Artrosan, 6 mg/ml 2.5 ml 3 pcs.

Pharmacotherapeutic group:nonsteroidal anti-inflammatory drug

ATX code: M01AC06

Pharmacological properties.

Pharmacodynamics

Meloxicam is a non-steroidal anti-inflammatory drug, refers to enolic acid derivatives and has anti-inflammatory, analgesic and antipyretic effects.The pronounced anti-inflammatory effect of meloxicam was established in all standard models of inflammation. The mechanism of action of meloxicam consists in its ability to inhibit the synthesis of prostaglandins – known mediators of inflammation. Meloxicam inhibits the synthesis of prostaglandins at the site of inflammation to a greater extent than in the gastric mucosa or kidneys.

These differences are associated with a more selective inhibition of cyclooxygenase-2 (COX-2) compared to cyclooxygenase-1 (COX-1). Inhibition of COX-2 is thought to provide the therapeutic actions of NSAIDs, whereas inhibition of the ever-present iso-enzyme COX-1 may be responsible for gastric and renal side effects. The selectivity of meloxicam against COX-2 has been confirmed in various test systems, both in-vitro and in-vivo. The selective ability of meloxicam to inhibit COX-2 was shown when using human whole blood in-vitro as a test system.Meloxicam (at doses of 7.5 and 15 mg) was found to be more active in inhibiting COX-2, having a greater inhibitory effect on lipopolysaccharide-stimulated prostaglandin E2 production (COX-2-controlled response) than on thromboxane production involved in blood clotting (COX-1-controlled response).These effects were dose-dependent.In exvivo studies, meloxicam (at doses of 7.5 mg and 15 mg) was shown to have no effect on platelet aggregation and bleeding time.

In clinical studies, gastrointestinal (GI) side effects were generally less frequent with meloxicam 7.5 and 15 mg than with the other NSAIDs compared. This difference in the frequency of gastrointestinal side effects is mainly due to the fact that such phenomena as dyspepsia, vomiting, nausea, and abdominal pain were observed less frequently while taking meloxicam. The frequency of upper gastrointestinal perforations, ulcers and bleeding associated with meloxicam use was low and depended on the size of the drug dose.

Pharmacokinetics

Absorption

Meloxicam is completely absorbed after intramuscular administration. The relative bioavailability compared to the bioavailability with oral administration is almost 100%. Therefore, no dosage adjustment is required when switching from injectable to oral forms. After administering 15 mg of the drug intramuscularly, the peak plasma concentration (about 1.6-1.8 µg/ml), is reached within approximately 60 to 96 minutes.

Distribution

Meloxicam binds very well to plasma proteins, mainly to albumin (99%). It penetrates the synovial fluid, the concentration in the synovial fluid is about 50% of the plasma concentration. The volume of distribution is low, approximately 11 liters. Individual differences are 7 – 20%.

Metabolism

Meloxicam is almost completely metabolized in the liver to form 4 pharmacologically inactive derivatives. The main metabolite, 5-carboxymeloxicam (60% of the dose value), is formed by oxidation of an intermediate metabolite, 5- hydroxymethylmeloxicam, which is also excreted, but to a lesser extent (9% of the dose value). In-vitro studies have shown that CYP2C9 isoenzyme plays an important role in this metabolic transformation, CYP3A4 isoenzyme has additional importance. Peroxidase, which activity probably varies individually, takes part in formation of two other metabolites (which are 16% and 4% of drug dose, respectively).

Elimation

Elimated equally through intestine and kidneys, mainly as metabolites. Less than 5% of daily dose is excreted unchanged in the feces, the drug is excreted unchanged in the urine only in trace amounts. Mean elimination half-life of meloxicam varies from 13 to 25 hours.

Plasma clearance averages 7-12 ml/min after a single use.

Meloxicam demonstrates linear pharmacokinetics at doses of 7.5-15 mg when administered intramuscularly.

Inadequate hepatic and/or renal function

Inadequate hepatic function and mild renal insufficiency have no significant effect on the pharmacokinetics of meloxicam. The elimination rate of meloxicam from the body is significantly higher in patients with moderately severe renal insufficiency. Meloxicam binds less well with plasma proteins in patients with terminal renal failure. In terminal renal failure, increased volume of distribution may lead to higher concentrations of free meloxicam, so in these patients the daily dose should not exceed 7.5 mg.

