Instructions for use of Daxas (Roflumilast):
Daxas is a member of a relatively new class of phosphodiesterase-4 (PDE4) inhibitors.
The main substance Roflumilast has a targeted anti-inflammatory effect and acts through a fundamentally new mechanism. By blocking the PDE-4 enzyme contained in cells involved in the inflammatory process, it is possible to significantly suppress the dysfunction of leukocytes and slow down inflammatory phenomena. Roflumilast helps reduce the number of neutrophils contained in sputum, and also prevents eosinophils from being in the respiratory tract. You can buy Daxas by placing an order on our website. Our price for this drug is one of the lowest on the Internet. When entering the body, Daxas undergoes active metabolism. Bioavailability is 80%, protein binding is almost 100%. An hour after taking the standard dose, the maximum content of the active substance is observed in the blood. The inhibitory activity of Roflumilast does not depend on food intake, however, when simultaneously administered to the body with food, the onset of its maximum concentration significantly slows down. Most of the drug (70%) is excreted in feces, less in urine. In severe renal failure, Roflumilast shows a lesser inhibitory effect (by 9%). Daxas is available in tablet form.
Side effects
The most common side effects are: diarrhea (5.9%), weight loss (3.4%), nausea (2.9%), abdominal pain (1.9%), headache (1.7%) – these reactions usually occur in the first weeks of treatment, are often mild or moderate in nature and, as a rule, go away on their own as therapy continues.
Possible side effects:
- from the nervous system and psyche: often (from ≥ 1/100 to < 1/10) – headache, insomnia; uncommon (from ≥ 1/1000 to < 1/100) – vertigo, tremor, anxiety; rarely (from ≥ 1/10,000 to < 1/1000) – nervousness, dysgeusia, depression; very rarely (<1/10,000) - suicidal thinking and behavior (including suicide);
- from the digestive system: often – diarrhea, abdominal pain, nausea; uncommon – dyspepsia, vomiting, gastritis, gastroesophageal reflux disease; rarely - constipation, hematochezia, increased activity of gamma-glutamyltransferase, aspartate aminotransferase;
- from the respiratory system: rarely - respiratory tract infections (with the exception of pneumonia);
- from the cardiovascular system: infrequently – tachycardia;
- on the part of metabolism and nutrition: often – loss of appetite, loss of body weight;
- from the endocrine system: rarely – gynecomastia;
- from the musculoskeletal system: infrequently - back pain, muscle spasms, myalgia, muscle weakness; rarely - an increase in creatine phosphokinase in the blood;
- dermatological and allergic reactions: uncommon – rash, hypersensitivity reactions; rarely - urticaria, Quincke's edema;
- other: infrequently - asthenia, malaise, fatigue.
Indications and contraindications:
Roflumilast can be prescribed to patients with chronic obstructive pulmonary disease (COPD) - it is used as part of maintenance therapy for severe disease accompanied by frequent exacerbations. One of the main symptoms that is taken into account when prescribing the drug is the presence of a post-bronchodilator forced expiratory volume during the first second (FEV1) of less than 50% compared to the normal value.
The use of Daxas should be excluded in the following cases:
- Increased sensitivity to the components of the product.
- Liver failure.
- Under 18 years of age.
- Gestation/breastfeeding.
- Serious immunodeficiency diseases, for example, HIV infection, multiple sclerosis, systemic lupus erythematosus, etc.
- Concurrent use of immunosuppressive drugs, namely methotrexate, azathioprine, infliximab, etanercept.
- Depressive state accompanied by suicidal thoughts and behavior.
Before recommending the purchase of Daxas, all possible contraindications should be excluded. The patient is also required to inform the doctor about mental disorders.
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 often observed: headache, gastrointestinal disturbances, tachycardia, dizziness, clouding of consciousness, sweating and arterial hypotension.
Treatment: in case of overdose, appropriate symptomatic therapy is recommended. Roflumilast is highly bound to plasma proteins, so hemodialysis is not an effective method of removing it. It is not known whether roflumilast is amenable to peritoneal dialysis.
Directions for use and dosage regimen:
Roflumilast is intended for oral administration, i.e. inside, through the mouth. The standard dose is 0.5 mg/day. The same interval of time should be observed between taking tablets. You can take the medicine regardless of eating. It usually takes several weeks to achieve an adequate clinical response. There is information from clinical studies about taking the drug Daxas for about 1 year.
There is no need to adjust the dosage in case of kidney disease, or in patients over 65 years of age. Information regarding dose adjustment in the presence of class A liver dysfunction is insufficient, so therapy in this group of patients should be carried out with caution.
