2010/09/17

Accolat

Composition, structure and packing

Tablets, coated in white or almost white, round, biconvex, engraved with "ACCOLATE 20" on one side.

1 tab. zafirlukast 20 mg.

Excipients: sodium croscarmellose, lactose monohydrate, microcrystalline cellulose, povidone, magnesium stearate, gipromelloza, titanium dioxide.

Clinico-pharmacological group: Drug for treatment of bronchial asthma. Antagonist leykotrienovyh receptors.

Pharmacological action

The competitive, highly selective and highly active antagonist of peptide leukotrienes LTC4, LTD4, LTE4 - components of slow reacting substance of anaphylaxis.

The synthesis of leukotrienes and their interactions with receptors have been studied in relation to the pathophysiology of asthma.

Their effects include increased tone of smooth muscles, swelling of the mucous membrane of the respiratory tract and changes in the cellular activity associated with inflammation, including the influx of eosinophils to the lungs. These effects are associated with clinical symptoms and manifestations of asthma. Accolate acts as an anti-inflammatory agent that prevents the action of these mediators of inflammation. Studies have shown that accolate equally counteracts the reduction of smooth muscle under the influence of all three peptide leukotrienes (LTC4, LTD4, LTE4).

Experimental studies on animals have shown that accolate effectively prevents both caused by leukotrienes increase vascular permeability, leading to edema, and caused by leukotrienes influx of eosinophils to the lungs.

Specificity accolate been proven in clinical studies, where it was shown that accolate acts only on receptors for leukotriene and does not act on receptors for prostaglandins, thromboxanes, cholinergic and histamine receptors.

In clinical studies accolate showed the presence of anti-inflammatory properties. Receiving accolate for 5 days decreased the cellular and noncellular components of inflammation in the airways of antigen provocation.

In placebo-controlled studies in segmental bronhoprovokatsii, followed by 48 h bronchoalveolar lavage, accolate reduced level rise basophils, lymphocytes and histamine, and reduced stimulated superoxide alveolar macrophages. Accolate increasingly weakened after provocation with inhaled allergen bronchial hyperreactivity and bronhokonstriktsiyu induced factor that activates platelets.

In addition, decreased sensitivity to methacholine after long-term use accolate 20 mg 2 times / day. During clinical trials with long-term therapy accolate showed improvement in lung function, defined at the time of the lowest level of drug in plasma, consistent with the concept of long-term reduction of obstruction, induced by an inflammatory component. Accolate showed a dose-dependent inhibition of bronchoconstriction caused by inhaled leukotriene D4. It is known that patients with asthma is about 10 times more sensitive to the action bronhospasticheskomu leukotriene D4. Ingestion of a single dose accolate allows asthma to inhale a hundred times the dose leukotriene D4, and thus the protective effect observed after 12 and 24 h.

Accolate inhibits bronchoconstriction caused by several kinds of provocations, such as sulfur dioxide, exercise, cold air, but also weakens the early and late phase inflammatory reactions induced by various antigens, such as plants, animal dander, ragweed, and mixed antigens. Some patients accolate completely prevents asthma attacks caused by physical stress and allergens.

In patients with asthma that does not yield adequate control of beta-stimulants (taken when necessary), use accolate as maintenance therapy facilitates the state reduces the daytime and nighttime asthma symptoms, improve lung function, reduces the need to receive beta-stimulants and reduces the frequency of exacerbations of the disease.

In clinical studies, there was a significant effect on basal tone bronhomotorny observed within 2 h after the first dose accolate, when the maximum peak concentration has not yet been reached.

The therapeutic effect occurs within the first weeks, and sometimes the first days of admission accolate.

Pharmacokinetics

Absorption

Cmax zafirlukasta in plasma obtained at 3 h after administration accolate inside. Acceptance of the drug simultaneously with food increases bioavailability zafirlukasta variability and reduces the bioavailability in most cases (75%). The overall decline in the bioavailability of dietary - about 40%.

Distribution

The value of Css is proportional to the dose and predictable on the basis of pharmacokinetic patterns of unit dose. Binding to plasma proteins (mainly albumin) is 99%, with a concentration range 0.25-4 mg / ml.

When receiving the drug in doses ranging from 30 to 80 mg 2 times / day zafirlukasta cumulation in plasma was low (from undetectable to 2.9-fold, the average value - 1.45, median - 1.27).

Metabolism

Zafirlukast is extensively biotransformiruetsya. Metabolites identified in plasma, were 90 times less active than zafirlukast in a standard definition of activity in vitro.

Withdrawal

Zafirlukast in unmodified form is not detected in the urine. Derivation of metabolites is due to excretion in the urine (approximately 10%) and feces (89%). T1 / 2 zafirlukasta - 10 am

Pharmacokinetics in special clinical situations

No significant differences between the pharmacokinetic parameters zafirlukasta in patients with impaired renal function and in healthy individuals.

In the elderly (65 years) and in patients with cirrhosis of alcoholic etiology, clearance zafirlukasta reduced so that the Cmax and AUC about 2 times higher than in healthy individuals (with the same dose accolate). However, cumulation zafirlukasta in elderly people does not happen. Pharmacokinetic parameters zafirlukasta in adolescents are similar to those in adults. After adjusting dose to body weight no significant differences in pharmacokinetic parameters in men and women.

Statement
prevention of attacks and maintenance therapy in bronchial asthma (including both first-line drugs for failure of beta-sympathomimetics).

Dosage regimen

Due to the fact that accolate used to prevent asthma attacks, it is designed for continuous use.

