Zerodol

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZERODOL (ZERODOL)

Composition:

Active substance: aceclofenac;

One tablet contains aceclofenac 100 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, sodium lauryl sulfate, iron oxide red (E 172), hydrogenated castor oil, hypromellose, crospovidone, stearic acid;

Film coating: talc, titanium dioxide (E 171), dibutyl phthalate, hypromellose, iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: reddish-brown, round, biconvex, film-coated tablets with a dividing line on one side and embossing “ZRD” on the other.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and anti-rheumatic drugs. Acetic acid derivatives and related substances. ATC code M01A B16.

Pharmacological properties.

Pharmacodynamics.

A non-steroidal anti-inflammatory and anti-rheumatic agent, a derivative of phenylacetic acid, chemically similar to diclofenac. Aceclofenac exerts anti-inflammatory, analgesic, and antipyretic effects. By inhibiting cyclooxygenase (COX), aceclofenac suppresses prostaglandin synthesis and thereby affects the pathogenesis of inflammation, pain, and fever. In rheumatic diseases, the anti-inflammatory and analgesic action of aceclofenac contributes to significant pain relief, reduction of morning stiffness and joint swelling, thus improving the patient's functional status.

Pharmacokinetics.

Absorption.

Aceclofenac is well absorbed after oral administration, with its bioavailability being almost 100%. Peak plasma concentration is reached approximately within 1.25–3 hours after administration. The time to reach maximum concentration increases when taken concomitantly with food, whereas the extent of absorption remains unaffected.

Distribution.

Aceclofenac is highly protein-bound (> 99.7%). The drug penetrates into synovial fluid, where its concentration reaches 60% of the plasma concentration. The volume of distribution is approximately 30 L.

Elimination.

The mean plasma elimination half-life is 4–4.3 hours. Clearance is 5 L/h. Approximately two-thirds of the administered dose is excreted in urine as conjugated hydroxylated metabolites. Only 1% of an orally administered single dose is excreted unchanged.

Aceclofenac is metabolized primarily in the liver to 4’-hydroxyaceclofenac and other metabolites, including diclofenac. Aceclofenac is likely metabolized via CYP2C9 to the main metabolite 4-OH-aceclofenac, which has negligible clinical activity. Diclofenac and 4-OH-diclofenac have been identified among the numerous metabolites.

Special patient groups.

No changes in the pharmacokinetics of aceclofenac have been observed in elderly patients.

A reduced elimination rate after a single dose of aceclofenac has been observed in patients with impaired liver function. In a repeated-dose study using 100 mg of the drug once daily, no differences in pharmacokinetic parameters were observed between patients with mild to moderate liver cirrhosis and healthy subjects.

In patients with mild or moderate renal impairment, no clinically relevant differences in pharmacokinetics were observed after a single dose.

Chemical structure of Aceclofenac

Clinical characteristics.

Indications.

Symptomatic therapy of pain and inflammation in osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, as well as in other musculoskeletal disorders associated with pain (e.g., periarthritis of the shoulder or extra-articular rheumatism).

As an analgesic in conditions associated with pain (including low back pain, dental pain, and primary (functional) dysmenorrhea).

Contraindications.

Aceclofenac is contraindicated:

• in patients with hypersensitivity to aceclofenac or to any excipient of the medicinal product (see section "Composition");
• in patients in whom acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs) induce asthma attacks, bronchospasm, acute rhinitis, angioedema, or urticaria, as well as in patients with hypersensitivity to these agents;
• in patients with a history of gastrointestinal bleeding or ulcer perforation associated with previous NSAID therapy;
• in patients with active peptic ulcer or gastrointestinal bleeding, including in the past (two or more separate documented episodes of ulcer development or bleeding);
• in patients with active bleeding or disorders associated with bleeding (hemophilia or coagulation disorders);
• in patients with congestive heart failure (functional class II–IV according to NYHA — New York Heart Association classification), ischemic heart disease, peripheral arterial disease, or cerebrovascular disorders;
• in patients with cerebrovascular disease who have had a stroke or episodes of transient ischemic attacks;
• in patients with ischemic heart disease who have angina or have had a myocardial infarction;
• for the treatment of perioperative pain in coronary artery bypass grafting (or when using a cardiopulmonary bypass machine);
• in patients with severe hepatic or renal impairment;
• during pregnancy and breastfeeding;
• in children (under 18 years of age).

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted, except for interaction with warfarin.

Aceclofenac is metabolized via cytochrome P450 2C9, and in vitro data indicate that aceclofenac may be an inhibitor of this enzyme. Therefore, a pharmacokinetic interaction between aceclofenac and phenytoin, cimetidine, tolbutamide, phenylbutazone, amiodarone, miconazole, and sulfaphenazole is possible. When aceclofenac is used, as with other NSAIDs, the risk of pharmacokinetic interaction increases with other drugs eliminated by active renal secretion, such as methotrexate and lithium preparations. Aceclofenac is almost completely bound to plasma albumin; therefore, interaction via displacement may occur with other drugs that bind to proteins.

