| Active Ingredient | ROFLUMILAST |
|---|
| Drug Name | FDA Application No. | Company | Dosage Form;Route | Strength | RLD Strength | Original Approval or Tentative Approval Date |
Exclusivity Expiration (NCE) |
Exclusivity Expiration (ODE) |
Chemical Type |
Review Classification |
Marketing Status |
TE Code |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DALIRESP | (NDA) 022522 | ASTRAZENECA PHARMS | TABLET;ORAL | 500MCG | 500MCG (RS) | February 28, 2011 | - | - | 1 New molecular entity (NME) | S Standard review drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | N-(3,5dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide |
| CAS No | 162401-32-3 |
| Molecular Formula | C17H14Cl2F2N2O3 |
| Molecular Weight | 403.22 |
| Appearance | a white to off-white powder |
| Solubility | It is practically insoluble in water and hexane, sparingly soluble in ethanol and freely soluble in acetone. The solubility in aqueous solvents increases from about 0.8 mg/l under neutral conditions to about 35.8 mg/l at pH 10. |
| Water Solubility | 0.52-0.56 mg/L at 22°C |
| Polymorphism | There is no evidence of polymorphic forms. |
| pKa (Strongest Acidic) | 8.74 |
| pKa (Strongest Basic) | - |
| Log P | 3.99 |
| Identification | IR spectra and HPLC |
| Degradation | Whenroflumilast (in solid state) is stored in a drying oven at 100 °C for up to 14 days, no change in content nor an increase in impurities could be observed. Roflumilast in solid state is not affected by exposure to light, however, solutions in acetonitrile of the drug substance are sensitive to light. At room temperature, solutions of roflumilast in 0.1 M hydrochloric acid, demineralised water and 0.1 M sodium hydroxide are stable within 24 hours. |
| Hygroscopic | non-hygroscopic |
| Photostability study | - |
| Melting Point | 160°C |
| BCS Class | - |
| Manufacture of API | The manufacture of roflumilast consists of a four-step process. Adequate in-process controls are in place and appropriate specifications have been adopted for the starting materials, solvents and reagents. |
| Parameters | Details |
|---|---|
| Indications and Usage | 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. DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm. |
| Dosage and Administration | The recommended dose of DALIRESP is one 500 microgram (mcg) tablet per day, with or without food. |
| Mechanism of action | 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. |
| 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). An in vitro study showed that roflumilast and roflumilast N-oxide did not inhibit P-gp transporter. |
| Food Effect | 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. |
| 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 CYP 1A2 and 3A4. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not inhibit CYP 1A2, 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 CYP 2B6 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. |
| Peak plasma time (Tmax) | Roflumilast-0.5 to 2 hours (Fasted), N-oxide metabolite-4 to 13 hours, Roflumilast-1.5 to 3 hours (Fed) |
| Half life | 17 and 30 hours |
| Bioavailability | 80% |
| Age, gender |
Roflumilast 500 mcg once daily for 15 days was studied in young, middle aged, and elderly healthy subjects. The exposure in elderly (>65 years of age) were 27% higher in AUC and 16% higher in Cmax for roflumilast and 19% higher in AUC and 13% higher in Cmax for roflumilast-N-oxide than that in young volunteers (18-45 years old). No dosage adjustment is necessary for elderly patients. In a Phase I study evaluating the effect of age and gender on the pharmacokinetics of roflumilast and roflumilast N-oxide, a 39% and 33% increase in roflumilast and roflumilast N-oxide AUC were noted in healthy female subjects as compared to healthy male subjects. No dosage adjustment is necessary based on gender. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 26764 | A | II | December 27, 2012 | SCINOPHARM TAIWAN LTD |
| 27612 | A | II | November 30, 2013 | MSN LABORATORIES PRIVATE LTD |
| 27779 | A | II | March 28, 2014 | ALP PHARM BEIJING CO LTD |
