Daxas (Daxas®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceRoflumilastRoflumilast
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  • Daxas
    pills inwards 
    AstraZeneca AB     Sweden
    • Dosage form: & nbspfilm coated tablets
    Composition:

    AT 1 The tablet contains:

    Active substance: roflumilast 0.5 mg

    Excipients:

    core: lactose monohydrate 198.64 mg, corn starch 53.56 mg, povidone (K90) 3.90 mg, magnesium stearate 2.60 mg.

    shell: hypromellose-2910 3.00 mg, macrogol-4000 4.00 mg, titanium dioxide (E 171) 1.25 mg, ferric oxide yellow oxide (E 172) 0.25 mg.

    Description:

    D-like tablets covered with a film shell of yellow color, with engraving "D" on one side. On the fracture, the core is white or almost white.

    Pharmacotherapeutic group:Anti-inflammatory agent - phosphodiesterase 4 (PDE4) inhibitor
    ATX: & nbsp

    R.03.D.X   Other medications for the treatment of bronchial asthma for systemic use

    R.03.D.X.07   Roflumilast

    Pharmacodynamics:

    Roflumilast is a phosphodiesterase 4 inhibitor, a non-steroidal, anti-inflammatory agent directed at the elimination of inflammatory processes associated with chronic obstructive pulmonary disease (COPD). The mechanism of action is the inhibition of phosphodiesterase-4 (PDE4), the main cyclic adenosine monophosphate (cAMP), a metabolic enzyme contained in cells involved in inflammatory processes, and is important in the pathogenesis of COPD.The action of roflumilast is mainly directed to PDE4A, 4B and 4D, with a similar potential in the nanomolar range. Affinity to the type of PDE4C is 5-10 times lower. This mechanism of action and selectivity are also applicable to N-oxide, which is the main active metabolite of roflumilast.

    Pharmacodynamics

    Inhibition of PDE4 leads to an increase in the intracellular cAMP index and a decrease in leukocyte dysfunction, smooth muscle cells of the respiratory tract and pulmonary vessels, endothelial cells and respiratory epithelial cells, as well as fibroblasts in the experiment. Stimulation of human neutrophils, monocytes, macrophages or lymphocytes (in vitro) showed that roflumilast and N- Roflumilast oxide inhibits the release of inflammatory mediators, such as leukotriene B4, active oxygen species, tumor necrosis factor α, interferon γ and granzyme B.

    In patients with COPD roflumilast reduces the neutrophil count in sputum, and also reduces the inflow of neutrophils and eosinophils into the respiratory tract of healthy volunteers who received endotoxin.

    Pharmacokinetics:

    Roflumilast is actively metabolized in the human body with the formation of the main pharmacodynamically active metabolite N-oxidized roflumilast. Since u roflumilast and N-oxidum roflumilast involved in the inhibition of PDE activity (in vivo) pharmacokinetics is described based on an estimate of the overall inhibitory effect on PDE4.

    Suction

    The full bioavailability of roflumilast after oral administration of 0.5 mg is approximately 80%. The maximum concentration of roflumilast in plasma is usually achieved one hour after admission (within 0.5 to 2 hours) on an empty stomach. Maximum concentration Noxide is reached after 8 hours (from 4 to 13 hours). Eating does not affect the overall inhibitory activity of PDE4, but delays the time to reach the maximum concentration (T Cmah) roflumilast for one hour and reduces the maximum concentration (Cmax) by about 40%. However, eating does not affect FROMmax and tmax Noxide roflumilast.

    Distribution

    Binding to plasma proteins of roflumilast and NRoflumilast oxide is approximately 99% and 97%, respectively. The volume of distribution of a single dose, 0.5 mg of roflumilast, is about 2.9 l / kg. Thanks to its physicochemical properties, roflumilast easily distributed to organs and tissues, including adipose tissue. The early phase distribution with a characteristic penetration into the tissue is accompanied by a phase of excretion from adipose tissue, which is due, most likely,intensive decomposition of the starting material with formation of N- Roflumilast oxide. Preclinical studies of roflumilast with a radioactive label indicate low penetration across the blood-brain barrier. There is no evidence of specific cumulation or delay of roflumilast or its metabolites in organs and adipose tissue.

    Metabolism

    Roflumilast is actively metabolized. the reactions proceeding in two stages: Stage I (cytochrome P450) and Phase II (conjugation). NOxide metabolite is the main metabolite found in human blood plasma. Area under the curve "concentration - time" (AUC) for NThe average oxide content is approximately 10 times greater than AUC for roflumilast. In this way, NOxide metabolite is considered to be a more important substance to provide a general inhibitory activity against PDE4 in vivo.

