Flexibon - instructions for use, doses, side effects, contraindications

Excipients: lactose monohydrate 12.5 mg, microcrystalline cellulose 47.0 mg, crospovidone 5.0 mg, povidone K30 1.0 mg, sodium citrate 15.0 mg, silicon dioxide colloid 1.0 mg, magnesium stearate 1.0 mg.

Active substance: meloxicam - 15.0 mg;

Excipients: lactose monohydrate 25.0 mg, microcrystalline cellulose 94.0 mg Crospovidone 10.0 mg, Povidone K30 2.0 mg Sodium citrate 30.0 mg silica colloidal 2.0 mg magnesium stearate 2.0 mg.

Description:

Tablets 7.5 mg

Light yellow color, round, biconvex tablets with engraving "RA61 "on one side and with a chamfer on both sides. Presence of marble is admissible.

Tablets 15 mg

Light yellow color, round, biconvex tablets with engraving "RA62 "on one side and with a chamfer on both sides. Presence of marble is admissible.

Pharmacotherapeutic group:NSAIDs

ATX: & nbsp

M.01.A.C.06 Meloksikam

M.01.A.C Oksikamy

Pharmacodynamics:

Nonsteroidal anti-inflammatory drug, refers to derivatives enolovoy acid and has anti-inflammatory, analgesic and antipyretic effect.

The pronounced anti-inflammatory effect of meloxicam is established on all standard models of inflammation. The mechanism of action of meloxicam is its ability to inhibit the synthesis of prostaglandins - known inflammatory mediators.

In vivo meloxicam inhibits prostaglandin synthesis at the site of inflammation to a greater extent than in the gastric mucosa and kidney.

These differences are associated with a more selective inhibition of cyclooxygenase-2 (COX-2) compared to cyclooxygenase-1 (COX-1). It is believed that inhibition of COX-2 provides a therapeutic effect of NSAIDs, whereas inhibition of the constantly present isoenzyme COX-1 can cause side effects on the part of the stomach and kidneys. The selectivity of meloxicam against COX-2 was confirmed in various test systems as in vitro, and ex vivo. The selective ability of meloxicam to inhibit COX-2 is shown by using human whole blood as a test system in vitro. Ex vivo determined that meloxicam (in effect on the production of prostaglandin E2 stimulated by lipopolysaccharide (a reaction controlled by COX-2) than on the production of thromboxane involved in the coagulation process (a reaction controlled by COX-1). These effects depended on the dose value. Ex vivo shown, that meloxicam in recommended doses did not affect platelet aggregation and bleeding time, in contrast to indomethacin, diclofenac, ibuprofen and naproxen, which significantly suppressed platelet aggregation and increased bleeding time.

In clinical trials, side effects from the gastrointestinal tract (GIT) as a whole occurred less often with meloxicam 7.5 and 15 mg than with other NSAIDs with which the comparison was made. This difference in the frequency of side effects from the gastrointestinal tract is mainly due to the fact that when taking meloxicam, there were fewer phenomena such as dyspepsia, vomiting, nausea, abdominal pain.

Pharmacokinetics:

Absorption

Meloksikam is well absorbed from the digestive tract, as evidenced by high absolute bioavailability (90%) after ingestion. After a single application of meloxicam C_mOh in plasma is achieved within 5-6 hours. Simultaneous intake of food and inorganic antacids does not change the absorption. When using the drug inside (in doses of 7.5 and 15 mg), its concentrations are proportional to the doses. Steady state of pharmacokinetics is achieved within 3-5 days. The range of differences between the maximum and basal concentrations of the drug after its administration once a day is relatively small and amounts to a dose of 7.5 mg 0.4-1.0 μg / ml, and when a dose of 15 mg is 0.8-2, 0 μg / ml (the values of C_min and C_mOh (minimum and maximum plasma concentrations) during the steady state of pharmacokinetics), although values outside this range were also noted. The maximum concentration of meloxicam in plasma in the period of steady state of pharmacokinetics is reached within 5-6 hours after ingestion.

Distribution

Meloxicam binds well to plasma proteins, especially albumin (99%). It penetrates into the synovial fluid, the concentration in the synovial fluid is approximately 50% of the concentration in the plasma. The volume of distribution after repeated ingestion of meloxicam (in doses from 7.5 mg to 15 mg) is about 16 liters, with a coefficient of variation of 11% to 32%.

