Roflumilast

Roflumilast belongs to the pharmacological class Phosphodiesterase 4 Inhibitor. Roflumilast appears to have anti-inflammatory and immunomodulatory effects in the pulmonary system. The increased levels of the intracellular cyclic AMP are responsible for the therapeutic action of Roflumilast.

Roflumilast has been approved for relieving symptoms and also for the treatment and maintenance of episodes of COPD, i.e., Chronic Obstructive Pulmonary Disease and Plaque Psoriasis.

Roflumilast is completely and rapidly absorbed with an oral bioavailability of 80%. Roflumilast achieved a mean volume of distribution of 2.9 l/kg at a dose of 500mcg. The Roflumilast is found to be metabolized by the cytochrome CYP3A4 and CYP1A2 enzymes into roflumilast N-oxide, an active metabolite. Roflumilast is found to be excreted about 70% in urine in the form of the active metabolite.

The common side effects associated with Roflumilast are headache, fever, diarrhea, nausea, back pain, muscle spasm.etc.

Roflumilast is available in the form of Tablets and Topical cream. Roflumilast is available in U.S., Canada,E.U., India

Roflumilast belongs to the pharmacological class Phosphodiesterase 4 Inhibitor. Roflumilast appears to have anti-inflammatory and immunomodulatory effects in the pulmonary system. The increased levels of intracellular cyclic AMP is responsible for the therapeutic action of Roflumilast.

Roflumilast has been approved for relieving symptoms and also for the treatment and maintenance of episodes COPD, i.e. Chronic Obstructive Pulmonary Disease and Plaque Psoriasis.

The mean Roflumilast for 500mcg, Cmax was found to be reduced by 40% and Tmax was found to be 0.25 to 2.0hrs.

Roflumilast is available in Tablets and Topical cream.

Roflumilast can be used in the treatment of:

• COPD i.e. Chronic Obstructive Pulmonary Disease
• Plaque Psoriasis

Roflumilast can help to relieve symptoms and also for the treatment and maintenance of episodes COPD i.e. Chronic Obstructive Pulmonary Disease and Plaque Psoriasis

Roflumilast is approved for use in the following clinical indications:

• COPD i.e. Chronic Obstructive Pulmonary Disease
• Plaque Psoriasis

Roflumilast can be administered orally before/ after meals. The dosage and duration of treatment should be as per the clinical judgment of the treating physician.

Tablets: The initial dose of 250mcg once daily for four weeks followed by 500mcg once daily.

Topical cream: Apply 0.3% Roflumilast topical cream at the site of application

Tablets, Topical cream.

• Dosage Adjustments in Kidney Patients:

No dosage adjustments are needed for renal Impairment

• Dosage Adjustments in Hepatic Impairment Patients:

Use of Roflumilast is contraindicated, hence the Roflumilast should be used with caution.

• Dosage Adjustments in Pediatric Patients:

No dosage adjustments are necessary as COPD does not occur in pediatric populations.

Smoking cessation and maintaining health is a must.

Caffeine should be avoided or limited to use as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Alcohol should be avoided in the patient especially with an underlying liver disorder or liver dysfunction

Diet containing food with a high glycemic index, saturated and trans fat food, red and processed meat, added sugar, salt, preservatives, refined and high energy-dense foods, low fiber, low antioxidants, and vitamins needs to be restricted.

The dietary restrictions is needed to be individualized as per the patient's requirements.

Roflumilast may be contraindicated during the coadministration with the following drugs:

• Hypersensitivity to the ingredients of the medication

The treating physician should closely monitor the patients and keep pharmacovigilance as follows:

Acute Bronchospasm

Treatment

Roflumilast acts as a bronchodilator and hence, should not be used for the relief in the condition of acute bronchospasm.