    Research in vitro and clinical studies of interaction suggest that the metabolism of roflumilast with formation N-oxide metabolite is carried out by cytochromes CYP1A2 and 3A4. Based on the results of additional studies conducted in vitro on microsomes from human liver, the therapeutic concentrations of roflumilast and N- Roflumilast in blood plasma does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 / 5 or 4A9 / 11. Therefore, the probability of significant interaction with substances metabolized by these varieties of cytochromes P450 is extremely small. In addition, studies in vitro showed no induction of cytochromes CYP1A2, 2A6, 2C9, 2C19 or 3A4 / 5 and only weak induction CYP2B6 under the action of roflumilast.

    Excretion

    The plasma clearance after short-term intravenous infusion of roflumilast is about 9.6 l / h. After oral administration, the half-life of roflumilast and N- Roflumilast oxide in plasma is approximately 17-30 hours, respectively. Stable concentration of roflumilast and its metabolite NThe oxide is reached after about 4 days for roflumilast and 6 days for N- Roflumilast oxide after taking one dose per day. After intravenous or oral administration of roflumilast with a radioactive label, about 20% of the radioactivity was detected in the feces and 70% in the urine, in the form of inactive metabolites.

    Linearity / Nonlinearity

    Pharmacokinetics of roflumilast and its metabolite NThe oxide is proportional to the dosage in the range from 0.25 mg to 1.0 mg.

    Special patient groups

    In elderly patients, women and non-Caucasoid individuals, the overall inhibitory activity of PDE4 increased. The overall inhibitory activity of PDE4 decreased somewhat in smokers. One of these changes can not be regarded as clinically significant. Therefore, no dose adjustments are recommended for these patient groups.

    The data obtained in the study ex vivo, showed that when compared with the general population, the total inhibitory activity of PDE4, as measured by free fractions, was 15% higher in patients over the age of 75 and 11% higher in patients with a baseline body weight of less than 60 kg.

    Renal insufficiency

    The total inhibitory activity of PDE4 decreased by 9% in patients with severe renal insufficiency (creatinine clearance is 10-30 ml / min). Correction of the dose is not required.

    Liver failure

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

    Indications:Daxas is used as maintenance therapy for the treatment of severe COPD (the post-bronchodilation volume of forced expiration in the first second (FEV1) should be less than 50% of the calculated expected value) in adult patients with frequent exacerbations in the anamnesis.
    Contraindications:Hypersensitivity to roflumilast or any other component of the drug.

    Moderately severe or severe form of hepatic insufficiency (class B and C according to Child-Pugh classification).

    Age to 18 years (effectiveness and safety not established).

    Pregnancy and lactation.

    Due to the lack of sufficient experience of use: serious immunodeficiency diseases (HIV infection, multiple sclerosis, systemic lupus erythematosus, progressive multifocal leukoencephalopathy and others), serious acute infectious diseases (such as tuberculosis or acute hepatitis), cancer (except basal cell carcinoma, slow a growing type of skin cancer), chronic heart failure of functional class 3 and 4 (NYHA - New York Heart Association).

    Due to a lack of sufficient experience of use: treatment with immunosuppressive drugs (such as methotrexate, azathioprine, infliximab, etanercept, as well as in individuals receiving continuous maintenance therapy with oral glucocorticosteroids).

    Rare hereditary diseases, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

    Depression associated with the emergence of suicidal thinking and behavior.

    Carefully:

    Mental disorders in history; treatment with an inhibitor isoenzyme of cytochrome CYP1A2 fluvoxamine or two inhibitors CYP3A4/1A2 enoxacin and cimetidine.

    The mild form of hepatic insufficiency (class A according to the Child-Pugh classification).

    Pregnancy and lactation:

    Pregnancy

    Data on the use of roflumilast by pregnant women are limited.

    According to preclinical research roflumilast penetrates the placental barrier.

    Studies in animals showed reproductive toxicity of the drug. Daxas is not recommended for pregnant women and women of reproductive age who do not use contraceptives.

    Lactation

    The available pharmacokinetic data obtained in animals showed the isolation of roflumilast or its metabolites into milk. It is impossible to exclude the risk of getting the drug by the child. Daxas is not recommended for use during lactation.

    Women of childbearing age

    Women of childbearing age are recommended to use effective methods of contraception during treatment with Daxas. Roflumilast It is not recommended to use women of childbearing age who do not use reliable methods of contraception.

