Universal reference book for medicines
Product name: DAXAS (DAXAS ® )

Active substance: roflumilast

Type: Anti-inflammatory drug - inhibitor PDE4

Manufacturer: TAKEDA (Germany)
Composition, form of production and packaging
The tablets covered with a film cover of
yellow color, D-shaped, with engraving "D" on one side;
on the fracture - the core is white or almost white.
1 tab.

roflumilast 500 mcg

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

Composition of the membrane: hypromellose 2910-3 mg, macrogol 4000-4 mg, titanium dioxide (E171) 1.25 mg, ferric oxide yellow oxide (E172) 0.25 mg.

10 pieces.
- blisters (1) - packs of cardboard.
10 pieces.
- blisters (3) - packs of cardboard.
10 pieces.
- blisters (9) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2015.

PHARMACHOLOGIC EFFECT

Anti-inflammatory drug, inhibitor PDE4.
The action of roflumilast is aimed at eliminating the inflammatory processes associated with COPD. The mechanism of action is the inhibition of PDE4, the main cyclic adenosine monophosphate, a metabolic enzyme contained in cells involved in inflammatory processes, and is an important link 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 the N-oxide, which is the main active metabolite of roflumilast.
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) has shown that roflumilast and Roflumilast N-oxide inhibits 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 respiratory tract of healthy volunteers receiving endotoxin.

PHARMACOKINETICS

Roflumilast is actively metabolized in the human body to form the main pharmacodynamically active metabolite of Roflumilast N-oxide.
Because roflumilast and Roflumilast N-oxide are involved in the inhibition of PDE activity (in vivo), the pharmacokinetics are described based on an estimate of the overall inhibitory effect on PDE4.
The pharmacokinetics of roflumilast and its metabolite N-oxide is proportional to the dose in the range from 0.25 mg to 1 mg.

Suction

After oral administration of 0.5 mg, the full bioavailability of roflumilast is approximately 80%.
C max of roflumilast in plasma is usually achieved 1 hour after admission (within 0.5 to 2 h) on an empty stomach. The C max of the N-oxide is reached after 8 h (from 4 to 13 h). Eating does not affect the overall inhibitory activity of PDE4, but delays T Cmax of roflumilast for 1 hour and reduces Cmax by about 40%. However, food intake does not affect C max and T Cmax N-oxide roflumilast.
Distribution

The binding to plasma proteins of roflumilast and Roflumilast N-oxide is approximately 99% and 97%, respectively.
With a single dose of roflumilast 0.5 mg V d is about 2.9 l / kg. Due to its physico-chemical properties, roflumilast is easily distributed to organs and tissues, including adipose tissue. The early phase of distribution with a characteristic penetration into the tissue is accompanied by a phase of excretion from adipose tissue, which is most likely due to the intensive decomposition of the starting material with the formation of N-roflumilast oxide.
Preclinical studies of roflumilast with a radioactive label indicate low penetration through the BBB.
There is no data on the specific cumulation or delay of roflumilast or its metabolites in organs and adipose tissue.
Metabolism

Rflumilast is actively metabolized, the reactions being in two stages: Stage I (cytochrome P450 isoenzymes) and Phase II (conjugation).
N-oxide metabolite is the main metabolite found in human blood plasma. AUC for the N-oxide on average turns out to be about 10 times greater than the AUC for roflumilast. Thus, the N-oxide metabolite is considered to be a more important substance to provide a general inhibitory activity against PDE4 in vivo.
In vitro studies and clinical studies of interaction suggest that the metabolism of roflumilast with the formation of the N-oxide metabolite is carried out with the participation of isoenzymes CYP1A2 and 3A4.
Based on the results of additional studies conducted in vitro on microsomes from human liver, the therapeutic concentrations of roflumilast and Roflumilast N-oxide in blood plasma do not inhibit the isoenzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 / 5 or 4A9 /eleven. Therefore, the probability of significant interaction with substances metabolized by these isoenzymes of cytochrome P450 is extremely small. In addition, in vitro studies showed no induction of isoenzymes CYP1A2, 2A6, 2C9, 2C19 or 3A4 / 5 and only weak induction of CYP2B6 by roflumilast.
Excretion

After a short-term intravenous infusion, the plasma clearance of roflumilast is about 9.6 l / h.
After oral administration, T 1/2 of roflumilast and Roflumilast N-oxide in plasma is approximately 17 hours and 30 hours, respectively. The stable concentration of roflumilast and its metabolite N-oxide is reached after about 4 days for roflumilast and 6 days for Roflumilast N-oxide after taking one dose per day. After intravenous administration of orally ingesting 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.
Pharmacokinetics in special clinical cases

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. None of these changes can be regarded as clinically significant. Therefore, no dose adjustments are recommended for these patient groups.
In patients with severe renal insufficiency (CC 10-30 ml / min), the total inhibitory activity of PDE4 decreased by 9% (dose adjustment is not required).

