Remoxicam®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REUMOXICAM® (REUMOXICAM)

Composition:

Active ingredient: meloxicam;

1 suppository contains meloxicam 15 mg;

Excipient: hard fat.

Pharmaceutical form. Rectal suppositories.

Main physicochemical properties: suppositories are light yellow with a greenish tint, cigar-shaped. A surface film on the suppository is permissible.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Meloxicam. ATC code: M01A C06.

Pharmacological Properties

Pharmacodynamics

An anti-inflammatory, analgesic, and antipyretic agent. Its mechanism of action is primarily due to selective inhibition of cyclooxygenase-2 (COX-2), resulting in suppressed biosynthesis of pro-inflammatory prostaglandins at the site of inflammation. Due to its low affinity for cyclooxygenase-1 (COX-1), the drug, at therapeutic doses, does not exert a negative effect on the biosynthesis of cytoprotective prostaglandins in the gastrointestinal tract and kidneys, and does not inhibit platelet functional activity. It is a chondroneutral drug and does not affect proteoglycan synthesis by chondrocytes of articular cartilage.

Pharmacokinetics

After rectal administration, meloxicam is well absorbed into the systemic circulation, with a bioavailability of 89%. A stable therapeutic concentration in the blood is achieved within 3–5 days after initiation of treatment. Plasma protein binding exceeds 99%. The drug undergoes hepatic biotransformation, primarily via oxidation, forming four inactive metabolites. Enzymes CYP2C9 and CYP3A4, as well as peroxidase, play the main role in meloxicam metabolism. The volume of distribution is low—on average 11 L—and plasma clearance is 8 mL/min. The elimination half-life is approximately 20 hours, allowing for once-daily dosing. Elimination occurs equally via the kidneys and the intestine; 5% of the daily dose is excreted unchanged in the feces. The drug crosses histohematic barriers and penetrates well into synovial fluid, where its concentration reaches 50% of the plasma level.

In elderly individuals, only a slight increase in the elimination half-life and a reduction in plasma clearance (particularly in women) are observed.

No significant changes in meloxicam pharmacokinetics or increased risk of adverse effects have been noted when the drug is administered to patients with hepatic impairment or moderate renal insufficiency (creatinine clearance of 20–40 mL/min).

Clinical characteristics.

Indications.

Long-term symptomatic treatment of rheumatoid arthritis and ankylosing spondylitis. Short-term symptomatic treatment of osteoarthritis flare-ups when clinical response to meloxicam at a dose of 7.5 mg/day is insufficient.

Contraindications.

• Hypersensitivity to meloxicam or to any of the excipients of the medicinal product, or to other drugs with similar action, such as nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin;
• meloxicam must not be administered to patients who have symptoms of asthma, nasal polyps, angioedema, or urticaria associated with the use of acetylsalicylic acid or other NSAIDs, due to possible cross-reactivity;
• gastrointestinal bleeding or perforation related to previous NSAID therapy in medical history;
• active or recurrent peptic ulcer/hemorrhage in medical history (two or more separate confirmed episodes of ulcers or bleeding);
• history of proctitis and rectal bleeding;
• severe hepatic impairment;
• severe renal impairment without dialysis;
• gastrointestinal bleeding, cerebrovascular hemorrhage in medical history, or other coagulopathies;
• other disorders of hemostasis or concomitant therapy with anticoagulants;
• severe heart failure;
• third trimester of pregnancy;
• children and adolescents under 16 years of age;
• treatment of perioperative pain in coronary artery bypass grafting (CABG).

Interaction with other medicinal products and other types of interactions.

Risks associated with hyperkalemia.

Some medicinal products may contribute to hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus, and trimethoprim.

Development of hyperkalemia may depend on associated factors. The risk of hyperkalemia increases if the above-mentioned medicinal products are used concomitantly with meloxicam.

Pharmacodynamic interactions.

Other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid > 3 g/day.

Concomitant administration of prostaglandin synthetase inhibitors may lead to an increased risk of gastrointestinal bleeding and ulceration due to synergistic effects; therefore, such combination therapy is not recommended. Combination with other NSAIDs, including acetylsalicylic acid administered at doses ≥ 500 mg per single dose or ≥ 3 g daily, is not recommended.

Corticosteroids (e.g., glucocorticoids).