Metabolism

Meloksikam is almost completely metabolized in the liver with the formation of 4 pharmacologically inactive derivatives. The main metabolite, 5'-carboxymeloxicam (60% of the dose value), is formed by oxidation of the intermediate metabolite, 5'-hydroxymethylmeloxicam, which is also excreted, but to a lesser degree (9% of the dose value). Research in vitro showed that in this metabolic transformation an important role is played by the isoenzyme CYP2C9, the isozyme has an additional value CYP3A4. In the formation of two other metabolites (constituting 16% and 4% of the dose, respectively), peroxidase takes part, the activity of which probably varies individually.

Excretion

It is excreted equally through the intestines and kidneys, mainly in the form of metabolites. In unchanged form with feces less than 5% of the daily dose is excreted, in the urine in unchanged form the drug is found only in trace amounts. Average T_1/2meloxicam varies from 13 to 25 hours. Plasma clearance is an average of 7-12 ml / min after a single dose of meloxicam.

Liver and / or kidney failure

Lack of liver function, as well as mild renal failure, does not significantly affect the pharmacokinetics of meloxicam. The rate of excretion of meloxicam from the body is much higher in patients with moderate renal insufficiency. Meloksikam worse binds to plasma proteins in patients with terminal renal failure. In terminal renal failure, an increase in the apparent volume of distribution (V_d) can lead to higher concentrations of free meloxicam, so in these patients the daily dose should not exceed 7.5 mg.

Elderly patients

In elderly patients, the average plasma clearance during the equilibrium state of pharmacokinetics is slightly lower than in young patients. In elderly women, higher values AUC (the area under the concentration-time curve is a longer half-life, compared to young patients of both sexes.

Indications:

Symptomatic treatment: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis.

The drug is intended for symptomatic therapy, reducing pain and inflammation at the time of use, the progression of the disease is not affected.

Contraindications:

- Hypersensitivity to the active substance or auxiliary components of the drug. There is a possibility of cross-sensitivity to acetylsalicylic acid and other NSAIDs;

- PComplete or incomplete combination of bronchial asthma, angioedema or urticaria, recurrent nasal polyposis and paranasal sinuses and intolerance to acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (including in history);

- erozivno-ulcerative lesions of the stomach and duodenum in the acute stage or recently transferred;

- atInflammatory bowel disease: Crohn's disease or ulcerative colitis in the acute stage;

- Mr.severe liver function;

- tsevere renal failure (if hemodialysis is not performed, creatinine clearance is less than 30 ml / min, and with confirmed hyperkalemia), progressive kidney disease;

- achronic gastrointestinal bleeding, recent cerebrovascular bleeding or an established diagnosis of coagulation system diseases;

- zabolition of the thyroid gland;

- dCompensated heart failure;

- bVariability;

- gOre-feeding;

- tTherapy of perioperative pain during coronary artery bypass grafting;

- dEthnic age up to 12 years;

- Mr.hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Carefully:

- Diseases of the gastrointestinal tract in the anamnesis (peptic ulcer of stomach and duodenum, liver disease); infection Helicobacter pylori;

- ischemic heart disease, chronic heart failure;

- cerebrovascular diseases;

- kidney failure (creatinine clearance 30-60ml / min);

- dyslipidemia / hyperlipidemia;

- diabetes;

- simultaneous administration of oral glucocorticosteroids (including prednisolone), anticoagulants (including warfarin), antiaggregants (including clopidogrel), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline);

- severe physical illness; systemic lupus erythematosus and other autoimmune diseases;

- diseases of peripheral arteries;

- elderly age;

- long-term use of non-steroidal anti-inflammatory drugs.

To reduce the risk of developing adverse events from the gastrointestinal tract (GIT), a minimum effective dose should be used with the minimum possible short course.