• Psychiatric Events, such as Suicidality

Treatment with Roflumilast is related to an increase in psychiatric adverse reactions. In eight controlled clinical trials, 5.9% i.e.around 263 patients who were treated with Roflumilast 500 mcg daily had reported psychiatric adverse reactions compared to 3.3%, i.e., about 137 patients treated with placebo. The most commonly reported psychiatric adverse reactions associated were anxiety, depression and insomnia which were reported at higher rates in those treated with a 500 mcg daily of Roflumilast. Instances such as suicidal ideation and behavior, including completed suicide, had been observed in clinical trials. Three patients had experienced suicide-related adverse reactions while receiving Roflumilast doses as compared to one patient with suicidal ideation who had received placebo. The cases of suicidal ideation and behavior, including completed suicide, had been observed in the post-marketing reports in patients with or without a history of depression.

• Weight Loss

Weight loss was found to be a common adverse reaction in Roflumilast clinical trials. It was reported in 7.5% i.e.331 patients treated with Roflumilast 500 mcg once-a-day compared to 2.1% i.e.89 patients treated with placebo. In addition to weight being reported as adverse reactions, weight had been prospectively assessed in about two placebo-controlled clinical trials for a duration of one year. In these studies, about 20% of patients receiving roflumilast have experienced moderate weight loss, which is defined as between 5-10% of body weight when compared to 7% of patients who had received placebo. In addition, 7% of patients who had received roflumilast as compared to 2% of patients receiving placebo experienced severe, i.e.>10% body weight loss. During the follow-up after treatment discontinuation of Roflumilast, the majority of patients with weight loss had regained weight that they had lost while on Roflumilast medication. Patients who are treated with Roflumilast medication should have their weight monitored regularly.

Avoid alcohol usage while on Roflumilast medication as alcohol can worsen the effects of any underlying disease condition, including conditions such as dizziness, blurred vision etc.

There is found no data regarding the presence of Roflumilast in breast milk, the effects on the breastfed baby, or the effects on milk secretion. Roflumilast and its metabolites are found to be excreted into the milk of the lactating rats. Excretion of roflumilast and its metabolites breast human milk might be probable. Hence, Roflumilast should not be used by women who are lactating.

There were found to be no randomized clinical studies of Roflumilast in pregnant women. In animal reproductive toxicity studies, Roflumilast is administered to pregnant rats and rabbits in animal studies during the period of organogenesis ,had produced no fetal structural abnormalities. The highest dose of Roflumilast in these studies was found to be approximately 30 and 26 times, respectively. Roflumilast induced post-implantation loss in rats at doses which are greater than or equal to approximately around 10 times the MRHD. Roflumilast induced stillbirths and decreased pup viability in mice had occurred at doses corresponding to approximately 16 and 49 times, respectively, the MRHD. Roflumilast had been shown to adversely affect pup's post-natal development when dams were treated with Rolfumilast during pregnancy and lactation periods in mice at doses that correspond to 49 times the MRHD. The background risk of major miscarriage and major birth effects for the indicated population related to Roflumilast is unknown.

No sufficient scientific evidence traceable regarding the use and safety of Roflumilast in concurrent use with any particular food. Roflumilast can be taken without regard to the food or meals.

The adverse reactions related to Roflumilast can be categorized as:

Common

• Nausea
• Backache
• Diarrhea
• Weight loss
• Headache

Less common

• Difficulty Sleeping
• Muscle Tremors
• Decreased Appetite
• Vomiting
• Intense Abdominal Pain
• Anxious Feeling
• Sinuses
• Flu
• Gastritis
• Indigestion
• Urinary Tract Infection
• Muscle Spasm
• Dizziness

Rare

• Suicidal thoughts and behaviors
• Angioedema

The clinically relevant drug interactions of Roflumilast is briefly summarized here:

Inhibitors of CYP3A4 and CYP1A2 enzymes

Erythromycin: In an open-label crossover study consisting of 16 healthy volunteers, the co-administration of CYP3A4 enzyme inhibitor erythromycin i.e.500 mg thrice daily for 13 days, along with a single oral dose of about 500 mcg Roflumilast had resulted in a increase of about 40% and 70% in Cmax and AUC for roflumilast, respectively, and about 34% decrease and a 4% increase in Cmax and AUC for metabolite roflumilast N-oxide, respectively.

