Movalis (Meloxicam) tablets, ampoules

The composition and form of issue: 

Solution for intramuscular injection. 1 ampoule contains active substance:

meloxicam 15 mg

excipients: meglumin glucotrol poloxamer 188 (Pluronic F68) sodium chloride glycine sodium hydroxide water for injection 

in vials of colourless glass type I 1, 5 ml, in a contour acheikova packing 3 or 5 ampoules in a cardboard pack 1 pack.

Tablets. 1 tablet contains active substance:

meloxicam 7.5 and 15 mg

auxiliary substances: sodium citrate lactose microcrystalline povidone (kollidon 25), silicon dioxide colloidal crospovidone magnesium stearate 

in blister 10 PCs in the paper cartons 1 or 2 blisters.

Suppositories for rectal application. 1 supp. contains active substance:

meloxicam 7.5 and 15 mg

excipients: suppository mass (suppocire BP), glycerylmonostearate macrogol (polyethylene glycol glycerylmonostearate — cremophor RH40) 

in packages contour cell for 6 PCs in a box 1 or 2 packaging.

Description pharmaceutical form:

The solution for the/m introduction transparent, yellow with green tint.

Tablets: round, pale yellow to yellow. One side is convex with a beveled edge. On the convex side — company logo on the other side — the concave risk, on both sides of which is engraved “59D” — for tablets 7 5 mg or “77С” — for tablets of 15 mg. the Surface tablets can be rough.

Suppositories: smooth, yellowish-green, with a recess in the base.

Pharmacokinetics:

Solution

Meloxicam is completely absorbed in the/m introduction. Relative bioavailability compared to the oral bioavailability is almost 100%. Therefore, the transition from injection to oral forms dose adjustment is not required. After the introduction of 15 mg/m peak plasma concentrations of approximately 1, 62 mcg/ml is achieved within about 60 min. is very good Meloxicam is bound to plasma proteins, mainly to albumin (99%). Penetrates into synovial fluid, the concentration in synovial fluid is approximately 50% of plasma concentration. Vd is low, on average 11 L. Interindividual differences amount to 30-40%.

Tablets

Meloxicam is well absorbed from the gastrointestinal tract, as evidenced by high absolute oral bioavailability of 89%. In single dose of the drug in the form of tablets, the average Cmax in plasma achieved within 5-6 hours after repeated application of steady state pharmacokinetics is achieved in a period of 3 to 5 days. The range of differences between the maximum (Cmax) and the basal concentrations (Cmin) of a drug in a period of steady state pharmacokinetics after taking it once a day is relatively small and is 0, 4-1 µg/ml for doses of 7, 5 mg, and 0 8-2 µg/ml — for dose of 15 mg. Cmax in plasma during steady state pharmacokinetics is achieved within 5-6 hours when taking the pills.

The concentration of the drug after continuous use for more than 6 months are similar to the concentrations observed after 2 weeks oral administration of 15 mg a day. Simultaneous eating does not affect the absorption of the drug.

Suppositories

It is shown that suppositories are bioequivalent to the tablets. Cmax of the drug in plasma during steady state pharmacokinetics is achieved approximately 5 h after drug administration.

The ranges of differences between the maximum (Cmax) and the basal concentrations (Cmin) similar to tablets, and suppositories.

Distribution

Meloxicam is well bound with plasma proteins (albumin — 99%).

Meloxicam penetrates into synovial fluid, a local concentration of approximately 50% of concentrations in plasma.

Vd low, on average 11 L. Individual variations of 30-40%.

Metabolism

Meloxicam is almost completely metabolized in the liver with the formation of 4 pharmacologically inactive derivatives. The main metabolite is 5′-carboxymethoxy (60% of the dose) is formed by oxidation of an intermediate metabolite 5′-hydroxymethyluracil, which is also excreted, but to a lesser extent (9% of the dose). In vitro studies showed that this metabolic transformation plays an important role of CYP2C9, additional important isoenzyme CYP3A4. The formation of two other metabolites (respectively 16 components and 4% of the dosage) participating peroxidase, activity which, probably, individually varies.