Pregnancy and lactation:

Meloksikam is contraindicated during pregnancy. Suppressing the synthesis of prostaglandins can have an undesirable effect on pregnancy and fetal development.Data from epidemiological studies indicate an increased risk of spontaneous abortions and heart defects in the fetus after using inhibitors of prostaglandin synthesis during pregnancy. The absolute risk of heart disease increased from less than 1% to 1.5%. This risk increases with increasing dose and duration of therapy. AT III trimester of pregnancy, the use of prostaglandin synthesis inhibitors can lead to the following fetal development disorders:

- premature closure of the arterial duct and pulmonary hypertension due to toxic effects on the cardiopulmonary system;

- renal dysfunction, with the further development of renal failure with a decrease in the amount of amniotic fluid.

The mother during the birth can increase the duration of bleeding and decrease the contractile capacity of the uterus, and as a result, the time of delivery increases.

It is known that NSAIDs penetrate into breast milk, so meloxicam it is not recommended to use during lactation.

Dosing and Administration:

General recommendations

The maximum daily dose should not exceed 15 mg.

Tablets should be washed down with water or another liquid and taken in food Time.

Osteoarthritis: 7.5 mg per day. If necessary, this dose can be increased to 15 mg per day.

Rheumatoid arthritis: 15 mg per day. Depending on the therapeutic effect, this dose can be reduced to 7.5 mg per day.

Ankylosing spondylitis: 15 mg per day. Depending on the therapeutic effect, this dose can be reduced to 7.5 mg per day.

In patients with an increased risk of adverse reactions, it is recommended to start treatment with a dose of 7.5 mg per day.

In patients with severe renal failure who are on hemodialysis, the dose should not exceed 7.5 mg per day.

In adolescents (over 12 years):

The maximum dose in adolescents is 0.25 mg / kg.

Since the risk of adverse reactions depends on the size of the dose and duration of application, meloxicam should be applied within the shortest possible course with the lowest possible effective dose.

Side effects:

Below are described the undesirable phenomena, the relationship of which with the use of meloxicam was regarded as possible.

The adverse events presented below are listed according to anatomophysiological classification and frequency of occurrence.The frequency of occurrence is determined according to WHO criteria and has the following gradation: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000); frequency is unknown (can not be estimated from available data).

On the part of the hematopoiesis and lymphatic system: rarely - a change in the number of blood cells, including changes in the leukocyte formula: leukopenia, thrombocytopenia, anemia.

From the immune system: not established - anaphylactic shock, anaphylactoid / anaphylactic reactions.

From the nervous system: often - headache; infrequently - dizziness, drowsiness.

Disorders of the psyche: often - mood changes; frequency is unknown - confusion, disorientation.

From the sense organs: rarely - conjunctivitis, visual impairment, including blurred vision, tinnitus.

From the gastrointestinal tract: often - abdominal pain, indigestion, diarrhea, nausea, vomiting; rarely - gastroduodenal ulcers, colitis, esophagitis; infrequently - latent or obvious gastrointestinal bleeding, gastritis, stomatitis, constipation, bloating, eructation, very rarely - perforation of the gastrointestinal tract.

From the side of the liver: infrequently - transient changes in liver function (for example, increased activity of transaminases or bilirubin); very rarely - hepatitis.

From the skin and subcutaneous tissues: often - itching, skin rash; infrequently - toxic epidermal necrolysis, very rarely - severe skin reactions (Stevens-Johnson syndrome), angioedema, frequency unknown - allergic dermatitis, photosensitivity.

From the respiratory system: rarely - bronchial asthma in patients with an allergy to acetylsalicylic acid or other NSAIDs.

From the cardiovascular system: infrequently - increased blood pressure, a feeling of "tide" of blood to the face, rarely - a feeling of palpitations.

From the genitourinary system: infrequent - changes in renal function (increased serum creatinine and / or urea levels), urination disorders, including acute urinary retention; very rarely acute renal failure.

Joint application with drugs that depress the bone marrow (for example, methotrexate) can provoke cytopenia.

Gastrointestinal bleeding, ulcer or perforation can lead to death.

When using meloxicam, as well as other NSAIDs, the possibility of interstitial nephritis, glomerulonephritis, renal medullary necrosis, nephrotic syndrome is not ruled out.

Overdose:

Symptoms: drowsiness, impaired consciousness, nausea, vomiting, epigastric pain, gastrointestinal bleeding, possibly increased blood pressure or collapse, acute renal failure, hepatic insufficiency, respiratory arrest, asystole.

