Daksas film coated pills 0,5mg N30
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Active ingredients
Roflumilast
Release form
Pills
Composition
Roflumilast 500 mcg. Excipients: lactose monohydrate - 198.64 mg, corn starch - 53.56 mg, povidone K90 - 3.9 mg, magnesium stearate - 2.6 mg. The composition of the shell: hypromellose 2910 - 3 mg, macrogol 4000 - 4 mg, titanium dioxide (E171) - 1.25 mg, iron dye yellow oxide (E172) - 0.25 mg.
Pharmacological effect
Anti-inflammatory drug, PDE4 inhibitor. The action of roflumilast is aimed at eliminating the inflammatory processes associated with COPD. The mechanism of action is to inhibit PDE4, the main cyclic adenosine monophosphate - a metabolizing enzyme contained in cells involved in inflammatory processes, and an important link in the pathogenesis of COPD. The effect of roflumilast is mainly directed to PDE4A, 4B and 4D, with a similar potential in the nanomolar range. The affinity to the type of PDE4S 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. Inhibition of PDE4 leads to an increase in intracellular cAMP and a decrease in dysfunction of leukocytes, smooth muscle cells of the respiratory tract and pulmonary vessels, endothelial cells and epithelial cells of the respiratory tract, 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 an indicator of neutrophils in sputum, and also reduces the flow of neutrophils and eosinophils into the respiratory tract of healthy volunteers who received endotoxin.
Pharmacokinetics
Roflumilast is actively metabolized in the human body to form the main pharmacodynamically active metabolite of the N-oxide, roflumilast. Since roflumilast and roflumilast N-oxide are involved in the inhibition of PDE activity (in vivo), the pharmacokinetics are described based on an assessment of the overall inhibitory effect on PDE4. The pharmacokinetics of roflumilast and its N-oxide metabolite is proportional to the dose in the range from 0.25 mg to 1 mg.Absorption After oral administration of 0.5 mg, the total bioavailability of roflumilast is approximately 80%. Cmax of roflumilast in plasma is usually achieved 1 h after administration (ranging from 0.5 to 2 h) on an empty stomach. Cmax of N-oxide is reached after 8 hours (from 4 to 13 hours). Meal does not affect the overall inhibitory activity of PDE4, but it delays the TCmax of roflumilast for 1 hour and reduces the Cmax by about 40%. However, food intake does not affect the Cmax and TCmax of the N-oxide roflumilast. Distribution 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 Vd is about 2.9 L / kg. Due to its physicochemical properties, roflumilast is easily distributed throughout organs and tissues, including adipose tissue. The early distribution phase with a characteristic penetration into the tissues is accompanied by a phase of elimination from adipose tissue, which is most likely due to the intense decomposition of the original substance with the formation of roflumilast N-oxide. Data from preclinical studies with radioactive label roflumilast show low penetration through the BBB. There is no evidence of specific cumulation or delay of roflumilast or its metabolites in organs and adipose tissue. Metabolism Roflumilast is actively metabolized, and the reactions take place in two stages: stage I (isoenzymes of the cytochrome P450 system) and stage II (conjugation). The N-oxide metabolite is the major metabolite found in human plasma. The AUC for the N-oxide is on average about 10 times greater than the AUC for roflumilast. Thus, the N-oxide metabolite is considered to be the more important substance for providing total inhibitory activity against PDE4 in vivo. In vitro studies and clinical studies of the interaction suggest that the metabolism of roflumilast with the formation of the N-oxide metabolite is carried out with the participation of CYP1A2 and 3A4 isoenzymes. Based on the results of additional studies performed in vitro on human liver microsomes, therapeutic concentrations of roflumilast and roflumilast N-oxide in plasma do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C6, 2D6, 2E1, 3A4 / 5 or 4A9 isoenzymes /eleven. Therefore, the probability of a significant interaction with substances metabolized by these cytochrome P450 isoenzymes is extremely small. In addition, in vitro studies have shown the absence of induction of CYP1A2, 2A6, 2C9, 2C19 or 3A4 / 5 isoenzymes and only a weak induction of CYP2B6 under the action of roflumilast.Withdrawal After a short intravenous infusion, the plasma clearance of roflumilast is about 9.6 l / h. After oral administration of T1 / 2 of roflumilast and N-oxide of roflumilast in plasma is approximately 17 h and 30 h, respectively. A stable concentration of roflumilast and its N-oxide metabolite is reached after about 4 days for roflumilast and 6 days for r-flumilast N-oxide after taking one dose per day. After iv administration 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. Pharmacokinetics in special clinical situations In elderly patients, women and non-Caucasians, the total inhibitory activity of PDE4 increased. The total inhibitory activity of PDE4 decreased slightly in smokers. None of these changes should be considered clinically significant. Therefore, it is not recommended to make any dose adjustments for these groups of patients. In patients with severe renal failure (CC 10-30 ml / min), the total inhibitory activity of PDE4 decreased by 9% (dose adjustment is not required). The pharmacokinetics of roflumilast when taken 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 about 20% in patients with hepatic insufficiency of class A according to the Child-Pugh classification, and by about 90% in patients with hepatic insufficiency of class B according to the Child-Pugh classification.