Ketoconazole: In an open-label crossover study consisting of 16 healthy volunteers, the co-administration of a strong CYP3A4 enzyme inhibitor ketoconazole i.e.200 mg twice daily for 13 days along with a single oral dose of 500 mcg Roflumilast had resulted in increase of about 23% and 99% in Cmax and AUC for roflumilast, respectively, and about 38% reduction and 3% increase in Cmax and AUC for metabolite roflumilast N-oxide, respectively.

Fluvoxamine: In an open-label crossover study consisting of 16 healthy volunteers, the coadministration of dual CYP 3A4/1A2 enzyme inhibitor fluvoxamine i.e.50 mg daily for 14 days along with a single oral dose of 500 mcg Roflumilast had showed an increrase in 12% and 156% in roflumilast's Cmax and AUC along with a 210% decrease and 52% increase in metabolite roflumilast N-oxide Cmax and AUC, respectively.

Enoxacin: In an open-label crossover study consisting of 16 healthy volunteers, the coadministration of dual CYP 3A4/1A2 enzyme inhibitor enoxacin i.e.400 mg twice daily for 12 days along with a single oral dose of 500 mcg of Roflumilast had resulted in an increased Cmax and AUC of roflumilast by around 20% and 56%, respectively. The metabolite Roflumilast N-oxide Cmax was found to be decreased by 14% while metabolite roflumilast N-oxide AUC was found to be increased by 23%.

Cimetidine: In an open-label crossover study consisting of 16 healthy volunteers, the co-administration of a dual CYP 3A4/1A2 enzyme inhibitor cimetidine i.e.400 mg twice daily for 7 days along with a single dose of 500 mcg oral Roflumilast had resulted in a increase in about 46% and 85% in roflumilast Cmax and AUC; and a around 4% decrease in Cmax and 27% increase in AUC for metabolite roflumilast N-oxide, respectively.

Oral Contraceptives containing Gestodene and Ethinyl Estradiol: In an open-label crossover study consisting of 20 healthy adult volunteers, the co-administration of a single oral dose of 500 mcg of Roflumilast along with repeated doses of a fixed combination oral contraceptive which consisted of 0.03 mg Ethinyl estradiol and 0.075 mg gestodene to steady state had lead to an 38% increase and 12 % decrease in Cmax of roflumilast and metabolite roflumilast N-oxide, respectively. Roflumilast and the metabolite roflumilast N-oxide AUCs were found to be increased by 51% and 14%, respectively.

Inducers of CYP enzymes: Rifampicin: In an open-label, three-period, fixed-sequence study consisting of 15 healthy volunteers, co-administration of the strong CYP3A4 enzyme inducer rifampicin i.e.600 mg once daily for 11 days along with a single oral dose of 500 mcg Roflumilast had resulted in decrease in the roflumilast's Cmax and AUC by around 68% and 79%, respectively; and followed by an increase of roflumilast N-oxide Cmax by around 30% and reduced roflumilast N-oxide AUC by about 56%.

The common side effects of Roflumilast include the following:

• Back pain
• Muscle spasm
• Decrease in appetite
• Diarrhea
• Nausea
• Dizziness
• Headache

Pregnancy

There were found to be no randomized clinical studies of Roflumilast in pregnant women. In animal reproductive toxicity studies, Roflumilast is administered to pregnant rats and rabbits in animal studies during the period of organogenesis ,had produced no fetal structural abnormalities. The highest dose of Roflumilast in these studies was found to be approximately 30 and 26 times, respectively. Roflumilast induced post-implantation loss in rats at doses of Roflumilast greater than or equal to approximately around 10 times the MRHD. Roflumilast induced stillbirths and decreased pup viability in mice had occurred at doses of Roflumilast corresponding to approximately 16 and 49 times, respectively, the MRHD. Roflumilast had been shown to adversely affect pup's post-natal development when dams were treated with Rolfumilast during pregnancy and lactation periods in mice at doses of Roflumilast that correspond to 49 times the MRHD. The background risk of major miscarriage and major birth effects for the indicated population related to Roflumilast is unknown.