    Fertility

    In the study of human spermatogenesis, roflumilast in a dosage of 0.5 mg did not affect the parameters of sperm or sex hormones during a 3-month treatment and during the subsequent 3 months after discontinuation of treatment.

    Dosing and Administration:

    Inside. The drug Daxas is prescribed in tablets of 0.5 mg once a day. Tablets should be taken with water and taken daily at the same time, regardless of food intake.

    To achieve a therapeutic effect, treatment may be required within a few weeks. There are data from clinical studies on the duration of Daxas administration up to one year.

    Dose adjustments are not required depending on the age of the patient (over 65 years of age). Clinical data on the use of Daxas in patients with impaired hepatic class A liver function are not sufficient to recommend dose adjustment, so the drug should be used with caution in the treatment of such patients.

    Patients with kidney diseases do not need a dose adjustment.

    Side effects:

    The most frequent complaints are diarrhea (5.9%), weight loss (3.4%), nausea (2.9%), abdominal pain (1.9%) and headache (1.7%). Most of these adverse reactions are mild or moderate. Such undesirable reactions mainly occur during the first weeks of treatment and in most cases disappear as the treatment continues.

    Undesirable reactions are classified according to the frequency of occurrence:

    most frequent ≥1 / 10

    Frequent ≥1 / 100 and <1/10

    Uncommon ≥1 / 1000 and <1/100

    rare ≥1 / 10000 and <1/1000 very rare <1/10000

    Immune system disorders:

    Infrequent: hypersensitivity

    Rare: angioedema

    Disorders from the endocrine system:

    Rare: gynecomastia

    Disorders from the metabolism and nutrition:

    Frequent: decreased body weight, decreased appetite.

    Mental disorders:

    Frequent: insomnia.

    Infrequent: anxiety.

    Rare: nervousness, depression, panic attack. During clinical trials, reports of rare cases of suicidal thinking and behavior (including completed suicide) have been reported. Patients should be instructed to tell their doctor about all manifestations of suicidal thinking.

    Impaired nervous system:

    Frequent: headache.

    Infrequent: tremor, vertigo, dizziness.

    Rare: dysgeusia.

    Disorders from the cardiovascular system:

    Infrequent: tachycardia.

    Disturbances from the respiratory system, organs of the thorax and mediastinum:

    Rare: respiratory infections (except pneumonia).

    Disorders from the gastrointestinal tract:

    Frequent: diarrhea, nausea, abdominal pain.

    Infrequent: gastritis, vomiting, gastroesophageal reflux disease, dyspepsia.

    Rare: hematocheia, constipation.

    Disorders from the liver and bile ducts:

    Rare: increased activity of gamma-glutamyltransferase, increased activity of aspartate aminotransferase.

    Disturbances from the skin and subcutaneous tissues:

    Infrequent: rash.

    Rare: hives.

    Disturbances from the musculoskeletal and connective tissue:

    Infrequent: muscular spasms and muscle weakness, myalgia, back pain.

    Rare: increase in creatine phosphokinase in the blood.

    Complications of a general nature and reaction at the site of administration:

    Infrequent: malaise, asthenia, fatigue.

    Overdose:

    During the first phase of clinical trials after taking a single oral dose of 2.5 mg and a single dose of 5.0 mg (ten times the recommended dose), the following symptoms were more common: headache, gastrointestinal disturbances, tachycardia, dizziness, blurred vision, sweating and hypotension.

    In case of an overdose, it is recommended that appropriate symptomatic therapy be carried out. As roflumilast is largely associated with plasma proteins, hemodialysis is not an effective method of its elimination. There is no data whether roflumilast peritoneal dialysis.

    Interaction:

    The main stage in the metabolism of roflumilast is N-oxidation of roflumilast in NRoflumilast oxide with cytochrome CYP3A4 and CYP1A2. AND roflumilast, and N- Roflumilast oxide possess internal inhibitory activity of PDE4. Therefore, after taking roflumilast, the total inhibitory activity of PDE4 is the combined effect of both roflumilast and N- Roflumilast oxide. Clinical studies of interaction with cytochrome inhibitors CYP 3A4, erythromycin and ketoconazole, showed an increase in the total inhibitory activity of PDE4 by 9%. Studies of the interaction with a cytochrome inhibitor CYP1A2, fluvoxamine, and inhibitors CYP3A4 and CYP31A2, enoxacin and cimetidine, showed an increase in the total inhibitory activity of PDE4 - 59%, 25% and 47%, respectively. The combined use of Daxas with these active substances can lead to increased action and development of intolerance. In this case, it is necessary to revise the question of treatment with Daxas.