Indications
- as a maintenance therapy in the treatment of severe COPD (post-bronchodilation FEV1 should be less than 50% of the calculated due indicator) in adult patients with frequent exacerbations in history.
Contraindications
- moderate or severe liver failure (class B and C according to Child-Pugh classification); - age up to 18 years (efficacy and safety have not been established); - pregnancy; - lactation period (breastfeeding); - hypersensitivity to 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 for basal cell carcinoma, a slowly growing type of skin cancer); - chronic heart failure 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 continuous supportive therapy with oral corticosteroids); - rare inherited diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption; - depression associated with the appearance of suicidal thinking and behavior. With caution should use the drug for mental disorders in history; with a mild form of liver failure (class A according to Child-Pugh classification); treatment with CYP1A2 isoenzyme inhibitor fluvoxamine or two CYP3A4 / 1A2 inhibitors enoxacin and cimetidine.
Use during pregnancy and lactation
The use of the drug Daxas during pregnancy and lactation (breastfeeding) is contraindicated. Data on the use of roflumilast in pregnant women is limited. It is not recommended to prescribe the drug to women of childbearing age who do not use reliable methods of contraception. It is possible that the infant will receive the drug during breastfeeding, therefore, if necessary, use of the drug during lactation should decide on the termination of 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 the next 3 months after cessation of treatment. Experimental studies on animals have shown that roflumilast penetrates the placental barrier; has reproductive toxicity. Pharmacokinetic data obtained in animals showed the release of roflumilast or its metabolites in breast milk.
Dosage and administration
The drug is administered orally at a dose of 500 µg 1 time / day. Treatment may take several weeks to achieve a therapeutic effect. There are data from clinical studies on the duration of the drug Daxas up to one year.Elderly patients (over 65 years) do not require dose adjustment. Clinical data on the use of the drug Daxas in patients with impaired liver function class A according to the Child-Pugh classification is not enough to recommend dose adjustment, therefore the drug should be used with caution in treating such patients. In patients with kidney disease dose adjustment is not required. Tablets need to be washed down with water and taken daily at the same time, regardless of the meal.
Side effects
The most common are 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). On the part of the digestive system: often - diarrhea, nausea, abdominal pain; infrequently - gastritis, vomiting, gastroesophageal reflux disease, dyspepsia; rarely - hematochezia, constipation, increased activity of GGT, AST. On the part of the psyche: often - insomnia; infrequently - anxiety; rarely - nervousness, depression. In clinical trials, reports of rare cases of suicidal thinking and behavior (including completed suicide) were received. Patients should be instructed to inform their physician about all manifestations of suicidal thinking. Since the cardiovascular system: infrequently - tachycardia. On the part of the respiratory system: rarely - respiratory tract infections (except pneumonia). From the nervous system: often - headache; infrequently - tremor, vertigo, dizziness; rarely - dysgeusia. On the part of the endocrine system: rarely - gynecomastia. Metabolism and nutrition: often - weight loss, loss of appetite. Dermatological reactions: infrequently - rash. Allergic reactions: infrequently - hypersensitivity; rarely - urticaria, angioedema. On the part of the musculoskeletal system: infrequently - muscle spasms and muscular weakness, myalgia, back pain; rarely, an increase in blood CPK. Other: infrequently - malaise, asthenia, fatigue.
Overdose
During the first phase of clinical studies after taking a single oral dose of 2.5 mg and a single dose of 5 mg (10 times the recommended dose), the following symptoms were more common: headache, gastrointestinal dysfunction, tachycardia, dizziness, clouding of consciousness, sweating and arterial hypotension. Treatment: in case of overdose, it is recommended to carry out appropriate symptomatic therapy. Roflumilast largely binds to plasma proteins, so hemodialysis is not an effective method for its elimination. There is no evidence of whether roflumilast is amenable to peritoneal dialysis.