| 28440 | A | II | April 9, 2014 | MYLAN LABORATORIES LTD |
| 28471 | A | II | July 31, 2014 | INTERQUIM SA |
| 28506 | A | II | July 22, 2014 | CHONGQING HUAPONT PHARMACEUTICAL CO LTD |
| 28516 | A | II | August 27, 2014 | HETERO DRUGS LTD |
| 28657 | A | II | October 31, 2014 | CADILA HEALTHCARE LTD |
| Parameters | Details |
|---|---|
| Strength | 500MCG |
| Excipients used | lactose monohydrate, corn starch, povidone (K90) and magnesium stearate |
| Composition of coating material |
hypromellose, Macrogol 4000, titanium dioxide (E171), and iron oxide yellow (E172) |
| Composition of caspule shell | - |
| Pharmaceutical Development |
The aim of the pharmaceutical development was to develop an immediate-release tablet that can be handled easily by the target patient population of elderly chronic obstructive pulmonary disease (COPD) patients. Physicochemical and biological properties of the drug substance have been studied. The active substance can be classified as a Class II active substance (high permeability, low solubility) according to the Biopharmaceutics Classification System (BCS). This implies that particle size is expected to impact dissolution of the active substance and thus bioavailability. Therefore the active substance is micronized in order to improve its solubility. Dissolution studies have been performed to support the specification of the particle size range for the active substance. Due to the low drug content (500 microgram) in the tablets, special focus was taken on blend and content uniformity during development, scale-up and validation, and that the homogeneous distribution of the drug substance and homogeneity of the granules is determined for each batch during release testing by content uniformity. The development of the formulation has been adequately explained and justified. Different immediate release tablet formulations were used throughout drug development and the amount of excipients was changed to increase the tablet weight and volume. This leads to improved patient handling of the dosage form. Finally a film-coated formulation was chosen for marketing authorisation. To allow easy tablet differentiation, the tablets were given a unique D-shaped form and it was decided to coat the tablets with a yellow (non functional) coating. |
| Manufacture of the product | Roflumilast film-coated tablets are manufactured by a conventional wet granulation process with a final film-coating. |
| Tablet / Capsule Image |
|
| Appearance | white to off-white, round tablets, embossed with “D” on one side and “500” on the other side |
| Imprint code / Engraving / Debossment | embossed with “D” on one side and “500” on the other side |
| Score | no score |
| Color | white to off-white |
| Shape | ROUND |
| Dimension | 5mm |
| Mfg by | Takeda GmbH (EU) |
| Mfg for | - |
| Marketed by |
AstraZeneca Pharmaceuticals LP (US), Takeda GmbH (EU) |
| Distributed by | AstraZeneca Pharmaceuticals LP (US) |
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N022522 | 1 | 5712298 | January 27, 2020 | Y | Y | U - 1115 | - | Download |
| N022522 | 1 | 8431154 | February 19, 2023 | - | Y | - | - | Download |
| N022522 | 1 | 8618142 | March 8, 2024 | - | Y | - | - | Download |
| N022522 | 1 | 8536206 | March 8, 2024 | - | - | U - 1115 | - | Download |
| N022522 | 1 | 8604064 | March 8, 2024 | - | - | U - 1115 | - | Download |
| - | 1 | 9468598 | February 19, 2023 | - | DP | - | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) | 50 | 1.0% SDS (sodium dodecyl sulfate) in Phosphate Buffer, pH 6.8 | 1000 | 5, 10, 15, 20, 30 and 45 | August 15, 2013 |
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | Download |
| FDA Pharmacology Review(s) | Download |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | Download |
| European Public Assessment Report | Download |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | DAXAS | Download |
| UK | DAXAS | Download |
| US | DALIRESP | Download |
| US | MYLAN PHARMS INC (ANDA # 208257)* | Download |
| US | STRIDES PHARMA (ANDA # 208247)* |
| - |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