Breeding

Excreted equally in feces and urine, primarily as metabolites. In unaltered with faeces output of less than 5% of the magnitude of the daily dose, in the urine in an unmodified form the drug is detected only in trace amounts. The average T1/2 of meloxicam is 20 h. Plasma clearance averages 8 ml/min.

Meloxicam demonstrates linear pharmacokinetics in doses of 7, 5 to 15 mg when administered in or/m introduction.

Insufficiency of the liver and/or kidney

Failure of the liver, and mild to moderate renal insufficiency significant effect on the pharmacokinetics of meloxicam has not. When ESRD, the increase in Vd may result in higher free meloxicam concentrations, therefore, these patients daily dose should not exceed 7, 5 mg.

Elderly patient

In elderly patients, the mean plasma clearance during steady-state pharmacokinetics slightly lower than in younger patients.

Children

During the studies of meloxicam in children has been studied the pharmacokinetics of the drug in the doses used is based 0, 25 mg/kg. compared With the figures of children of different age (2-6 years, n = 7 and 7-14 years, n = 11) there was a trend towards lower Cmax (?34%) and AUC0-&infin (?28%) in children of younger age, and clearance of the drug (adjusted for body weight) in this group of children was higher. Concentrations of meloxicam in plasma in older children and adults are similar. Children in both age groups the T1/2 of meloxicam from plasma was similar (13 hours) and are slightly shorter than in adults (15-20 h).

Description of the pharmacological action:

Movalis is a NSAID, refers to a derivative analboy acid and has anti-inflammatory, analgesic and antipyretic effect. Pronounced anti-inflammatory effect of meloxicam is installed on all standard models of inflammation. The mechanism of action of meloxicam is its ability to inhibit the synthesis of PG — known mediators of inflammation.

Meloxicam in vivo inhibits the synthesis of GHGs in the site of inflammation to a greater extent than in the mucous membrane of the stomach or the kidneys.

These differences are associated with a selective inhibition of COX-2 over COX-1. It is believed that inhibition of COX-2 provides therapeutic action of NSAIDs, whereas inhibition of constantly the presence of the isoenzyme COX-1 may be responsible for side effects stomach and kidneys. Selectivity of meloxicam in relation to COX-2 has been confirmed in various test systems, both in vitro and in vivo. The selective ability of meloxicam to inhibit COX-2 indicated for use as a test system human whole blood in vitro. Set, what meloxicam (at doses of 7, 5 and 15 mg) actively inhibited COX-2, exerting a greater inhibitory effect on the production ПГЕ2 stimulated by the lipopolysaccharide (reaction, controlled by COX-2), than thromboxane production, involved in blood clotting (reaction, controlled by COX-1). These effects depended on the dose.

Ex vivo it was shown that meloxicam in the recommended doses did not affect platelet aggregation and bleeding time in contrast to indometacin, diclofenac, ibuprofen and naproxen that significantly inhibited platelet aggregation and increased bleeding time. In clinical studies, side effects from the gastrointestinal tract generally occurred less frequently when taking meloxicam 7, 5 and 15 mg than when taking other NSAIDs, which were compared. This difference in the frequency of side effects from the gastrointestinal tract mainly due to the fact that when taking meloxicam rarely observed phenomena such as dyspepsia, vomiting, nausea, abdominal pain. The frequency of perforations in the upper gastrointestinal divisions, ulcers and bleeding, which were associated with the use of meloxicam, was low and depended on the dose of the drug.

Indications:

The solution for the on/m introduction

The initial period of treatment of pain syndrome and short-term symptomatic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis.

Tablets and suppositories

Symptomatic treatment:

osteoarthritis (arthrosis, degenerative joint disease)

rheumatoid arthritis

ankylosing spondylitis.

