (except to treat acute exacerbations); long-acting beta agonist or inhaled corticosteroid monotherapy; short-acting muscarinic antagonists; any short-acting beta agonists (with the exception of salbutamol) or oral beta agonists
- PRIMARY OUTCOME: Rate of moderate-to-severe COPD exacerbations per patient per year. Moderate exacerbations were defined as those that needed treatment with oral or parenteral glucocorticosteroids (with or without antibiotics), and severe exacerbations were defined as those that needed hospital admission, led to death, or both. Patients were treated and followed-up for one year.
- After 1 year, the following was seen:
- Primary outcome (events/patient/year): Group 1 - 0.805, Group 2 - 0.927 (RR 0.868, 95%CI [0.753 - 1.002], p=0.0529)
- Median time to first exacerbation: Group 1 - 103.5 days, Group 2 - 111.5 days (HR 0.918, 95%CI [0.800 - 1.054], p=0.22)
- Change in postbronchodilator FEV1 (baseline to Week 52): Group 1 +52 ml, Group 2 -4 ml (p<0.0001)
- Discontinuation of therapy due to adverse event: Group 1 - 11%, Group 2 - 5%
- Diarrhea: Group 1 - 10%, Group 2 - 4%
- Weight loss: Group 1 - 9%, Group 2 - 3%
- Nausea: Group 1 - 6%, Group 2 - 2%
- Professional guidelines:
- The 2017 GOLD COPD guidelines state that roflumilast should be considered in patients with severe COPD if their FEV1 is < 50% and they have chronic bronchitis
- StraightHealthcare analysis:
- In the REACT trial, roflumilast did not have a significant effect on COPD exacerbations, but it did improve FEV1 at one year
- The effects of roflumilast are modest at best, and it should only be used as a last resort
- SIDE EFFECTS
- Common side effects
- Roflumilast has significant gastrointestinal side effects. In trials, 14.8% of roflumilast-treated patients discontinued treatment due to adverse effects compared to 9.9% of placebo-treated patients.
- In 2018, the manufacturer of roflumilast introduced a 250 mcg dose to be used for 4 weeks before increasing to 500 mcg. The 250 mcg dose is not therapeutic, but titrating roflumilast may decrease side effects and improve compliance.
|Side effect||Roflumilast 500 mcg once daily
|Placebo once daily
- Psychiatric events
- In trials, 5.9% of roflumilast-treated patients reported adverse psychiatric events compared to 3.3% of placebo-treated patients
- The most common types of events were insomnia, anxiety, and depression
- Patients with mental illness should use caution when taking roflumilast
- Moderate to severe liver disease (Child-Pugh B or C)
- KIDNEY DISEASE
- No dose adjustment necessary
- LIVER DISEASE
- Mild (Child-Pugh A): clearance is decreased. Use caution.
- Moderate to severe (Child-Pugh B/C): DO NOT USE
- WEIGHT LOSS
- In trials, weight loss occurred in 7.5% of roflumilast-treated patients compared to 2.1% of placebo-treated patients
- In the REACT trial detailed above, the roflumilast group lost an average of 5.8 lbs (2.65 kg) at one year compared to 0.33 lbs (0.15 kg) in the placebo group
- Patients taking roflumilast should monitor their weight
- MENTAL ILLNESS
- In trials, roflumilast-treated patients reported a higher incidence of psychiatric adverse events (see psychiatric events above)
- Use caution in patients with mental illness
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- HIGH ALERT INTERACTIONS
- NOTE: High alert interactions are interactions that are known to be significant and occur between two medications that are likely to be prescribed together
- Strong CYP inducers
- Strong CYP inducers (e.g. rifampicin, phenobarbital, carbamazepine, and phenytoin) may decrease exposure to roflumilast and they should not be used concomitantly
- CYP3A4 inhibitors
- Roflumilast is a CYP3A4 sensitive substrate. CYP3A4 inhibitors may increase exposure to roflumilast. Use caution when combining.
- CYP1A2 inhibitors
- Roflumilast is a CYP1A2 sensitive substrate. CYP1A2 inhibitors may increase exposure to roflumilast. Use caution when combining.
- Oral contraceptives (OCPs)
- OCPs containing gestodene and ethinyl estradiol may increase exposure to roflumilast. Use caution.
- METABOLISM AND ELIMINATION
- NOTE: Drugs can be metabolized by more than one enzyme. Drugs may be metabolized by an enzyme and inhibit/induce the enzyme at the same time. Drug transporters (ex. p-glycoprotein) can play a role in drug metabolism. Not all drug interactions are clinically significant. Consult your physician or pharmacist if you are taking medications together and are concerned about a possible interaction.
- Dosage form
- 250 mcg
- 500 mcg
- Standard dosing
- Starting: 250 mcg once daily for 4 weeks
- Maintenance: 500 mcg once daily
- The starting dose of 250 mcg may help to decrease side effects and prevent discontinuation, but it is not an effective treatment dose
- May take without regard to food
- > $150 for 30 pills
- LONG-TERM SAFETY
- Roflumilast was FDA-approved in 2011
- It is not widely prescribed
- Long-term safety has not been established
- GENERIC AVAILABILITY
- Generic / Cost:
- None / > $150 for 30 pills
- Patent expiration:
- NOTE: Drug companies typically file multiple patents on their drugs in order to protect them from competition. The patent expiration listed here is the date that the earliest patent on the drug expires (accounting for pediatric exclusivity). Because drug companies use numerous techniques to extend the life of their patents, it does not necessarily mean a generic will become available around this date.
- What is PMID?
- PI = Manufacturer's Package Insert
- # PMID
- 1 - Manufacturer's Package Insert