Elderly patients

Elderly patients compared to younger patients have similar pharmacokinetic parameters. Elderly patients have slightly lower mean plasma clearance during equilibrium pharmacokinetics than younger patients. Elderly women have higher AUC values (area under the concentration-time curve) and a longer half-life compared to younger patients of both sexes.

In elderly patients, the average plasma clearance during the equilibrium state of pharmacokinetics is slightly lower than in younger patients.

Indications

Start therapy and short-term symptomatic treatment for:

– osteoarthritis (osteoarthritis, degenerative joint disease);

– rheumatoid arthritis;

– ankylosing spondylitis;

– Other inflammatory and degenerative musculoskeletal conditions such as arthropathies, dorsopathies (e.g. sciatica, low back pain, periarthritis in the shoulder, etc.) which are painful.

Active ingredient

Composition

Active substance: Meloxicam-6,00 mg
Associates: Meglumine-3.75 mg, poloxamer 188-50.00 mg, tetrahydrofurfurylmacrogol (glycofurole)-100.00 mg, glycine-5.00 mg, sodium chloride-3.00 mg, 1 M sodium hydroxide solution- to pH 8.2-8.9, water for injections- to 1 ml.
One ampoule (2.5 ml) contains 15 mg of meloxicam.

How to take, the dosage

Osteoarthritis with pain syndrome: 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 may be reduced to 7.5 mg per day.
Ankylosing spondylitis: 15 mg per day.
In patients with increased risk of adverse reactions (history of gastrointestinal tract diseases, presence of cardiovascular risk factors) it is recommended to start therapy with the dose of 7.5 mg per day (see section “Special indications”).
In patients with significant renal impairment who are on hemodialysis, the dose should not exceed 7.5 mg per day.

General recommendations
Since the potential risk of adverse reactions depends on the dose and duration of treatment, the lowest possible dose and duration of use should be used. The maximum recommended daily dose is 15 mg.

Combined use
Do not use the drug simultaneously with other NSAIDs. The total daily dose of Artrosan® used in different dosage forms should not exceed 15 mg.
Intramuscular administration of the drug is indicated only during the first few days of therapy. Further treatment is continued with oral dosage forms. The recommended dose is 7.5 mg or 15 mg once a day depending on the pain intensity and severity of the inflammatory process.
The drug is administered by deep intramuscular injection.
The drug should not be administered intravenously.
In view of possible incompatibility Arthrosan® solution for intramuscular injection should not be mixed with other medicinal agents in one syringe.

Interaction

– Other prostaglandin synthesis inhibitors, including glucocorticoids and salicylates – concomitant use with meloxicam increases the risk of gastrointestinal ulcers and gastrointestinal bleeding (due to synergistic action) and therefore is not recommended. Concomitant use with other NSAIDs is not recommended.

– Anticoagulants for oral administration, heparin for systemic use, thrombolytics – simultaneous use with meloxicam increases the risk of bleeding. In case of concomitant use it is necessary to monitor closely the clotting system.

– Antiplatelet agents, serotonin reuptake inhibitors – concomitant use with meloxicam increases the risk of bleeding due to inhibition of platelet function. In case of concomitant use, close monitoring of the clotting system is required

Lithium drugs – NSAIDs increase the concentration of lithium in the plasma by reducing its excretion by the kidneys. Concomitant use of meloxicam with lithium drugs is not recommended. If concomitant use is necessary, it is recommended to carefully monitor the plasma concentration of lithium during the entire course of use of lithium drugs.

Methotrexate – NSAIDs reduce renal secretion of methotrexate, thereby increasing its concentration in plasma. Concomitant use of Veloxicam and methotrexate (at a dose greater than 15 mg per week) is not recommended. In case of concomitant use, close monitoring of renal function and blood counts is required.Meloxicam may increase hematologic toxicity of methotrexate, especially in patients with impaired renal function.

– Contraception – there is evidence that NSAIDs may reduce the effectiveness of intrauterine contraceptive devices, but this has not been proven.

– Diuretics- The use of NSAIDs in patients who are dehydrated is associated with a risk of acute renal failure.

Antihypertensives (beta-adrenoblockers, angiotensin converting enzyme inhibitors, vasodilators, diuretics). NSAIDs reduce the effect of antihypertensive drugs, due to inhibition of prostaglandins that have vasodilatory properties.

