Daxas^® (Tablets) Instructions for Use

Marketing Authorization Holder

AstraZeneca AB (Sweden)

Manufactured By

Takeda GmbH (Germany)

ATC Code

R03DX07 (Roflumilast)

Active Substance

Roflumilast (Rec.INN registered by WHO)

Dosage Form

Daxas®

Film-coated tablets, 500 mcg: 10, 30, or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow in color, D-shaped, engraved with “D” on one side; the core is white or almost white when broken.

Excipients: lactose monohydrate – 198.64 mg, corn starch – 53.56 mg, povidone K90 – 3.9 mg, magnesium stearate – 2.6 mg.

Shell composition hypromellose 2910 – 3 mg, macrogol 4000 – 4 mg, titanium dioxide (E171) – 1.25 mg, yellow iron oxide dye (E172) – 0.25 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Clinical-Pharmacological Group

Anti-inflammatory drug – PDE4 inhibitor

Pharmacotherapeutic Group

Anti-inflammatory agent – phosphodiesterase 4 (PDE4) inhibitor

Pharmacological Action

Anti-inflammatory agent, PDE4 inhibitor. The action of roflumilast is aimed at eliminating inflammatory processes associated with COPD. The mechanism of action involves inhibition of PDE4, the main cyclic adenosine monophosphate-metabolizing enzyme found in cells involved in inflammatory processes and which is an important link in the pathogenesis of COPD. The action of roflumilast is mainly directed at PDE4A, 4B and 4D, with similar potency in the nanomolar range. Affinity for the PDE4C type is 5-10 times lower. This mechanism of action and selectivity also applies to the N-oxide, which is the main active metabolite of roflumilast.

Inhibition of PDE4 leads to an increase in intracellular cAMP levels and a reduction in the dysfunction of leukocytes, airway and pulmonary vascular smooth muscle cells, endothelial cells and airway epithelial cells, as well as fibroblasts in experiments. Stimulation of human neutrophils, monocytes, macrophages, or lymphocytes (in vitro) showed that Roflumilast and roflumilast N-oxide inhibit the release of inflammatory mediators such as leukotriene B4, reactive oxygen species, TNFα, interferon gamma and granzyme B.

In patients with COPD, Roflumilast reduces the neutrophil count in sputum, and also reduces the influx of neutrophils and eosinophils into the airways of healthy volunteers receiving endotoxin.

Pharmacokinetics

Roflumilast is actively metabolized in the human body to form the main pharmacodynamically active metabolite roflumilast N-oxide. Since Roflumilast and roflumilast N-oxide are involved in inhibiting PDE activity (in vivo), the pharmacokinetics are described based on the assessment of the total inhibitory effect on PDE4.

The pharmacokinetics of roflumilast and its N-oxide metabolite are dose-proportional in the range from 0.25 mg to 1 mg.

Absorption

After oral administration of 0.5 mg, the complete (absolute) bioavailability of roflumilast is approximately 80%. C_max of roflumilast in plasma is usually reached within 1 hour after administration (ranging from 0.5 to 2 hours) on an empty stomach. C_max of N-oxide is reached within 8 hours (from 4 to 13 hours). Food intake does not affect the overall PDE4 inhibitory activity, but delays T_Cmax of roflumilast by 1 hour and reduces C_max by approximately 40%. However, food intake does not affect the C_max and T_Cmax of Roflumilast N-oxide.

Distribution

Plasma protein binding of roflumilast and roflumilast N-oxide is approximately 99% and 97%, respectively. After a single dose of roflumilast 0.5 mg, V_d is about 2.9 L/kg. Due to its physicochemical properties, Roflumilast is easily distributed to organs and tissues, including adipose tissue. The early distribution phase with characteristic penetration into tissues is followed by an elimination phase from adipose tissue, which is most likely due to intensive breakdown of the parent substance to form roflumilast N-oxide.

Data from preclinical studies of radiolabeled roflumilast show low penetration through the BBB. There is no data on specific accumulation or retention of roflumilast or its metabolites in organs and adipose tissue.

Metabolism

Roflumilast is actively metabolized, with reactions occurring in two stages: phase I (cytochrome P450 system isoenzymes) and phase II (conjugation). The N-oxide metabolite is the main metabolite found in human plasma. The AUC for N-oxide is on average approximately 10 times greater than the AUC for roflumilast. Thus, the N-oxide metabolite is considered more important for providing overall inhibitory activity against PDE4 in vivo.