Adults and children older than 7 years of therapy begins with 20 mg 2 times / day. Average maintenance dose is 20 mg 2 times / day. Increasing the dose may give an additional effect. The maximum daily dose: 40 mg 2 times / day. Accolate should not be taken simultaneously with food, because food reduces the bioavailability zafirlukasta.

In elderly patients treated with 20 mg 2 times / day and adjust the dose depending on clinical response. In clinical studies in elderly patients treated accolate 20 mg 2 times / day, there was no increase in the overall frequency of adverse events.

Safety and efficacy accolate children under 7 years is not installed. Therapy in patients with cirrhosis steady flow of alcohol etiology begin with 20 mg 2 times / day and adjust the dose depending on clinical response. Application accolate not been studied in patients with impaired liver function of another origin or chronic administration in patients with cirrhosis.

Patients with impaired renal function correct dosing regimen is not required.

Side effect

Allergic reactions: reported cases of urticaria and angioedema as well as the rash and blisters.

On the part of the digestive system: during clinical trials rarely saw the rise of the level of serum transaminases. These changes persisted with continued therapy or following its closure. Rarely dynamic changes transaminase level coincided with the hepatitis B drug that is allowed after the cessation of therapy accolate.

Other: a placebo-controlled clinical studies observed a higher rate of infections in elderly patients treated accolate. These infections usually occurs easily, mainly struck respiratory tract and did not require discontinuation of therapy accolate. Receiving accolate can cause headache and disturbance of the gastrointestinal tract. These symptoms are usually light and does not require the abolition of therapy.

Contraindications
Hypersensitivity to the drug history.

Pregnancy and lactation

Health & Safety accolate during pregnancy has not been established. Possible risks must be balanced against the benefits of continuing therapy during pregnancy accolate, accolate and should be used during pregnancy only if clearly needed its reception.

Zafirlukast is excreted in breast milk. Accolate not be assigned to nursing mothers. In experimental animal studies, zafirlukast did not show any visible effects on fertility and had no obvious teratogenic effects or toxicity to the fetus effects. Zafirlukast was not mutagenic action of all applicable tests. However, the data obtained in the experiment can not be transferred into clinical practice.

Cautions

To get the effect of treatment, accolate must be taken regularly, even if the symptoms of asthma are not worried. Therapy accolate also must continue during exacerbations of asthma. Accolate not indicated for the relief of bronchospasm in asthma.

Accolate not investigated in the treatment of unstable and subcompensated asthma. Accolate should not abruptly replace therapy with inhaled GCS. When considering the reduction of the dose of GCS in patients with severe asthma should be cautious. Cancel oral GCS in patients with severe asthma in rare cases causes eosinophilic infiltration, sometimes presented as-Strauss syndrome ńĆergov with clinical signs of systemic vasculitis. The causal link with the reception accolate not installed. Accolate taken by mouth, which is an advantage for patients who have difficulty using inhalers.

During therapy accolate possible rise in serum transaminases. Typically, these phenomena are transient and asymptomatic, but may also be early signs of hepatotoxicity. In the case of clinical signs or symptoms suggestive of liver dysfunction (eg, nausea, vomiting, pain in the upper right quadrant of the abdomen, fatigue, weakness, lethargy, flu-like symptoms, liver enlargement, itching and jaundice), it is necessary to investigate the level of serum transaminases, in particular serum ALT, and accordingly to the patient.

The decision to stop accepting accolate be taken individually, weighing the risk of hepatic dysfunction against the use of accolate a given patient. Accolate not recommended for patients with impaired liver function.

Experimental Results

When using multiple doses exceeding 40 mg / kg / day for 12 months in mice, rats and dogs, an increase in liver-related degenerative / fatty changes or deposits of glycogen. Aggregation of histiocytes was observed in some tissues of dogs.

In male mice receiving 300 mg / kg zafirlukasta a day, an increase in the frequency of hepatocellular adenomas, compared with a control group of animals. In rats treated with 2000 mg / kg zafirlukasta a day, an increase in the frequency of papilloma of the bladder, compared with a control group of animals. The clinical significance of these findings Propafenone accolate people have not been confirmed.

Effects on ability to drive vehicles and management mechanisms

No information that accolate affects driving ability and other machines. Overdosage No information on cases of overdose accolate humans.

Treatment.

Presumably therapy should be supportive, helpful perhaps removal of the drug by gastric lavage.

Drug Interactions

Accolate can be used simultaneously with other types of medication used for treatment of allergy and asthma. For example accolate used in conjunction with inhaled GCS, inhalation and oral therapy with bronchodilators, antibiotics and antihistamines with no signs of undesirable interactions.

Accolate can be used concurrently with oral contraceptive without unwanted interaction. Receiving accolate simultaneously with acetylsalicylic acid may lead to increased levels zafirlukasta in plasma by approximately 45%. It is unlikely that this increase could have a clinically significant effect. Receiving accolate simultaneously with erythromycin may lead to a decline in plasma zafirlukasta approximately 40%.

Receiving accolate simultaneously with theophylline may lead to a decline in plasma zafirlukasta about 30%, without affecting the level of theophylline in plasma.

Receiving accolate simultaneously with terfenadinom reduces AUC for zafirlukasta 54%, without affecting the level of terfenadina in plasma.

Receiving accolate simultaneously with warfarin increases the maximum prothrombin time by approximately 35%. It is therefore recommended to monitor prothrombin time if accolate used concurrently with warfarin.

It is assumed that this interaction is the result of inhibition zafirlukastom enzyme cytochrome P450 2C9.

Terms and Conditions of storage

The drug should be stored at temperatures not above 30 ° C.