Concomitant use of corticosteroids requires caution due to an increased risk of gastrointestinal bleeding or ulceration.

Oral anticoagulants, antiplatelet agents, systemic heparin, thrombolytics, and selective serotonin reuptake inhibitors: increased risk of bleeding due to inhibition of platelet function. Careful monitoring is recommended if such combination therapy is necessary.

The risk of bleeding is significantly increased due to inhibition of platelet function and damage to the gastroduodenal mucosa. NSAIDs may potentiate the effects of anticoagulants such as warfarin (see section "Special precautions for use").

Concomitant use of NSAIDs and anticoagulants or heparin is not recommended in geriatric practice or at therapeutic doses (see section "Special precautions for use"). In other cases (e.g., when used at prophylactic doses), caution is required when administering heparin due to an increased risk of bleeding. Close monitoring of INR (international normalized ratio) is necessary if this combination cannot be avoided.

Thrombolytic and antiplatelet agents.

Increased risk of bleeding due to inhibition of platelet function and damage to the gastroduodenal mucosa.

Selective serotonin reuptake inhibitors.

Increased risk of gastrointestinal bleeding.

Diuretics, ACE inhibitors, and angiotensin II antagonists.

NSAIDs may reduce the efficacy of diuretics and other antihypertensive agents. Angiotensin II receptor antagonists and ACE inhibitors have a synergistic effect with cyclooxygenase inhibitors on reducing glomerular filtration. In patients with pre-existing renal dysfunction (e.g., dehydrated patients or elderly patients with impaired renal function), this may lead to acute renal failure, which is usually reversible. Therefore, such combinations should be used with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive agents (e.g., beta-blockers).

NSAIDs reduce antihypertensive effects due to inhibitory effects on vasodilatory prostaglandins.

Calcineurin inhibitors (e.g., cyclosporine, tacrolimus).

The nephrotoxicity of calcineurin inhibitors may be enhanced by NSAIDs due to side effects mediated by prostaglandin inhibition. Renal function should be assessed during combination therapy. Close monitoring of renal function is recommended, especially in elderly patients.

Deferasirox. Concomitant use of meloxicam and deferasirox increases the risk of gastrointestinal adverse reactions. Caution should be exercised when combining these medicinal products.

Contraception. It has been reported that NSAIDs may reduce the effectiveness of intrauterine devices, but data require further confirmation.

Pharmacokinetic interaction: effect of meloxicam on the pharmacokinetics of other medicinal products.

Lithium. Data indicate that NSAIDs increase plasma lithium levels (due to reduced renal excretion of lithium). Concomitant use of lithium and NSAIDs is not recommended. Plasma lithium levels should be monitored at the beginning of treatment, during dose adjustment, and upon discontinuation of meloxicam.

Methotrexate. NSAIDs may reduce tubular secretion of methotrexate, thereby increasing its plasma concentration. Therefore, concomitant use of NSAIDs is not recommended in patients undergoing high-dose methotrexate therapy (>15 mg/week) (see section "Special precautions for use"). The risk of interaction between NSAIDs and methotrexate should also be considered in patients receiving low-dose methotrexate, particularly those with impaired renal function. If combination therapy is required, blood test parameters and renal function should be monitored. Caution is advised when NSAID and methotrexate administration occurs for 3 consecutive days, as plasma methotrexate levels may increase and enhance toxicity. Although the pharmacokinetics of methotrexate (15 mg/week) are not affected by concomitant meloxicam treatment, hematological toxicity of methotrexate may increase during NSAID therapy (see section "Adverse reactions").

Pemetrexed. When concomitant use of meloxicam with pemetrexed is required in patients with creatinine clearance between 45 and 79 mL/min, meloxicam administration should be withheld for 5 days before pemetrexed infusion, on the day of infusion, and for 2 days after infusion. If combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, particularly for myelosuppression and gastrointestinal adverse reactions. Concomitant use of meloxicam with pemetrexed is not recommended in patients with severe renal impairment (creatinine clearance <45 mL/min).

In patients with normal renal function (creatinine clearance ≥80 mL/min), 15 mg doses of meloxicam may reduce pemetrexed elimination and thus increase the frequency of pemetrexed-related adverse reactions. Therefore, caution is advised when administering 15 mg meloxicam concomitantly with pemetrexed in patients with normal renal function (creatinine clearance ≥80 mL/min).