In vitro studies and clinical interaction studies indicate that the metabolism of roflumilast to form the N-oxide metabolite is carried out with the participation of CYP1A2 and 3A4 isoenzymes.

Elimination

After a short-term IV infusion, the plasma clearance of roflumilast is about 9.6 L/h. After oral administration, the T_1/2 of roflumilast and roflumilast N-oxide in plasma is approximately 17 hours and 30 hours, respectively. Steady-state concentration of roflumilast and its N-oxide metabolite is reached in approximately 4 days for roflumilast and 6 days for roflumilast N-oxide after taking a single daily dose. After IV or oral administration of radiolabeled roflumilast, about 20% of the radioactivity was found in feces and 70% in urine, in the form of inactive metabolites.

Pharmacokinetics in special clinical cases

In elderly patients, women, and persons of non-Caucasian race, the overall PDE4 inhibitory activity increased. The overall PDE4 inhibitory activity decreased somewhat in smokers. None of these changes can be considered clinically significant. Therefore, no dose adjustments are recommended for these patient groups.

In patients with severe renal failure (CrCl 10-30 ml/min), the overall PDE4 inhibitory activity decreased by 9% (dose adjustment not required).

The pharmacokinetics of roflumilast when taken once daily was studied in 16 patients with mild and moderate hepatic impairment (Child-Pugh class A and B). PDE4 inhibitory activity increased by approximately 20% in patients with Child-Pugh class A hepatic impairment, and by approximately 90% in patients with Child-Pugh class B hepatic impairment.

Indications

As maintenance therapy in the treatment of severe COPD (post-bronchodilator FEV1 should be less than 50% of the predicted value) in adult patients with a history of frequent exacerbations.

ICD codes

Dosage Regimen

Take one 500 mcg tablet orally once daily.

Administer the tablet at the same time each day, with or without food.

Swallow the tablet whole; do not crush or chew it.

Be aware that it may take several weeks of continuous treatment to achieve the full therapeutic effect.

Do not use Daxas for the relief of acute bronchospasm or sudden breathing problems.

Monitor for adverse effects, particularly gastrointestinal symptoms (diarrhea, nausea, abdominal pain), headache, and weight loss, especially during the initial weeks of therapy.

If persistent intolerance occurs, re-evaluate the need for continued treatment.

Avoid concurrent use with strong CYP450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) as they may reduce efficacy.

Use caution with strong dual CYP3A4/1A2 inhibitors (e.g., fluvoxamine, enoxacin, cimetidine) due to potential for increased exposure and side effects.

No dose adjustment is required for elderly patients, specific races, or patients with renal impairment.

Contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh class B or C).

Adverse Reactions

Most commonly diarrhea (5.9%), weight loss (3.4%), nausea (2.9%), abdominal pain (1.9%) and headache (1.7%). These adverse reactions mainly occur during the first weeks of treatment and in most cases disappear with continued treatment; most of them are mild or moderate in severity.

From the digestive system often – diarrhea, nausea, abdominal pain; infrequently – gastritis, vomiting, gastroesophageal reflux disease, dyspepsia; rarely – hematochezia, constipation, increased GGT, AST activity.

From the psyche often – insomnia; infrequently – anxiety; rarely – nervousness, depression. During clinical trials, rare cases of suicidal thinking and behavior (including completed suicide) have been reported. Patients should be instructed to report any manifestations of suicidal thinking to their doctor.

From the cardiovascular system infrequently – tachycardia.

From the respiratory system rarely – respiratory tract infections (excluding pneumonia).

From the nervous system often – headache; infrequently – tremor, vertigo, dizziness; rarely – dysgeusia.

From the endocrine system rarely – gynecomastia.

From metabolism and nutrition often – weight loss, decreased appetite.

Dermatological reactions infrequently – rash.

Allergic reactions infrequently – hypersensitivity; rarely – urticaria.

From the musculoskeletal system infrequently – muscle spasms and muscle weakness, myalgia, back pain; rarely – increased blood CPK.

Other infrequently – malaise, asthenia, fatigue.