Nursing Mothers

There is found no data regarding the presence of Roflumilast in breast milk, the effects on the breastfed baby, or the effects on milk secretion. Roflumilast and its metabolites are found to be excreted into the milk of the lactating rats. Excretion of roflumilast and its metabolites breast human milk might be probable. Hence, Roflumilast should not be used by women who are lactating.

Pediatric Use

Chronic Obstructive Pulmonary Disease does not normally occur in pedeatric patients. The safety and effecacy of Roflumilast in pediatric patients has not been established.

Geriatric Use

Out of the 4438 Chronic Obstructive Pulmonary Disease subjects who were on Roflumilast medication for up to 12 months in eight controlled clinical trials, 2022 were aged >65 years and 471 were aged >75 years. No overall differences in the safety or efficacy had been observed between these older subjects and younger subjects, and the other reported clinical experience had not identified the differences in responses between the older and younger patients. Based on available reported data of roflumilast, no adjustment of dosage in geriatric patients is needed.

Physician should be knowledgeable and vigilant about the treatment pertaining to the identification and treatment of overdosage of Roflumilast.

No mortality has occurred following single oral doses of Roflumilast, which is up to 5000 mg/kg in rats and mice. The specific information is found to be available on the treatment of overdosage with Roflumilast medication. In patients suffering from chronic asthma , during clinical studies, Roflumilast had been administered to adult patients at doses up to 200 mg/day for about 22 weeks. In short-term clinical studies, up to 900 mg/day to the patients for approximately a 7 days without any clinically important adverse experiences. In the event of overdose, one should employ some usual supportive measures such as removal of unabsorbed material from the gastrointestinal tract, employing clinical monitoring, and instituting supportive therapy, if required. There were no adverse experiences observed and reported in the majority of overdosage reports in the post-marketing experience. The frequently occurring adverse experiences were found to be consistent with the safety profile of Roflumilast which included thirst, headache, vomiting, abdominal pain, somnolence, and psychomotor hyperactivity. It is not known whether the drug Roflumilast can be removed by peritoneal dialysis or hemodialysis

Pharmacodynamics

In Chronic Obstructive Pulmonary Disease patients, four-week treatment with Roflumilast 500 mcg oral once a day had reduced sputum neutrophils and eosinophils by around 31%, and 42%, respectively. In a pharmacodynamic study consisting of healthy volunteers, Roflumilast 500 mcg once a day had reduced neutrophils and eosinophils found in bronchoalveolar lavage fluid, the number of total cells, followed by segmental pulmonary lipopolysaccharide also called LPS, challenge by 35%, 38% and 73%, respectively. The clinical importance of these findings is unknown.

Pharmacokinetics

• Absorption

The absolute bioavailability of roflumilast after a 500 mcg oral dose is found to be approximately 80%. The Maximum plasma concentrations (Cmax) of roflumilast typically occurs approximately one hour post-dosing i.e. ranging from 0.5 to 2 hours in the fasted state while plateau-like maximum concentrations of the metabolite N-oxide are reached in approximately 8 hours i.e.ranging from 4 to 13 hours. It was observed that food had no effect on total drug absorption of roflumilast, but it delayed time to maximum concentration (Tmax) of roflumilast by about one hour and reduced Cmax by approximately by 40%, however, Tmax and Cmax of metabolite roflumilast N-oxide are found to be unaffected. An in vitro study showed that roflumilast and metabolite roflumilast N-oxide did not inhibit P-gp transporter.