Pharmacokinetic interaction: effect of other medicinal products on the pharmacokinetics of meloxicam.

Cholestyramine accelerates meloxicam elimination due to disruption of enterohepatic circulation, resulting in a 50% increase in meloxicam clearance and a reduction in half-life to 13±3 hours. This interaction is clinically significant.

Pharmacokinetic interaction: effect of the combination of meloxicam and other medicinal products on pharmacokinetics.

Oral antidiabetic agents (sulfonylurea derivatives, nateglinide).

Meloxicam is almost entirely metabolized by hepatic metabolism, approximately two-thirds via cytochrome (CYP) P450 (mainly CYP 2C9 and secondary pathway CYP 3A4) and one-third via other pathways, such as peroxidase oxidation.

A pharmacokinetic interaction between meloxicam and other drugs that strongly inhibit or are metabolized by CYP 2C9 and/or CYP 3A4 is possible. Interactions mediated by CYP 2C9 may be expected when combining meloxicam with drugs such as oral antidiabetic agents (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of both agents. Patients receiving meloxicam and sulfonylurea or nateglinide should be closely monitored for hypoglycemia.

No clinically significant pharmacokinetic interactions between meloxicam and antacids, cimetidine, or digoxin have been observed with concomitant administration.

Special precautions for use.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

The recommended maximum daily dose should not be exceeded if the therapeutic effect is inadequate, and additional NSAIDs should not be used concomitantly, as this may increase toxicity without proven therapeutic benefits. Concomitant use of meloxicam with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Meloxicam is not suitable for treatment of patients requiring relief from acute pain.

In the absence of improvement after several days, the clinical benefits of treatment should be re-evaluated.

Particular attention should be paid to a history of esophagitis, gastritis, and/or peptic ulcer to ensure complete treatment prior to initiating meloxicam therapy. The possibility of recurrence should be considered in patients who have used meloxicam and in those with such history.

Gastrointestinal disorders.

As with other NSAIDs, careful monitoring is required in patients with gastrointestinal disorders and those taking anticoagulants. Meloxicam is contraindicated in the presence of peptic ulcer or gastrointestinal bleeding.

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration, or perforation may occur at any time during treatment, with or without preceding symptoms or a history of serious gastrointestinal disorders. The most severe outcomes have been observed in elderly patients.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a complicated ulcer history (especially with bleeding or perforation complications), and in elderly patients. These patients should initiate treatment with the lowest available dose. For such patients, combination therapy with protective agents (misoprostol or proton pump inhibitors) should be considered, as well as for patients requiring concomitant use of low-dose acetylsalicylic acid or other agents increasing gastrointestinal risks.

Patients with a history of gastrointestinal toxicity, particularly elderly patients, should be informed about any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly in the initial stages of treatment.

Concomitant use of meloxicam with drugs that increase the risk of ulceration or bleeding, such as heparin used as definitive therapy or in geriatric practice, anticoagulants such as warfarin, or other NSAIDs, including acetylsalicylic acid at doses ≥ 500 mg — single dose or ≥ 3 g — total daily dose, is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in patients taking meloxicam, treatment should be discontinued.

NSAIDs should be used cautiously in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as these conditions may worsen (see section "Adverse reactions").

Hepatic disorders.

Elevations in one or more liver function tests may occur in up to 15% of patients receiving NSAIDs (including Rheumoxicam®). These laboratory abnormalities may progress, remain unchanged, or resolve during continued treatment. Marked increases in ALT [alanine aminotransferase] or AST [aspartate aminotransferase] (approximately three times or more above normal) were observed in 1% of patients during clinical trials with NSAIDs. Rare cases of severe hepatic reactions, including jaundice, fulminant fatal hepatitis, liver necrosis, and liver failure, sometimes fatal, have also been reported.

Patients with symptoms or suspected hepatic dysfunction, as well as those with abnormal liver function tests, should be monitored for signs of more severe hepatic failure during treatment with Rheumoxicam®. If clinical signs and symptoms suggest hepatic disease or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), use of Rheumoxicam® should be discontinued.

Cardiovascular disorders.