Interaction with other drugs
The main step in the metabolism of roflumilast is N-oxidation with the formation of N-oxide roflumilast with the participation of CYP3A4 and CYP1A2 isoenzymes. Both roflumilast and roflumilast N-oxide possess intrinsic inhibitory activity against PDE4. Therefore, after taking roflumilast, the total inhibitory activity of PDE4 is the cumulative effect of both roflumilast and roflumilast N-oxide. Clinical studies of interactions with CYP3A4 isoenzyme inhibitors, erythromycin and ketoconazole showed an increase in the total inhibitory activity of PDE4 by 9%. Studies of interactions with the CYP1A2 isoenzyme inhibitor, fluvoxamine, and CYP3A4 and CYP31A2 inhibitors, 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 the development of intolerance. In this case, it is necessary to reconsider the issue of treatment with Daxas. Acceptance of the isoenzyme inducer of the cytochrome P450 system of rifampicin resulted in a decrease in the total inhibitory activity of PDE4 by approximately 60%. Therefore, the use of powerful inducers of this enzyme system (for example, phenobarbital, carbamazepine, phenytoin) can lead to a decrease in the therapeutic effect of roflumilast. Simultaneous administration with theophylline led to an 8% increase in the total inhibitory activity of PDE4. In the study of interaction with oral contraceptives containing gestodene and ethinyl estradiol, the total inhibitory activity of PDE4 increased by 17%.There was no interaction with inhalation drugs salbutamol, formoterol, budesonide and oral preparations of montelukast, digoxin, warfarin, sildenafil and midazolam. Simultaneous administration with antacid preparations (a combination of aluminum hydroxide and magnesium hydroxide) did not change the absorption rates or pharmacokinetic properties of roflumilast or roflumilast N-oxide.
special instructions
Daxas is a non-steroidal anti-inflammatory agent intended for the maintenance treatment of patients with severe COPD with frequent exacerbations. Due to the fact that in the general population of COPD, patients over the age of 40 years predominate significantly, when prescribing the drug to patients under 40 years of age, spirometric confirmation of the diagnosis of COPD is required. According to the indications for use of the drug, it is necessary that the value of post-bronchodilation FEV1 should be less than 50% of the calculated proper indicator. Daxas is not intended to treat an acute attack of shortness of breath (acute bronchospasm). The patient should be warned that in order to relieve an acute attack, it is important to always have a medicine prescribed by the doctor to stop the attack. Daksas in this case is not effective. In the course of studies conducted during the year, there was more often a decrease in body weight in patients who received Daxas, compared with patients who received placebo. After discontinuing the drug, Daxas in most patients was restored to body weight within 3 months. In patients with underweight should be monitored at each visit to the doctor. Patients should be advised to regularly monitor their body weight. In the case of an unexplained or clinically significant weight loss, you must stop taking Daxas and monitor the dynamics. Due to the lack of sufficient experience, it is not advisable to start treatment with Daxas for patients receiving continuous maintenance therapy with oral GCS, with the exception of short-term courses of systemic GCS. Experience with the use of the drug Daxas in patients with latent infections, such as tuberculosis, viral hepatitis, viral herpes and shingles, is limited.The use of Daxas is associated with an increased risk of mental disorders such as insomnia, anxiety, nervousness, and depression. In clinical studies, rare cases of suicidal thinking and behavior have been identified. Therefore, if patients report previously manifested symptoms from the psyche or such symptoms are presently present, or if concomitant therapy with other drugs is planned, related to the likelihood of mental disorders, a careful assessment of the risks and benefits associated with the onset or continuation of drug treatment Daxas. Patients should be instructed to notify the physician prescribing the treatment of any changes in the behavior, mood or occurrence of suicidal thoughts of any nature. 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 go away with continued treatment, if these symptoms persist, the issue of treatment with Daxas should be reconsidered. Intolerance can occur in the case of special populations of patients, in particular, in non-smoking black women or patients receiving treatment with a CYP1A2 inhibitor fluvoxamine or two inhibitors of CYP3A4 / 1A2 enoxacin and cimetidine. There is no clinical data regarding concomitant treatment with theophylline as maintenance therapy. Therefore, concomitant therapy with theophylline is not recommended. Impact on the ability to drive motor vehicles and control mechanisms Because of the possibility of adverse reactions, patients should be careful when driving and other potentially hazardous activities that require increased concentration and psychomotor reactions.