Contraindications:

Common to all dosage forms

hypersensitivity to the active ingredient or auxiliary components of the drug. There is a possibility of cross-hypersensitivity to acetylsalicylic acid and other NSAIDs

the symptoms of asthma, nasal polyps, angioedema or urticaria after taking acetylsalicylic acid or other NSAIDs history

peptic ulcer/perforation of the stomach and duodenum in the acute stage or recently migrated

Crohn’s disease or ulcerative colitis in the acute stage

severe liver failure

severe renal failure (unless hemodialysis is performed, Cl creatinine less than 30 ml/min, and when confirmed hyperkalemia), a progressive disease of the kidneys

acute gastrointestinal bleeding, recent cerebrovascular bleeding or established diagnosis of diseases of the blood coagulation system

severe uncontrolled heart failure

pregnancy

breast feeding

therapy of perioperative pain when performing bypass surgery of the coronary arteries.

For solution for intramuscular injection additionally:

children up to age 18 years.

For tablets and suppositories are additionally:

children up to age 12 years, with the exception of the use in juvenile rheumatoid arthritis (in the case of this testimony).

With caution

Solution of diseases of the gastrointestinal tract in the anamnesis (H. pylori) congestive heart failure renal failure (Cl creatinine 30-60 ml/min) ischemic heart disease cerebrovascular disease dyslipidemia/hyperlipidemia diabetes mellitus concomitant therapy with the following drugs: anticoagulants, oral corticosteroids, antiplatelet agents, SSRIs peripheral arterial disease, older age, prolonged use of NSAIDs Smoking, frequent alcohol consumption.

Tablets and suppositories — NSAIDs inhibit the renal synthesis of PG involved in the maintenance of renal perfusion. The use of NSAIDs in patients with reduced renal blood flow or reduced volume may lead to decompensation stratopause renal failure. After the abolition of NPVS kidney function is usually restored to the original level. In greatest risk of this reaction affects elderly patients patients with marked dehydration, congestive heart failure, liver cirrhosis, nephritic syndrome or overt kidney disease patients receiving diuretics, ACE inhibitors, receptor antagonists at-II, and patients undergoing major surgery, leading to hypovolaemia. In these patients, at the beginning of therapy should carefully monitor urine output and renal function.

In rare cases, NSAIDs may cause interstitial nephritis, glomerulonephritis, renal medullary necrosis or nephrotic syndrome.

In patients with end-stage renal disease, hemodialysis dose of Movalis should not exceed 7, 5 mg. in patients with mild or moderate impaired renal function i.e., if Cl creatinine greater than 25 ml/min, a dose reduction is not required.

Application of pregnancy and breastfeeding:

Movalis is contraindicated during pregnancy. The suppression of PG synthesis may adversely affect pregnancy and fetal development. Data from epidemiological studies suggest an increased risk of spontaneous abortion, heart defects and gastroschisis in the fetus after the application of inhibitors of PG synthesis during pregnancy.

The absolute risk of heart diseases increased from less than 1 to 1, 5%. This risk increases with dose and duration of therapy.

In the third trimester of pregnancy the use of inhibitors of PG synthesis may cause the following disorders in the fetus:

– premature closure of the ductus arteriosus and pulmonary hypertension due to toxic effects on the cardiopulmonary system

– renal dysfunction with subsequent development of renal failure with a decrease in the amount of amniotic fluid.

The mother during labor can increase the duration of bleeding and to decrease uterine contractility, and as a consequence, to increase childbirth. Antiplatelet effect can emerge even when receiving low doses.

It is known that NSAIDs penetrate into breast milk, therefore, Movalis is not recommended for use during breast-feeding.

Side effect:

Common to all dosage forms

Side effects, whose relationship to the drug was regarded as a possible, and that were registered with the broad use of the drug, marked with *.

Organs of hematopoiesis: changes in the number of blood cells, including changes in leukocyte, leukopenia, thrombocytopenia, anemia. Predisposing factors for the occurrence of cytopenia, apparently, is the simultaneous use of potentially myelotoxic drugs, in particular methotrexate.