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure should be closely monitored, as fluid retention and edema have been observed during NSAID therapy.

Clinical monitoring of blood pressure is recommended at the beginning of therapy, especially at the start of meloxicam treatment, in patients with cardiovascular risk factors.

Clinical and epidemiological data suggest that use of certain NSAIDs (particularly at high doses and during prolonged treatment) may slightly increase the risk of vascular thrombotic events (e.g., myocardial infarction or stroke). There is insufficient data to exclude such risk with meloxicam use.

Therapy with meloxicam in patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be initiated only after careful consideration. A similar assessment is required before initiating long-term treatment in patients with cardiovascular risk factors such as arterial hypertension, hyperlipidemia, diabetes mellitus, or smoking.

NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which may be fatal. This risk may increase with longer duration of treatment. The risk may be higher in patients with pre-existing cardiovascular disease or cardiovascular risk factors.

Skin disorders.

Serious skin reactions, some of which have been fatal, including exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis, have been observed very rarely with NSAID use. The highest risk of such reactions occurs early in treatment, with most cases appearing within the first month of therapy. Meloxicam use should be discontinued at the first appearance of skin rash, mucosal lesions, or other signs of hypersensitivity.

Due to the potential for adverse skin and mucosal reactions, such symptoms should be closely monitored. Treatment with meloxicam should be discontinued if such adverse effects occur.

If Stevens–Johnson syndrome or toxic epidermal necrolysis occurs during meloxicam use, the drug must never be used again.

Cases of fixed drug eruption have been reported with meloxicam use. Meloxicam should not be re-administered to patients with a history of fixed drug eruption associated with meloxicam.

Potential cross-reactivity with other oxicams may occur.

Anaphylactic reactions.

As with other NSAIDs, anaphylactic reactions may occur in patients without known sensitivity to meloxicam. Meloxicam should not be used in patients with aspirin triad—a symptomatic complex occurring in patients with asthma who have a history of rhinitis with or without nasal polyps, or who experience severe, potentially fatal bronchospasm after taking acetylsalicylic acid or other NSAIDs. Immediate emergency measures should be taken if an anaphylactoid reaction occurs.

Renal functional impairment.

NSAIDs may induce functional renal impairment due to reduced glomerular filtration by inhibiting the vasodilatory effect of renal prostaglandins. This adverse effect is dose-dependent. Careful monitoring of renal function, particularly urine output, is recommended at the beginning of treatment or after dose escalation in patients with risk factors such as: advanced age; concomitant use with ACE inhibitors, angiotensin II antagonists, sartans, or diuretics (see section "Interaction with other medicinal products and other forms of interaction"); hypovolemia (of any origin); congestive heart failure; renal insufficiency; nephrotic syndrome; lupus nephritis; or severe hepatic dysfunction (serum albumin < 25 g/L or Child–Pugh score ≥ 10).

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

The meloxicam dose in patients with end-stage renal failure on dialysis should not exceed 7.5 mg (in tablet form). For patients with mild to moderate renal impairment, dose reduction is not necessary (creatinine clearance >25 mL/min).

Liver parameters and renal function.

During treatment with most NSAIDs, including meloxicam, isolated cases of elevated serum transaminases, increased serum bilirubin, or other liver function parameters, as well as increased serum creatinine and blood urea nitrogen, and other laboratory abnormalities have been reported. These abnormalities are usually mild and transient. If significant or persistent abnormalities occur, meloxicam use should be discontinued and follow-up tests performed.

Sodium, potassium, and water retention.

NSAIDs may exacerbate sodium, potassium, and water retention and may interfere with the natriuretic effect of diuretics, potentially causing or worsening cardiac disorders or arterial hypertension. Clinical monitoring is recommended for such patients.

Additionally, the effect of antihypertensive agents may be reduced. Thus, edema, heart failure, or arterial hypertension may develop in susceptible patients. Clinical monitoring of at-risk patients is necessary.

Hyperkalemia.

Hyperkalemia may be promoted by diabetes mellitus or concomitant use of drugs that increase potassium levels (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, potassium levels should be monitored regularly.

Combination with pemetrexed.

When concomitant use of meloxicam with pemetrexed is required in patients with mild to moderate renal impairment, meloxicam treatment should be withheld at least 5 days before, on the day of, and for at least 2 days after pemetrexed administration (see section "Interaction with other medicinal products and other forms of interaction").