– Angiotensin II receptor antagonists, as well as angiotensin-converting enzyme inhibitors when combined with NSAIDs increase decrease glomerular filtration, which may lead to acute renal failure, especially in patients with impaired renal function.

– Colestiramine, by binding meloxicam in the gastrointestinal tract, leads to its faster excretion.

– Pemetrexed – when concomitant use of meloxicam and pemetrexed in patients with a clearance of 45 to 79 ml/min, meloxicam administration should be stopped five days before starting pemetrexed and possibly resumed 2 days after the end of administration. If there is a need for co-administration of meloxicam and pemetrexed, such patients should be closely monitored, especially with regard to myelosuppression and the occurrence of gastrointestinal side effects. In patients with creatinine clearance less than 45 mL/min, meloxicam should not be used with pemetrexed.

NSAIDs, by acting on renal prostaglandins, may increase the nephrotoxicity of cyclosporine.

When co-administering with meloxicam medicines which are known to inhibit CYP 2C9 and/or CYP 3A4 (or metabolized with participation of these enzymes) such as sulphonylurea derivatives or probenecid, the possibility of pharmacokinetic interaction should be taken into account. When co-administration with antidiabetic agents for oral administration (e.g., sulfonylurea derivatives, nateglinide) interactions mediated by CYP 2C9 are possible, which may lead to increased blood concentrations of both these medicines and meloxicam. Patients concomitantly taking meloxicam with sulfonylureas or nateglinide should carefully monitor blood sugar levels due to the possibility of hypoglycemia.

In concomitant use of antacids, cimetidine, digoxin and furosemide, no significant pharmacokinetic interactions were found.

Special Instructions

The drug may alter the properties of platelets, but it does not replace the preventive action of acetylsalicylic acid in cardiovascular diseases.

Cautious use of the drug should be observed in patients with a history of peptic ulcer disease and patients on anticoagulant therapy. These patients have an increased risk of gastrointestinal erosive ulcers.

We should use with caution and monitor daily urine output and renal function when using in elderly patients and patients with decreased circulating blood volume and glomerular filtration (dehydration, chronic heart failure, cirrhosis, nephrotic syndrome, clinically significant renal disease, use of diuretics, dehydration after major surgery).

In case of signs of liver damage (skin itching, yellowing of the skin, nausea, vomiting, abdominal pain, darkened urine, steady and significant increase in transaminases and other liver function parameters) the drug should be stopped and a physician should be consulted.

After two weeks of using the drug, the activity of “liver” enzymes should be monitored.

In patients with mild to moderate impairment of renal function (creatinine clearance ≥ 30 ml/min), no dose adjustment is required.

Patients taking diuretics and meloxicam at the same time should take adequate fluids.

If allergic reactions (itching, skin rash, urticaria, photosensitization) occur during treatment, the doctor should be consulted to decide whether to discontinue the drug.

Meloxicam, like other NSAIDs, may mask the symptoms of infectious diseases.

The use of meloxicam, as well as other drugs that block the synthesis of prostaglandins, may affect fertility, so it is not recommended for women planning to become pregnant.

The drug should not be used simultaneously with other NSAIDs.

Influence on the ability to drive and operate vehicles

Special clinical studies of the effect of the drug on the ability to drive and operate machinery have not been conducted. However, one should take into account the possibility of developing dizziness and somnolence, visual disturbances and other disorders of the central nervous system. During treatment, patients should use caution when driving vehicles and engaging in other activities that require high concentration and quick reaction time.

Synopsis

Contraindications

– Hypersensitivity to the active ingredient or excipients of the drug;

– Hypersensitivity (including to other non-steroidal anti-inflammatory drugs).

Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and sinuses, angioedema or urticaria, caused by intolerance to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs because of a history of possible cross-sensitivity;

– Erosive ulcers of the stomach and duodenum in the acute stage or recently suffered;

– Inflammatory bowel disease – Crohn’s disease or acute ulcerative colitis;

– Severe hepatic and cardiac failure;

– Severe renal failure (unless hemodialysis, creatinine clearance less than 30 ml/min, and with confirmed hyperkalemia);

– Active liver disease;

– Active gastrointestinal bleeding, recent cerebrovascular bleeding, or established diagnosis of blood clotting disorders;

– Under 18 years of age;

– Pregnancy;

– Breastfeeding period;

– Perioperative pain therapy for coronary artery bypass grafting;

– Concomitant therapy with anticoagulants because of the risk of intramuscular hematomas;

With caution

– history of gastrointestinal diseases (presence of Helicobacterpylori infection);

– congestive heart failure;

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

-ischemic heart disease;

– cerebrovascular disease;

-dyslipidemia/hyperlipidemia;

-diabetes;

– concomitant therapy with anticoagulants, oral glucocorticosteroids, antiaggregants, selective serotonin reuptake inhibitors;

– peripheral artery disease;

– advanced age;

– long-term use of NSAIDs;

-smoking;

– frequent use of alcohol.