The pharmacokinetics of roflumilast at the administration of 1 time / day was studied in 16 patients with mild and moderate hepatic insufficiency (class A and B according to the Child-Pugh classification).
The inhibitory activity of PDE4 increased by approximately 20% in patients with Child-Pugh class A liver failure, and by approximately 90% in patients with hepatic class B liver failure according to Child-Pugh classification.
INDICATIONS

- as a supportive therapy for the treatment of severe COPD (postbronchodilating FEV1 should be less than 50% of the calculated value) in adult patients with frequent exacerbations in the anamnesis.

DOSING MODE

The drug is administered orally at a dose of 500 mcg 1 time / day.

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.
In elderly patients (over 65 years of age), dose adjustment is not required.

Clinical data on the use of Daxas in patients with impaired hepatic class A liver function is not enough to recommend a dose adjustment, so the drug should be used with caution in the treatment of such patients.

In patients with kidney disease, dose adjustment is not required.

Tablets should be taken with water and taken daily at the same time, regardless of food intake.

SIDE EFFECT

Most common: 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 as the treatment continues; most of them are light or moderate.
Determination of the frequency of adverse reactions: very often (? 1/10), often (? 1/100 and <1/10), infrequently (? 1/1000 and <1/100), rarely (? 1/10 000 and <1 / 1000), very rarely (<1/10 000).

From the digestive system: often - diarrhea, nausea, abdominal pain;
infrequently - gastritis, vomiting, gastroesophageal reflux disease, dyspepsia; rarely - hematocheia, constipation, increased activity of GGT, AST.
From the side of the psyche: often - insomnia;
infrequent anxiety; rarely - nervousness, depression. When conducting 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.
From the cardiovascular system: infrequently - tachycardia.

From the respiratory system: rarely - respiratory tract infections (except pneumonia).

From the nervous system: often - headache;
infrequently - tremor, vertigo, dizziness; rarely - dysgeusia.
From the endocrine system: rarely - gynecomastia.

From the side of metabolism and nutrition: often - weight loss, loss of appetite.

Dermatological reactions: infrequent - rash.

Allergic reactions: infrequently - hypersensitivity;
rarely - hives, angioedema.
From the musculoskeletal system: infrequently - muscular spasms and muscle weakness, myalgia, back pain;
rarely - an increase in CK in the blood.
Other: infrequent - malaise, asthenia, fatigue.

CONTRAINDICATIONS

- moderate or severe form of hepatic insufficiency (class B and C according to the Child-Pugh classification);

- age under 18 years (effectiveness and safety not established);

- Pregnancy;

- the period of lactation (breastfeeding);

- Hypersensitivity to the components of the drug.

Contraindications due to lack of sufficient experience of use:

- 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 slowly growing type of skin cancer);

- chronic heart failure of NYHA functional class 3 and 4;

- treatment with immunosuppressive drugs (such as methotrexate, azathioprine, infliximab, etanercept, and also in patients receiving continuous maintenance therapy with oral GCS);

- rare hereditary diseases, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption;

- Depression associated with the emergence of suicidal thinking and behavior.

Caution should be applied to the drug with a history of mental illness;
with mild liver failure (Class A Child-Pugh classification); treatment with an inhibitor of the isoenzyme CYP1A2 fluvoxamine or two inhibitors of CYP3A4 / 1A2 enoxacin and cimetidine.
PREGNANCY AND LACTATION

Contraindicated use of Daxas during pregnancy and lactation (breastfeeding).

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

It is not recommended to prescribe the drug to women of childbearing age who do not use reliable methods of contraception.

It can not be ruled out that the baby will receive the drug during breastfeeding, so if it is necessary to use the drug during lactation it is necessary to resolve the issue of stopping breastfeeding.

In the study of human spermatogenesis, roflumilast at a dose of 500 μg did not affect sperm parameters or sex hormones during treatment for 3 months and for a further 3 months after cessation of treatment.

In experimental studies in animals, roflumilast is shown to penetrate the placental barrier;
has reproductive toxicity. Pharmacokinetic data obtained in animals showed the isolation of roflumilast or its metabolites with breast milk.
APPLICATION FOR FUNCTIONS OF THE LIVER

In patients with kidney disease, dose adjustment is not required.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Clinical data on the use of Daxas in patients with impaired hepatic class A liver function is not enough to recommend a dose adjustment, so the drug should be used with caution in the treatment of such patients.