Other warnings and safety precautions.

Adverse reactions are often less tolerated in elderly, debilitated, or weakened patients, who require careful monitoring. Caution is required when treating elderly patients with NSAIDs, including meloxicam, due to higher likelihood of impaired renal, hepatic, and cardiac function. Elderly patients have a higher incidence of adverse reactions with NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

Like other NSAIDs, meloxicam may mask symptoms of infectious diseases.

Masking of inflammation and fever.

The pharmacological action of meloxicam in reducing fever and inflammation may complicate diagnosis in suspected non-infectious painful conditions.

Use of meloxicam, like other drugs inhibiting cyclooxygenase/prostaglandin synthesis, may adversely affect reproductive function and is not recommended for women attempting to conceive. For women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered.

Corticosteroid therapy.

Meloxicam cannot serve as a substitute for corticosteroids in the treatment of corticosteroid deficiency.

Hematological effects.

Anemia may occur in patients receiving NSAIDs, including Rheumoxicam®. This may be related to fluid retention, occult or macroscopic gastrointestinal bleeding, or an incompletely described effect on erythropoiesis. Hemoglobin or hematocrit levels should be monitored during long-term NSAID therapy, including Rheumoxicam®, if symptoms or signs of anemia are present.

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively smaller, short-term, and reversible. Patients taking Rheumoxicam® who may experience adverse effects on platelet function, including coagulation disorders, and those receiving anticoagulants, should be closely monitored.

Use in patients with asthma.

Patients with asthma may have aspirin-sensitive asthma. Use of aspirin in such patients is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between aspirin and other NSAIDs, Rheumoxicam® should not be used in patients sensitive to aspirin and should be used cautiously in patients with asthma.

Use during pregnancy or breastfeeding.

Rheumoxicam® is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. This risk is believed to increase with higher doses and longer duration of treatment.

From the 20th week of gestation, meloxicam use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after treatment initiation and is usually reversible upon discontinuation. Additionally, there are reports of arterial duct constriction after second-trimester treatment, most of which resolved after stopping treatment. Therefore, meloxicam should be prescribed during the first and second trimesters only if absolutely necessary. If meloxicam is used by a woman planning pregnancy or during the first or second trimester, the dose should be as low as possible and treatment duration as short as possible. Monitoring for oligohydramnios and arterial duct constriction should be considered after meloxicam exposure for several days starting from the 20th gestational week. Rheumoxicam® use should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose fetal risks:

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal impairment, which may progress to renal failure with oligohydramnios (see above).

Potential risks in late pregnancy for mother and newborn:

• prolonged bleeding time and anti-aggregatory effect, even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Although specific data on meloxicam are lacking, NSAIDs are known to pass into breast milk; therefore, meloxicam is contraindicated in breastfeeding women.

Fertility. Meloxicam, like other drugs inhibiting cyclooxygenase/prostaglandin synthesis, may adversely affect reproductive function and is not recommended for women wishing to conceive. Therefore, for women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered.

Ability to affect reaction speed when driving or operating machinery.

No specific studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. Based on the pharmacodynamic profile and observed adverse reactions, meloxicam is expected to have no effect or a negligible effect on such activities. However, patients experiencing visual disturbances after taking the drug, such as blurred vision, dizziness, somnolence, vertigo, or other central nervous system disorders, are advised to refrain from driving or operating machinery.

Method of Administration and Dosage

For use in adults and children aged 16 years and older:

Exacerbation of osteoarthritis (in cases of insufficient clinical response to meloxicam at a dose of 7.5 mg/day): 15 mg/day (1 suppository).

Rheumatoid arthritis: 15 mg/day (1 suppository).

Ankylosing spondylitis: 15 mg/day (1 suppository).

The maximum recommended daily dose of meloxicam for adults is 15 mg.

Since the risk of adverse reactions increases with higher doses and prolonged duration of treatment, the lowest effective daily dose should be used for the shortest possible treatment duration.

When combining different dosage forms of meloxicam (capsules, tablets, suppositories, solution), the total daily dose must not exceed 15 mg.

Children. The drug is indicated for treatment of children aged 16 years and older.

Overdose.