The immune system: anaphylactic shock*, anaphylactoid/anaphylactic reactions* other reactions of hypersensitivity of immediate type*.

CNS: headache, dizziness, tinnitus, drowsiness, confusion*, disorientation* mood change*.

Gastrointestinal: perforation of the gastrointestinal tract, hidden or obvious gastrointestinal bleeding, possibly fatal, gastroduodenal ulcers, colitis, gastritis, esophagitis, stomatitis, abdominal pain, dyspepsia, diarrhea, nausea, vomiting, constipation, bloating, belching, transient changes of liver function tests (e.g. elevation of transaminases or bilirubin), hepatitis*.

The skin and skin appendages: toxic epidermal necrolysis*, Stevens-Johnson syndrome*, angiootek*, bullous dermatitis*, erythema multiforme*, pruritus, rash, urticaria, photosensitivity.

From the side of respiratory system: bronchial asthma in patients allergic to acetylsalicylic acid or other NSAIDs.

From the CCC: increased blood pressure, palpitations, flushed face, swelling.

With the genitourinary system: acute renal failure*, changes in indicators of kidney function (increased creatinine and/or urea in the blood serum), urination disorders, including acute urinary retention*.

On the part of the organ of vision: conjunctivitis*, visual disturbances, including blurred vision*.

For solution for I/m administration additional

With the genitourinary system: as with other NSAIDs do not rule out the possibility of interstitial nephritis, glomerulonephritis, renal medullary necrosis, nephrotic syndrome.

Common effects: pain and swelling at the injection site.

Drug interaction:

Total for all dosage forms

Other inhibitors of PG synthesis, including GK and salicylates, when administered simultaneously with meloxicam increase the risk of ulceration in the digestive tract and gastro-intestinal bleeding (due to synergistic action) and therefore their combination is not recommended. Concomitant use with other NSAIDs is not recommended.

SSRIs — increased risk of gastrointestinal bleeding.

Lithium drugs — NSAIDs increase lithium levels in the plasma by reducing its excretion by the kidneys. It is recommended to monitor the concentration of lithium in the period of the assignment Movalis, when changing the dose of lithium drugs and their cancellation.

Methotrexate — NSAIDs reduce tubular secretion of methotrexate, thereby increasing its concentration in the plasma and hematological toxicity, pharmacokinetics of methotrexate is not changed. In this regard, simultaneous treatment with Movalis and methotrexate in a dose of 15 mg/week is not recommended. The risk of interaction between NSAIDs and methotrexate can occur in patients who use methotrexate in low doses, especially in patients with impaired renal function. Therefore, a continuous monitoring of the number of red blood cells and renal function.

The simultaneous use of meloxicam does not affect the pharmacokinetics of methotrexate in a dose of 15 mg per week, but should take into account that the haematological toxicity of methotrexate increases while taking NSAIDs.

The joint use of meloxicam and methotrexate for 3 days increases the risk of toxicity of the latter.

Contraception NSAIDs reduce the effectiveness of intrauterine contraceptive devices.

Diuretics — NSAIDs in the case of dehydration of patients is accompanied by the risk of developing acute renal failure.

Patients receiving Movalis and diuretics, must maintain adequate hydration. Before treatment it is necessary to study renal function.

Antihypertensives (beta-blockers, ACE inhibitors, vasodilators, diuretics) — NSAIDs reduce the effect of antihypertensive drugs, due to inhibition of PG, vasodilating properties.

Angiotensin II receptor antagonists when administered together with NSAIDs increase decrease in glomerular filtration rate that may lead to the development of acute renal failure, especially in patients with impaired renal function. In the case of combination therapy should monitor kidney function.

NSAIDs, exerting effects on renal PG, may increase the nephrotoxicity of cyclosporine.

When used in conjunction with meloxicam drugs that have a known ability to inhibit CYP2C9 and/or CYP3A4 (or metabolized with the participation of these enzymes), it should take into account the possibility of pharmacokinetic interactions.