• Distribution

The Plasma protein binding of roflumilast and its metabolite N-oxide is found to be approximately 99% and 97%, respectively. The Volume of distribution for single-dose 500 mcg roflumilast was found to be about 2.9 L/kg. The animal studies in rats with radiolabeled roflumilast indicated a low penetration across the blood-brain barrier.

• Metabolism

Roflumilast was found to be extensively metabolized via Phase I i.e.cytochrome P450 and Phase II i.e.conjugation reactions. The N-oxide metabolite is found to be the only major metabolite that has been observed in the plasma of humans. Together, roflumilast and the metabolite roflumilast N-oxide account for the majority (87.5%) of the total dose administered in plasma. In urine, roflumilast was not foudn to be detectable while roflumilast N-oxide was only found as a trace metabolite i.e.less than 1%. Other conjugated metabolites examples: roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N-oxide were foudn to be detected in urine. While roflumilast is said to be 3 times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro, the plasma AUC of metabolite roflumilast N-oxide on average was found to be about ten-fold greater than the plasma Area under curve of roflumilast. The in-vitro studies and clinical drug-drug interaction studies suggested that the biotransformation of roflumilast to its N-oxide metabolite was mediated by enzymes such as CYP1A2 and CYP3A4. Based on further in vitro results in human liver microsomes,it is found that therapeutic plasma concentrations of roflumilast and the metabolite roflumilast N-oxide do not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11 enzymes. Therefore, it can be understood that there is found to be a low probability of relevant interactions with substances metabolized by P450 enzymes. In addition, it was demonstrated in in-vitro studies that no induction of the CYP 1A2, CYP2A6, CYP2C9, CYP2C19, or CYP3A4/5 and only a weak induction of CYP2B6 enzyme by roflumilast.

• Elimination

The plasma clearance after a short-term infusion of intravenous Roflumilast is on average of about 9.6 L/h.After an oral dose of Roflumilast, the median plasma effective half-life of roflumilast and its metabolite N-oxide were found to be approximately 17 and 30 hours, respectively. Steady-state plasma concentrations of Roflumilast and its N-oxide metabolite were reached after approximately four days for roflumilast and six days for roflumilast N-oxide following once a day dosing. After intravenous or also oral administration of radiolabeled roflumilast, around 70% of the radioactivity has been found to be recovered in the urine.

• Thappali SR, Varanasi KV, Veeraraghavan S, Vakkalanka SK, Mukkanti K: Simultaneous quantitation of IC87114, roflumilast and its active metabolite roflumilast N-oxide in plasma by LC-MS/MS: application for a pharmacokinetic study. J Mass Spectrom. 2012 Dec;47(12):1612-9.
• Giembycz MA, Field SK: Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther. 2010 Jul 21;4:147-58
• FDA Approved Drug Products: Roflumilast (roflumilast) tablets for oral use
• FDA Approved Drug Products: Zoryve (roflumilast) cream for topical use
• Arcutis Biotherapeutics: FDA Approves Arcutis' ZORYVE™ Roflumilast Cream of 0.3% strength for the Treatment of Plaque Psoriasis in Individuals Age 12 and Older.
• Meyers JA, Taverna J, Chaves J, Makkinje A, Lerner A: Phosphodiesterase 4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells. Clin Cancer Res. 2007 Aug 15;13(16):4920-7.
• Sanz MJ, Cortijo J, Taha MA, Cerda-Nicolas M, Schatton E, Burgbacher B, Klar J, Tenor H, Schudt C, Issekutz AC, Hatzelmann A, Morcillo EJ: Roflumilast inhibits expression of adhesion molecules ,leukocyte-endothelial cell interactions, and microvascular permeability. Br J Pharmacol. 2007 Oct;152(4):481-92. Epub 2007 Aug 20.
• Leung B, Black PN, et.al: Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011 May 11;(5):CD002309.
• Verhoosel RM, Sterk PJ, et.al: Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with chronic obstructive pulmonary disease. Thorax. 2007 Dec;62(12):1081-7. Epub 2007 Jun 15.