Side effects

The following are side effects that have been considered to be possibly associated with the use of meloxicam.

After-marketing side effects that have been considered to be possibly associated with the use of meloxicam are marked with a *.

Within the system-organ classes, the following categories are used for the frequency of adverse effects:

very common ( ≥ 1/10);

frequent (≥ 1/100. < 1/10);

infrequent (≥ 1/ 1,000.< 1/100);

infrequent (≥ 1/10,000.< 1/1,000);

very rarely (< 1/10,000);

not established.

Blood and lymphatic system:

Infrequent – anemia;

Rarely – leukopenia, thrombocytopenia, changes in blood cell count, including changes in the leukocytic formula.

Disorders of the immune system:

Infrequent other immediate-type hypersensitivity reactions*

Not established – anaphylactic shock*, anaphylactoid reactions.

Mental disorders:

Rarely – change in mood*;

None established – confusion*, disorientation*.

Nervous system side:

Frequently – headache;

Infrequent – dizziness, drowsiness

Sight, hearing and labyrinth disorders:

Infrequent – vertigo;

Rarely – conjunctivitis*, visual disturbances including blurred vision*, tinnitus.

Cardiovascular disorders:

Infrequent – increased blood pressure level, feeling of “rush” of blood to the face; Rarely – palpitation;

Relatory system disorders:

Rarely, bronchial asthma in patients allergic to acetylsalicylic acid and other NSAIDs.

Gastrointestinal disorders:

Frequently – dyspepsia, abdominal pain, diarrhea, nausea, vomiting;

Infrequent – latent or overt gastrointestinal bleeding, gastritis*, stomatitis, constipation, abdominal bloating, belching;

Rarely – gastroduodenal ulcers, colitis, esophagitis;

Very rarely – gastrointestinal perforation

Liver and biliary tract disorders:

Infrequent transient changes in liver function parameters (e.g., increased transaminasyl bilirubin activity);

Very rare – hepatitis*.

Skin and subcutaneous tissue disorders:

Infrequent – itching, skin rash, angioedema*;

Rarely – urticaria, toxic epidermal necrolysis*, Stevens-Johnson syndrome*;

Very rare- bullous dermatitis*, erythema multiforme*;

Not established- photosensitization.

Kidney and urinary tract side:

Infrequent – changes in renal function parameters (increased serum creatinine, and/or serum urea levels), urinary disorders, including acute urinary retention*;

Very rare – acute renal failure*.

General disorders and disorders at the site of administration:

Frequently, pain and swelling at the injection site;

Infrequent, edema

Combined use with drugs that depress bone marrow (such as methotrexate) may provoke cytopenia.

Gastrointestinal bleeding, ulceration or perforation may be fatal.

As with other NSAIDs do not exclude the possibility of interstitial nephritis, glomerulonephritis, renal medullary necrosis, nephrotic syndrome.

Overdose

There is insufficient data on cases associated with overdose of the drug. Symptoms typical of NSAID overdose are likely to be present in severe cases:

Sleepiness, impaired consciousness, nausea, vomiting, epigastric pain, gastrointestinal bleeding, acute renal failure, changes in blood pressure, respiratory arrest, asystole.

Treatment:Antidote is not known. In case of drug overdose, symptomatic therapy should be used. Colestiramine is known to accelerate excretion of meloxicam.

In case of overdose, symptomatic therapy should be used.

Pregnancy use

The use of Arthrozan® is contraindicated during pregnancy.

It is known that NSAIDs penetrate into the breast milk, so the use of Arthrozan® during lactation is contraindicated.

As a drug that inhibits cyclooxygenase/prostaglandin synthesis, meloxicam may affect fertility and therefore is not recommended for women planning to become pregnant. Meloxicam may lead to delayed ovulation. In this regard, in women who have problems with conception and are undergoing examination for such problems, it is recommended to cancel the drug.

Similarities