We cannot exclude the possibility of interaction with hypoglycemic drugs for oral administration.

With simultaneous use of antacids, cimetidine, digoxin and furosemide, significant pharmacokinetic interactions have been identified.

For tablets and suppositories are additionally

The combined use of aspirin (1000 mg 3 times a day) and meloxicam in healthy volunteers resulted in increased AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known.

Cholestyramine, linking meloxicam in digestive tract, leads to its more rapid removal.

Method of application and doses:

V/m.

The/m introduction the drug is indicated only for the first 2-3 days of therapy. Further treatment continues with the use of enteral forms. The recommended dose is 7 5 mg or 15 mg of 1 times a day, depending on the intensity of the pain and the severity of the inflammatory process.

The maximum recommended daily dose — 15 mg.

The drug is administered by deep I/m injection.

Given the possible incompatibility, the contents of the ampoule Movalis should not be mixed in the same syringe with other drugs.

Violations of kidney function. In patients with severe renal insufficiency, on hemodialysis, dose should not exceed 7, 5 mg/day.

The drug can be.

Inside, while eating, squeezed water or other liquid rectally.

Osteoarthritis, rheumatoid arthritis — 7, 5 mg/day. If necessary, the dose may be increased to 15 mg/day. Depending on the therapeutic effect, the dose can be reduced to 7, 5 mg/day.

Ankylosing spondylitis 15 mg/day. Depending on the therapeutic effect, the dose can be reduced to 7, 5 mg/day.

In patients with increased risk of adverse reactions is recommended to start treatment with doses of 7, 5 mg/day. For patients with severe renal insufficiency on hemodialysis, the dose should not exceed 7, 5 mg/day.

Teenagers

The maximum dose for adolescents is 0, 25 mg/kg.

As a rule, the drug should only be used in adolescents and adults (see “Contraindications”). The maximum recommended daily dose — 15 mg.

Rectal suppositories is recommended in a dose of 7, 5 mg of 1 times a day. In more severe cases, it is possible to use candles in the dose of 15 mg.

Due to the fact that the risk of adverse reactions depends on the dose and duration of use, the drug should be used for the shortest possible period of perhaps the lowest effective dose.

Combined use. The total daily dose of Movalis used in the form of tablets, suppositories, injection should not exceed 15 mg.

Overdose:

Symptoms: data on accidents related to drug overdose might not have enough. Likely to present the symptoms characteristic of an overdose of drugs group of NSAIDs, in severe cases, drowsiness, loss of consciousness, nausea, vomiting, epigastric pain, gastrointestinal bleeding, acute renal failure, changes in blood pressure, respiratory arrest, asystole. With an overdose of tablets or suppositories — gain side effects.

Treatment: no known antidote. In case of overdose of the drug should be used symptomatic therapy. When drug overdose — gastric lavage.

Special instruction:

Total for all dosage forms

Patients suffering from gastrointestinal diseases, should be monitored regularly. Upon the occurrence of ulcerative lesions of the gastrointestinal tract or gastrointestinal bleeding Movalis need to cancel. Ulcers in the digestive tract, perforation or bleeding may occur in the course of treatment at any time, with alarming symptoms or serious gastrointestinal complications in history, and in the absence of these signs. The consequences of these complications are generally more severe in the elderly.

If you are using Movalis (as well as most other NSAIDs) may occasional elevation of transaminases in the blood serum or other indicators of liver function. In most cases this increase was small and transient. If significant changes identified, or not decreasing over time, Movalis should be abolished, and conduct surveillance of the identified laboratory changes.

Weakened or depleted patients can worse carry adverse effects, therefore, such patients should be carefully monitored.

Like other NSAIDs, Movalis may hide the symptoms of an underlying infectious disease.

The solution for the on/m introduction

Special attention should be given to patients, informing about the development of adverse events in the skin and mucous membranes, as well as hypersensitivity reactions to the drug, especially if such a reaction was observed during previous courses of treatment. The development of such reactions can occur usually within the first month of treatment. In such cases, should be considered the question about the termination of the use of Movalis.