Treatment: there is no specific antidote; symptomatic therapy. Within the first hour after an overdose - gastric lavage, the reception of activated charcoal. Forced diuresis, alkalinization of urine, hemodialysis are ineffective because of the high connection of the drug with blood proteins. Cholestyramine accelerates the excretion of meloxicam.

Interaction:

Other inhibitors of prostaglandin synthesis, including glucocorticosteroids and NSAIDs.

Simultaneous application with meloxicam increases the risk of ulceration in the gastrointestinal tract and gastrointestinal bleeding due to synergistic action.

The combined use of meloxicam and other NSAIDs is not recommended.

The combined use of aspirin (1000 mg 3 times daily) and meloxicam in healthy volunteers resulted in an increase in AUC (10%) and C_max (24%) meloxicam. The clinical significance of this interaction is not known.

Anticoagulants for oral administration, antiplatelet agents, heparin for systemic use, thrombolytic agents. Simultaneous use with meloxicam increases the risk of bleeding. If it is not possible to avoid the simultaneous use of these drugs, careful monitoring of the effect of anticoagulants is necessary.

Lithium. NSAIDs increase the concentration of lithium in the plasma by decreasing the renal excretion of lithium. The concentration of lithium in plasma can reach toxic values. The combined use of lithium and NSAIDs is not recommended. If necessary, such combination therapy should monitor the concentration of lithium in the plasma at the beginning of treatment, when choosing a dose and canceling meloxicam.

Methotrexate. NSAIDs can reduce the tubular secretion of methotrexate and thus increase the concentration of methotrexate in the plasma. In this regard, patients receiving high doses of methotrexate (more than 15 mg per week) concurrent use of NSAIDs is not recommended.The risk of interaction with simultaneous use of methotrexate and NSAIDs is also possible in patients receiving low doses of methotrexate, especially in patients with impaired renal function. If necessary, combined therapy should monitor the blood formula and kidney function. Care should be taken if the NSAIDs and methotrexate apply simultaneously for 3 days, because the concentration of methotrexate in the plasma may increase and, as a consequence, toxic effects may occur. Simultaneous use of meloxicam did not affect the pharmacokinetics of methotrexate at a dose of 15 mg per week, but it should be taken into account that the hematological toxicity of methotrexate is enhanced by the simultaneous administration of NSAIDs.

Contraception. Earlier reports of a decrease in the effectiveness of intrauterine contraceptive devices when using NSAIDs. This observation requires further confirmation.

Mifepristone: in connection with the theoretical risk of changing the effectiveness of mifepristone under the influence of inhibitors of the synthesis of prostaglandins NSAIDs should not be prescribed earlier than 8-12 days after the withdrawal of mifepristone.

Diuretics. The use of NSAIDs increases the risk of developing acute renal failure in patients with dehydration. In patients receiving meloxicam and diuretics, adequate hydration should be maintained. Before the beginning of treatment it is necessary to study the function of the kidneys.

Antihypertensives (eg, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, vasodilators, diuretics). NSAIDs reduce the effect of antihypertensive drugs, due to the inhibition of prostaglandins, which have vasodilating properties.

Joint use of NSAIDs and angiotensin receptor antagonists II (as well as ACE inhibitors) enhances the effect of reducing glomerular filtration. In patients with impaired renal function, this can lead to the development of acute renal failure. Cholestyramine, binding meloxicam in the gastrointestinal tract, leads to its faster excretion.

NSAIDs, acting on renal prostaglandins, can enhance the nephrotoxicity of cyclosporine. In the case of combined therapy, kidney function should be monitored.

Meloksikam is metabolized primarily in the liver, about 2/3 by isoenzymes CYP450 (mostly CYP2C9 and optional CYP3A4), about 1/3 is metabolized by other systems, for example, by peroxidation. When used in conjunction with meloxicam, drugs that have the ability to inhibit CYP2C9 and / or CYP3A4 (or metabolized with the participation of these enzymes), the possibility of pharmacokinetic interaction should be taken into account.

With the simultaneous use of meloxicam and antacids, cimetidine, digoxin or furosemide, no significant pharmacokinetic interactions were identified.

At simultaneous reception meloxicam can strengthen the action of tablets antidiabetic drugs, thereby there is a risk of hypoglycemia.