Contraindications

Moderate or severe hepatic impairment (Child-Pugh class B and C); children and adolescents under 18 years of age; pregnancy; lactation period (breastfeeding); serious immunodeficiency diseases (including HIV infection, multiple sclerosis, systemic lupus erythematosus, progressive multifocal leukoencephalopathy); serious acute infectious diseases (such as tuberculosis or acute hepatitis); cancer (except basal cell carcinoma, a slow-growing type of skin cancer); chronic heart failure of functional class 3 and 4 according to the NYHA classification; treatment with immunosuppressive drugs (such as methotrexate, azathioprine, infliximab, etanercept, as well as in patients receiving constant maintenance therapy with oral corticosteroids); depression associated with the appearance of suicidal thoughts and behavior; hypersensitivity to roflumilast.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during lactation (breastfeeding).

Not recommended for use in women of childbearing potential who are not using reliable methods of contraception.

Special Precautions

Use with caution in case of a history of mental disorders; in case of mild hepatic impairment (Child-Pugh class A); treatment with the CYP1A2 isoenzyme inhibitor fluvoxamine or two CYP3A4/1A2 inhibitors enoxacin and cimetidine.

Not intended for the treatment of acute attacks of shortness of breath (acute bronchospasm).

In studies conducted over one year, weight loss was more frequently observed in patients receiving Roflumilast compared to patients receiving placebo. After discontinuation of roflumilast, most patients regained their weight within 3 months.

Treatment with roflumilast should not be initiated in patients receiving constant maintenance therapy with oral corticosteroids, except for short courses of systemic corticosteroids.

The use of roflumilast is associated with an increased risk of mental disorders such as insomnia, anxiety, nervousness and depression. Rare cases of suicidal thinking and behavior have been identified during clinical trials. Therefore, if patients report previously manifested psychiatric symptoms or if such symptoms are currently present, or if concomitant therapy with other drugs associated with the likelihood of mental disorders is planned, a thorough assessment of the risks and benefits associated with initiating or continuing treatment with roflumilast should be carried out.

Although adverse reactions such as diarrhea, nausea, abdominal pain and headache occur mainly in the first weeks of treatment and in most cases resolve with continued treatment, if these symptoms persist, the issue of treatment with roflumilast should be reconsidered.

Intolerance may occur in special patient populations, in particular, in black non-smoking women or patients receiving treatment with the CYP1A2 inhibitor fluvoxamine or two CYP3A4/1A2 inhibitors enoxacin and cimetidine.

There are no clinical data regarding concomitant treatment with theophylline as maintenance therapy. Therefore, concomitant treatment with theophylline is not recommended.

Effect on ability to drive vehicles and operate machinery

Due to the possibility of adverse reactions, patients should exercise caution when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

The main step in the metabolism of roflumilast is N-oxidation to form roflumilast N-oxide with the participation of CYP3A4 and CYP1A2 isoenzymes. Both Roflumilast and roflumilast N-oxide have intrinsic inhibitory activity against PDE4. Therefore, after taking roflumilast, the overall PDE4 inhibitory activity represents the combined effect of both roflumilast and roflumilast N-oxide. Clinical interaction studies with CYP3A4 isoenzyme inhibitors, erythromycin and ketoconazole, showed an increase in overall PDE4 inhibitory activity by 9%. Interaction studies with the CYP1A2 isoenzyme inhibitor, fluvoxamine, and CYP3A4 and CYP31A2 inhibitors, enoxacin and cimetidine, showed an increase in overall PDE4 inhibitory activity – 59%, 25% and 47%, respectively. Concomitant use of roflumilast with these active substances may lead to increased effects and the development of intolerance. In this case, it is necessary to reconsider the issue of treatment with roflumilast.

Administration of the cytochrome P450 system isoenzyme inducer rifampicin led to a decrease in overall PDE4 inhibitory activity by approximately 60%. Therefore, the use of potent inducers of this enzyme system (for example, phenobarbital, carbamazepine, phenytoin) may lead to a decrease in the therapeutic effect of roflumilast.

Concomitant administration with theophylline led to an 8% increase in overall PDE4 inhibitory activity.

In an interaction study with oral contraceptives containing gestodene and ethinyl estradiol, the overall PDE4 inhibitory activity increased by 17%.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.