Symptoms: Acute NSAID overdose is usually characterized by lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding may occur. Severe poisoning may lead to arterial hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, seizures, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions have been reported during therapeutic use of NSAIDs and may also occur in cases of overdose.

Treatment: Discontinue the drug, perform rectal irrigation, and provide symptomatic therapy. There is no specific antidote. In a clinical trial, accelerated elimination of meloxicam was demonstrated with oral administration of cholestyramine 4 g three times daily.

Adverse Reactions

The majority of adverse effects of the drug are gastrointestinal in origin. Peptic ulcer, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients (see section "Special Warnings and Precautions for Use"). After administration of meloxicam, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been observed; gastritis has been reported less frequently.

Data from clinical studies and epidemiological evidence suggest that the use of certain NSAIDs (especially at high doses and during long-term treatment) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Edema, hypertension, and heart failure have been reported during NSAID therapy.

Serious skin reactions have also been reported with NSAIDs, including Stevens–Johnson syndrome and toxic epidermal necrolysis (see section "Special Warnings and Precautions for Use").

The adverse reactions listed below were observed in 27 clinical trials with treatment duration of at least 14 days. Also included are adverse reactions identified from post-marketing experience.

Blood and lymphatic system disorders: Abnormal blood test results (including differential leukocyte count), leukopenia, thrombocytopenia, anemia. Very rare cases of agranulocytosis have been reported.

Concomitant use of potentially myelotoxic drugs, particularly methotrexate, may lead to the development of cytopenia.

Immune system disorders: Anaphylactic reaction, anaphylactoid reaction, and other immediate-type allergic reactions, including shock.

Psychiatric disorders: Confusion, disorientation, mood changes, night terrors, insomnia.

Nervous system disorders: Dizziness, somnolence, headache.

Eye disorders: Visual disturbances including blurred vision, conjunctivitis.

Ear and labyrinth disorders: Vertigo, tinnitus.

Cardiac disorders: Palpitations.

Heart failure associated with NSAID therapy has been reported.

Vascular disorders: Increased blood pressure, hyperemia, flushing.

Respiratory, thoracic and mediastinal disorders: Bronchial asthma in patients with aspirin or other NSAID allergy, upper respiratory tract infections, cough.

Gastrointestinal disorders: Gastrointestinal perforation, occult or gross gastrointestinal bleeding, gastroduodenal ulcer, colitis, gastritis, esophagitis, stomatitis, abdominal pain, dyspepsia, diarrhea, nausea, vomiting, constipation, flatulence, eructation.

Gastrointestinal bleeding, ulceration, or perforation may be potentially fatal.

Hepatobiliary disorders: Hepatitis, abnormalities in liver function tests (e.g., elevated transaminases or bilirubin), jaundice, hepatic failure.

Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens–Johnson syndrome, angioneurotic edema, bullous dermatitis, polymorphic erythema, rash, urticaria, photosensitivity, pruritus, exfoliative dermatitis, fixed drug eruption (see section "Special Warnings and Precautions for Use").

Renal and urinary disorders: Sodium and water retention (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"), hyperkalemia, acute renal failure—particularly in patients with risk factors (see section "Special Warnings and Precautions for Use"), changes in renal function parameters (increased serum creatinine and/or urea), urinary tract infections, disturbances in micturition frequency.

NSAID use may be associated with micturition disorders, including acute urinary retention.

Reproductive system and breast disorders: Female infertility, ovulation delay.

General disorders and administration site conditions: Edema, including peripheral edema, burning and itching in the anorectal area, influenza-like symptoms.

Musculoskeletal and connective tissue disorders: Arthralgia, back pain, signs and symptoms related to joints.

Specific serious and/or common adverse reactions.

Very rare cases of agranulocytosis have been reported in patients treated with meloxicam and other potentially myelotoxic medicinal products (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Adverse reactions not observed during drug use but typical for other compounds of the class.

Organic renal damage may lead to acute renal failure: very rare cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome, and papillary necrosis have been reported (see section "Special Warnings and Precautions for Use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 5 suppositories per blister. 1 blister per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's name and address.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.

Marketing Authorization Holder. JSC "Farmak".

Marketing Authorization Holder's name and address.

63 Kyrylivska Street, Kyiv, 04080, Ukraine.