    Receiving the inducer of cytochrome P450 rifampicin led to a decrease in the total inhibitory activity of PDE4 by approximately 60%. Therefore, the use of powerful inducers of cytochrome P450 (eg, phenobarbital, carbamazepine, phenytoin) may reduce the therapeutic effect of roflumilast.

    Simultaneous reception with theophylline led to an increase of 8% of the total inhibitory activity of PDE4. When investigating the interaction with oral contraceptives containing gestodene and ethinyl estradiol, the total inhibitory activity of PDE4 increased by 17%.

    There was no interaction with inhaled drugs salbutamol, formoterol, budesonide and drugs used internally montelukast, digoxin, warfarin, sildenafil and midazolam.

    Simultaneous reception with antacid preparations (combination of aluminum hydroxide and magnesium hydroxide) did not change the absorption or pharmacokinetic properties of roflumilast or N- Roflumilast oxide.

    Special instructions:

    Daxas is a non-steroidal anti-inflammatory drug intended for supporting treatment of patients with severe COPD with frequent exacerbations. Due to the fact that patients in the general population of COPD are significantly older than 40, the prescription of a drug for patients under 40 years of age requires spirometric confirmation of the diagnosis of COPD.According to the indications for the use of the drug, it is necessary that the value of postbronchodilator FEV1 is less than 50% of the calculated proper score.

    Daxas is not intended for the treatment of an acute attack of dyspnea (acute bronchospasm). To facilitate an acute attack, it is important to have a doctor prescribed medication, which will always be at your fingertips to cope with the attack. The drug Daksas in this situation will not help.

    Weight loss

    In the course of studies conducted during the year, there was a greater decrease in body weight in patients taking Daxas, compared with patients taking placebo. After discontinuation of Daxas, most patients regained their body weight within 3 months.

    In patients with underweight, the weight should be monitored at each visit to the doctor. Patients should be advised to regularly monitor their body weight. In the case of unexplained or clinically significant weight loss, it is necessary to stop taking Daxas and monitor the dynamics.

    Special clinical conditions

    Due to the lack of sufficient experience, do not start treatment with Daxas, in people receiving continuous maintenance therapy with oral glucocorticosteroids, with the exception of short-term courses of systemic glucocorticosteroids.

    The experience of Daxas in patients with latent infections, such as tuberculosis, viral hepatitis, viral herpes and herpes zoster, is limited.

    Due to the lack of data on the use of the drug in patients with chronic heart failure (3 and 4 functional class on NYHA), the use of roflumilast in this category of patients is not recommended.

    Mental disorders

    The use of Daxas is associated with an increased risk of psychiatric disorders such as insomnia, anxiety, nervousness and depression. In clinical trials, rare cases of suicidal thinking and behavior have been identified. Therefore, if patients report previously manifested symptoms from the psyche, or if such symptoms are present in them, or if concomitant therapy with other drugs is planned, associated with the likelihood of mental disorders,a thorough assessment of the risks and benefits associated with initiating or continuing treatment with Daxas should be conducted. Patients should be instructed to notify the doctor who prescribed the treatment of any changes in behavior, mood or appearance of suicidal thoughts of any kind.

    In the case of new or worsening of previously existing symptoms of mental disorders in patients, or detection of suicidal thoughts or suicidal attempts, it is recommended to stop taking Daxas.

    Intolerance

    Despite the fact that unwanted reactions such as diarrhea, nausea, abdominal pain and headache occur mainly in the first weeks of treatment and, in most cases, continue with treatment, if these symptoms persist, the question of treatment with Daxas should be reconsidered.

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

    Body weight less than 60 kg

    Roflumilast therapy may increase the risk of developing sleep disorders (mainly insomnia) in patients with a baseline body weight of less than 60 kg,in connection with the higher total inhibitory activity of PDE4 in such patients.

    Theophylline

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

    Effect on the ability to drive transp. cf. and fur:

    Due to the possibility of developing unwanted reactions, care should be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions.

    Form release / dosage:Film coated tablets 0.5 mg.
    Packaging:

    For 10 tablets per blister (PVC / PVDC / aluminum). 1, 3 or 9 blisters are placed in a cardboard box together with an instruction for use.

    Storage conditions:
    At a temperature of no higher than 30 ° C.
    Keep out of the reach of children.
    Shelf life:
    3 years.
    Do not use after the expiration date.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-000573
    Date of registration:22.08.2011 / 24.03.2017
    Expiration Date:Unlimited
    The owner of the registration certificate:AstraZeneca ABAstraZeneca AB Sweden
    Manufacturer: & nbsp
    Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.
    Information update date: & nbsp17.03.2017
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