Special instructions:

Care should be taken (as with other NSAIDs) in the treatment of patients with a history of gastrointestinal disease and in patients receiving anticoagulants. Patients who have symptoms from the gastrointestinal tract should be observed regularly.If there is a ulcerative lesion of the gastrointestinal tract or gastrointestinal bleeding, the drug must be canceled.

As with other NSAIDs, gastrointestinal bleeding, ulcers and perforations, potentially life-threatening to the patient, can occur during treatment at any time, as in the presence of alarming symptoms or information about serious gastrointestinal complications in the history, and when absence of these signs. The consequences of these complications in general are more serious elderly streets.

Particular attention should be given to patients reporting the development of adverse events from the skin and mucous membranes. In such cases, question about discontinuation of the drug.

NSAIDs inhibit the synthesis of prostaglandins in the kidneys, which are involved in maintaining renal perfusion. The use of NSAIDs in patients with reduced renal blood flow or a reduced volume of circulating blood can lead to decompensation of the secretive renal failure. After the abolition of NSAIDs, the kidney function is usually restored to its original level.The elderly are at greatest risk of developing this reaction; patients with dehydration, congestive heart failure, cirrhosis, nephrotic syndrome, or obvious kidney disease; patients receiving diuretics, ACE inhibitors, angiotensin II receptor antagonists, and patients who underwent serious surgical interventions leading to hypovolemia. In such patients at the beginning of therapy, diuresis and renal function should be carefully monitored.

In rare cases, NSAIDs can cause interstitial nephritis, glomerulonephritis, medullary kidney necrosis or nephrotic syndrome.

In patients with terminal stage of renal failure who are on hemodialysis, the dose of the drug should not exceed 7.5 mg. In patients with small or moderate impairment of renal function (ie, if creatinine clearance is greater than 25 ml / min.), A dose reduction is not required.

When meloxicam (as well as most other NSAIDs) was used, an episodic increase in the level of transaminases or other indicators of liver function in serum was reported.In most cases, this increase was small and transient. If the changes identified are significant or do not decrease over time, the drug should be withdrawn and monitored for laboratory changes identified.

In patients with clinically stable cirrhosis, a dose reduction is not required.

Weakened or depleted patients can tolerate undesirable events worse, so these patients should be carefully observed. Caution (as with other NSAIDs) should be observed in the treatment of elderly patients who are more likely to have impaired renal, hepatic, and cardiac function.

The use of NSAIDs in conjunction with diuretics can lead to a delay in sodium, potassium and water, and affect the natriuretic effect of diuretics. As a result, predisposing patients may have signs of heart failure or hypertension.

Meloxicam, as well as other NSAIDs, can mask the symptoms of an infectious disease.

The use of meloxicam, as well as other preparations blocking cyclooxygenase and the synthesis of prostaglandins, can affect fertility, so it is not recommended for women who want to become pregnant.If there is a violation of the ability to conceive in women or conducting a survey of infertility, it is necessary to consider the question of abolishing meloxicam.

Reported cases of thrombotic cardiovascular events with the administration of NSAIDs. The risk increases with prolonged use of the drug, as well as in patients with a history of venous thrombosis, angina pectoris, myocardial infarction, cerebral circulation disorder.

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

Special studies on the effect of the drug on the ability to drive vehicles and mechanisms were not carried out. This activity should be refrained to patients with visual impairment, patients who report drowsiness or other disorders from the central nervous system.

Form release / dosage:

Tablets, 7.5 mg and 15 mg.

Packaging:

For 10 tablets in a strip of aluminum foil.

For 1, 2 or 3 strips together with instructions for use in a cardboard bundle.

Storage conditions:

In a dry place, at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004123

Date of registration:08.02.2017

Expiration Date:08.02.2022

The owner of the registration certificate:San Pharmaceutical Industries Co., Ltd.San Pharmaceutical Industries Co., Ltd. India

Manufacturer: & nbsp

Sun Pharmaceutical Industries, Ltd. India

Representation: & nbspSAN PHARMACEUTICAL INDUSTRIES LTD. SAN PHARMACEUTICAL INDUSTRIES LTD. India

Information update date: & nbsp02.03.2017

Illustrated instructions

Instructions

Flexibon (Flexibon)