Like other NSAIDs, Movalis may increase the risk of serious cardiovascular thrombosis, myocardial infarction, strokes, possibly fatal. This risk increases with prolonged use of the drug, and in patients with above mentioned diseases in history and are predisposed to such diseases.

NSAIDs inhibit the renal synthesis of PG involved in the maintenance of renal perfusion. The use of NSAIDs in patients with reduced renal blood flow or reduced volume may lead to decompensation of latent renal failure. After the abolition of NPVS kidney function is usually restored to the original level. In greatest risk of this reaction affected, elderly patients, patients with marked dehydration, congestive heart failure, liver cirrhosis, nephrotic syndrome or acute renal dysfunction, at the same time taking diuretics, and patients who have undergone major surgery, leading to hypovolaemia. In these patients, at the beginning of therapy should carefully monitor urine output and renal function. The use of NSAIDs together with diuretics can lead to sodium retention, potassium and water, and reduce natriuretic action of diuretics. As a result, in predisposed patients may increase signs of heart failure or hypertension. Hence the need for careful control of the condition of such patients, and they must be supported by adequate hydration. Before treatment it is necessary to study renal function.

In the case of combination therapy should also be monitor renal function.

As the drug inhibiting COX and the synthesis of PG, Movalis may have an impact on fertility and is not recommended for women who have difficulty conceiving. In this regard, in women undergoing examinations for this reason, it is recommended that the cancellation of admission of Movalis.

Effects on ability to drive vehicles and mechanisms. Special clinical studies of the effect of the drug on the ability to drive and use machinery has not been. However, while driving and operating machinery should take into account the possibility of dizziness, drowsiness, or other disorders of the Central nervous system.

For tablets, suppositories additionally

Care should be taken (in the same way as when using other NSAIDs) in the treatment of patients with gastrointestinal diseases in history, and patients receiving anticoagulants. During the application of NSAIDs is very rarely reported on the development of severe allergic reactions (some of which ended in the death of patients), including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. The greatest risk of these reactions in patients, apparently, is celebrated at the beginning of treatment, these reactions are in most cases started during the first month of treatment. In the case of the first signs of rash, changes in mucous membranes or any other symptoms of hypersensitivity, meloxicam should be lifted. NSAIDs can increase the risk of serious thrombotic cardiovascular diseases, myocardial infarction and stroke, which can lead to death. This risk may increase with increasing duration of use of NSAIDs. The greatest risk can be observed in patients with cardiovascular disease or risk factors for cardiovascular disease, kidney failure, hemodialysis (dose Movalis should not exceed 7, 5 mg). In patients with mild or moderate impaired renal function (i.e., if Cl creatinine >25 ml/min) a dose reduction is not required. In patients with clinically stable liver cirrhosis a decrease of dose is not required.

Caution (as in the case of other NSAIDs) should be observed when treating elderly patients who have higher the probability of a human kidney, liver and heart. The use of NSAIDs together with diuretics can lead to sodium retention, potassium and water, and to influence the natriuretic effect of diuretics. As a result, in predisposed patients may increase signs of heart failure or hypertension. It is recommended clinical observation of patients with risk of developing these complications.

The medicine is intended for symptomatic therapy, reducing pain and inflammation. As with other NSAIDs, to influence the progression required combined treatment of the disease.

Suppositories should not be used in patients with any inflammatory lesions of rectum or anus, or in patients with recent bleeding from the rectum or anus.

Effects on ability to drive vehicles and mechanisms. Special studies on the impact of the drug on the ability to drive vehicles and mechanisms was conducted. From this activity you should refrain patients with disabilities, patients, marking the drowsiness or other disorders of the Central nervous system.

Tablets of 7, 5 and 15 mg contain 47 and 20 mg of lactose respectively.

Patients with rare hereditary intolerance to galactose, lapp-lactazna deficiency or impaired absorption of glucose/galactose should not take this drug.