Pharmacokinetics
Roflumilast is extensively metabolized in the human body to form the main pharmacodynamically active metabolite, roflumilast N-oxide. Because roflumilast and roflumilast N-oxide are involved in the inhibition of PDE activity (in vivo), pharmacokinetics are described based on an assessment of the overall inhibitory effect on PDE4.
The pharmacokinetics of roflumilast and its N-oxide metabolite are dose proportional, ranging from 0.25 mg to 1 mg.
Suction
After oral administration of 0.5 mg, the total (absolute) bioavailability of roflumilast is approximately 80%. Cmax of roflumilast in plasma is usually achieved 1 hour after dosing (ranging from 0.5 to 2 hours) on an empty stomach. Cmax of N-oxide is achieved after 8 hours (from 4 to 13 hours). Food intake does not affect the overall PDE4 inhibitory activity, but delays the Tmax of roflumilast by 1 hour and reduces the Cmax by approximately 40%. However, food intake does not affect the Cmax and Tmax of roflumilast N-oxide.
Distribution
Plasma protein binding 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 phase of distribution with characteristic penetration into tissue is accompanied by a phase of elimination from adipose tissue, which is most likely due to the intensive breakdown of the parent substance with the formation of roflumilast N-oxide.
Data from preclinical studies of radiolabeled roflumilast show low BBB penetration. There is no evidence of specific accumulation or retention 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 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 to be more important for overall PDE4 inhibitory activity in vivo.
In vitro studies and clinical interaction studies suggest that the metabolism of roflumilast to the formation of an N-oxide metabolite is carried out with the participation of the CYP1A2 and 3A4 isoenzymes. Based on the results of additional in vitro studies on microsomes from human liver, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 or 4A9 isoenzymes. /eleven. Therefore, the likelihood of significant interaction with substances metabolized by these cytochrome P450 isoenzymes is extremely low. In addition, in vitro studies showed no induction of CYP1A2, 2A6, 2C9, 2C19 or 3A4/5 isoenzymes and only a weak induction of CYP2B6 by roflumilast.
Removal
After a short-term intravenous infusion, the plasma clearance of roflumilast is approximately 9.6 l/h. After oral administration, the plasma T1/2 of roflumilast and roflumilast N-oxide is approximately 17 hours and 30 hours, respectively. Steady-state concentrations of roflumilast and its metabolite N-oxide are achieved after approximately 4 days for roflumilast and 6 days for roflumilast N-oxide after dosing once daily. Following intravenous or oral administration of radiolabeled roflumilast, approximately 20% of the radioactivity was detected in the feces and 70% in the urine, as inactive metabolites.
Pharmacokinetics in special clinical situations
In elderly patients, women, and non-Caucasians, overall PDE4 inhibitory activity was increased. Overall PDE4 inhibitory activity was slightly reduced 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 (creatinine clearance 10-30 ml/min), the total inhibitory activity of PDE4 decreased by 9% (no dose adjustment required).
The pharmacokinetics of roflumilast when administered once a day was studied in 16 patients with mild to moderate hepatic impairment (Child-Pugh class A and B). PDE4 inhibitory activity was 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.
Special instructions:
The diagnosis of COPD is often made in patients over 40 years of age, so Roflumilast should be prescribed to younger patients only based on the results of a spirometric study. The condition under which the use of the drug may be justified is a post-bronchodilator FEV1 of less than 50%.
It is worth considering that Daxas is not effective for acute attacks of shortness of breath. In this case, it is important to have with you the appropriate medication prescribed by your doctor.
Since the cost of using Roflumilast is often expressed in terms of weight loss, underweight patients should be carefully monitored. If body weight drops below a critical level, treatment with Daxas should be discontinued.
Drug interactions
- CYP3A4 isoenzyme inhibitors ketoconazole and erythromycin, CYP1A2 isoenzyme inhibitor fluvoxamine and CYP3A4 and CYP31A2 inhibitors enoxacin and cimetidine: the total inhibitory activity of PDE4 increases by 9, 59, 25 and 47%, respectively, as a result of which the effect of roflumilast may be enhanced and the development of intolerance;
- phenytoin, carbamazepine, phenobarbital, rifampicin: the total inhibitory activity is reduced by approximately 60%, as a result of which the therapeutic effect of roflumilast may be reduced;
- theophylline and oral contraceptives containing gestodene and ethinyl estradiol: the overall PDE4 inhibitory activity increases by 8 and 17%, respectively.
No interaction reactions occur when roflumilast is combined with inhaled agents (budesonide, formoterol and salbutamol), as well as with oral drugs (midazolam, warfarin, digoxin, montelukast, sildenafil).
With the simultaneous use of antacid drugs (containing a combination of aluminum hydroxide and magnesium hydroxide), the absorption rates and pharmacological properties of roflumilast and its active metabolite do not change.
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