Caution should be used for mild liver failure (Class A Child-Pugh classification).

APPLICATION FOR CHILDREN

Contraindicated in children and adolescents under 18 years.

APPLICATION IN ELDERLY PATIENTS

In elderly patients (over 65 years of age), dose adjustment is not required.

SPECIAL INSTRUCTIONS

Daxas is a non-steroidal anti-inflammatory drug intended for maintenance treatment of patients with severe COPD with frequent exacerbations.
Due to the fact that patients over 40 years of age predominate in the general population of COPD, spirometric confirmation of the diagnosis of COPD is required when the drug is prescribed to patients under 40 years of age.
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 due index.

Daxas is not intended for the treatment of an acute attack of dyspnea (acute bronchospasm).
The patient should be warned that to facilitate an acute attack it is important to always have a doctor prescribed medication to stop the attack. Daxas in this case is not effective.
In studies conducted during the year, a decrease in body weight was more common in patients receiving Daxas than in patients receiving placebo.
After discontinuation of Daxas preparation in most patients, the body weight was restored within 3 months.
Patients with insufficient body 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.
Due to lack of sufficient experience, Daxas should not be started by patients receiving continuous maintenance therapy with oral GCS, with the exception of short-term courses of systemic SCS.

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

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 risk and benefit associated with the onset or continuation of treatment with Daxas. 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.
Despite the fact that adverse 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 case of special populations of patients, in particular, in black smoking women or patients receiving treatment with inhibitor CYP1A2 fluvoxamine or two inhibitors of CYP3A4 / 1A2 with enoxacin and cimetidine.

There are no clinical data on the concomitant treatment with theophylline as maintenance therapy.
Therefore, concomitant therapy with theophylline is not recommended.
Impact on the ability to drive vehicles and manage mechanisms

Because of the potential for the development of adverse reactions, patients should be cautious when driving vehicles and engaging in other potentially hazardous activities that require increased attention and speed of psychomotor reactions.

OVERDOSE

During the first phase of clinical trials after taking a single oral dose of 2.5 mg and a single dose of 5 mg (10 times the recommended dose), the following symptomswere more common: headache, gastrointestinal disturbances, tachycardia, dizziness, blurred vision, sweating, and hypotension.

Treatment: in case of an overdose, it is recommended that appropriate symptomatic therapy be performed.
Roflumilast is largely associated with plasma proteins, so hemodialysis is not an effective method of removing it. There is no evidence whether roflumilast is susceptible to peritoneal dialysis.
DRUG INTERACTION

The main stage in the metabolism of roflumilast is N-oxidation with the formation of N-oxide roflumilast with the participation of isoenzymes CYP3A4 and CYP1A2.
Both roflumilast and Roflumilast N-oxide have internal inhibitory activity against PDE4. Therefore, after taking roflumilast, the total inhibitory activity of PDE4 is the combined effect of both roflumilast and Roflumilast N-oxide. Clinical studies of interaction with inhibitors of the isoenzyme CYP3A4, erythromycin and ketoconazole, showed an increase in the total inhibitory activity of PDE4 by 9%. Investigations with the inhibitor of the isoenzyme CYP1A2, fluvoxamine, and inhibitors of CYP3A4 and CYP31A2, enoxacin and cimetidine showed an increase in the total inhibitory activity of PDE4 - 59%, 25% and 47%, respectively.Combined use of the drug Daxas® with these active substances can lead to increased action and development intolerance. In this case it is necessary to reconsider the treatment of drug Daxas.
Receiving inducer of cytochrome P450 isoenzymes rifampicin resulted in a reduction in total PDE4 inhibitory activity by about 60%. Therefore the use of this powerful inducers an enzymatic system (e.g., phenobarbital, carbamazepine, phenytoin) may reduce the therapeutic effect of roflumilast.
Simultaneous treatment with theophylline resulted in an increase of 8% of the total PDE4 inhibitory activity. When studying interactions with oral contraceptives containing gestodene and ethinyl estradiol, total PDE4 inhibitory activity increased by 17%.
There was no interaction with inhaled drugs salbutamol, formoterol, budesonide and applied within drug montelukast, digoxin, warfarin, sildenafil and midazolam.
Simultaneous treatment with antacids (a combination of magnesium hydroxide and aluminum hydroxide) is not changed suction performance or pharmacokinetic properties of roflumilast or roflumilast N-oxide.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

Keep out of reach of children at a temperature not higher than 30 ° C.
Shelf life - 3 years.
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