Due to the lack of pharmacokinetic interaction studies with aceclofenac, the recommendations below are based on data from other NSAIDs.

Should be avoided

Methotrexate: NSAIDs inhibit tubular secretion of methotrexate; in addition, a minor metabolic interaction may occur, leading to reduced methotrexate clearance. Therefore, NSAIDs should always be avoided when high-dose methotrexate is administered.

Cardiac glycosides, digoxin: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate (GFR), and inhibit renal clearance of glycosides, leading to increased plasma levels of glycosides. Concomitant use should be avoided unless digoxin concentrations are monitored.

Lithium and digoxin preparations: some NSAIDs inhibit renal clearance of lithium and digoxin, leading to increased serum concentrations of both substances. Concomitant use should be avoided unless serum concentrations of lithium and digoxin are monitored.

Anticoagulants: NSAIDs inhibit platelet aggregation and damage the gastrointestinal (GI) mucosa, which may potentiate the effect of anticoagulants and increase the risk of gastrointestinal bleeding in patients taking anticoagulants. Concomitant use of aceclofenac with oral anticoagulants of the coumarin group, ticlopidine, thrombolytics, and heparin should be avoided unless careful patient monitoring is performed.

Quinolone antibiotics: animal studies show that NSAIDs increase the risk of seizures associated with quinolone antibiotic use.

In patients receiving NSAIDs and quinolones, the risk of developing seizures may be increased.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): when used concomitantly with NSAIDs, increase the risk of gastrointestinal bleeding (see section "Special precautions").

Combinations requiring dose adjustment and caution in use

Methotrexate: possible interaction between NSAIDs and methotrexate should be considered, even at low methotrexate doses, especially in patients with impaired renal function. Renal function parameters should be monitored during concomitant use. Caution is required when taking NSAIDs and methotrexate within 24 hours, as NSAIDs may increase methotrexate plasma concentrations, leading to increased toxicity of this drug.

Cyclosporine, tacrolimus: when NSAIDs are used concomitantly with cyclosporine or tacrolimus, the risk of increased nephrotoxicity due to reduced renal prostacyclin production should be considered. Therefore, renal function parameters should be closely monitored during concomitant use.

Other analgesics, NSAIDs, including selective cyclooxygenase-2 inhibitors: concomitant use of two or more NSAIDs (including acetylsalicylic acid) should be avoided, as this increases the frequency of adverse effects.

Mifepristone: NSAIDs should not be used within 8–12 days after mifepristone administration, as NSAIDs may reduce the effect of mifepristone.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section "Special precautions").

Diuretics: aceclofenac, like other NSAIDs, may suppress diuretic activity, reduce the diuretic effect of furosemide and bumetanide, and reduce the antihypertensive effect of thiazides. When used concomitantly with potassium-sparing diuretics, it may lead to increased potassium levels; therefore, serum potassium levels should be monitored regularly.

Antihypertensive agents: NSAIDs may also reduce the effect of antihypertensive drugs. Concomitant use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists with NSAIDs may lead to impaired renal function. The risk of acute renal failure, which is usually reversible, increases in certain patients with impaired renal function, such as elderly or dehydrated patients. Therefore, caution should be exercised when used concomitantly with NSAIDs, especially in elderly patients. Patients should consume adequate fluids and be under appropriate surveillance (monitoring of renal function at the start of concomitant use and periodically during treatment).

Aceclofenac did not affect blood pressure control when used concomitantly with bendroflumethiazide, although interactions with other diuretics cannot be excluded.

Hypoglycemic agents: clinical studies show that diclofenac can be used together with oral hypoglycemic agents without affecting their clinical efficacy. However, isolated reports of hypoglycemic and hyperglycemic effects have been reported. Thus, when taking Zerodol, dosage adjustment of agents that may cause hypoglycemia should be considered.

Zidovudine: concomitant use of NSAIDs and zidovudine increases the risk of hematological toxicity. Increased risk of hemarthrosis and hematomas has been confirmed in HIV(+) patients with hemophilia receiving zidovudine and ibuprofen.

Special precautions for use.

Concomitant use of the medicinal product Zerodol and NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and the risks related to gastrointestinal (GI) and cardiovascular systems described below).

Gastrointestinal (GI) effects

Peptic ulcers, gastrointestinal perforation, and GI bleeding, some of which were fatal, have been reported with the use of all NSAIDs at any time during therapy, both in the presence and absence of warning symptoms, regardless of prior history of serious gastrointestinal pathology.

The risk of developing peptic ulcers, GI perforation, and GI bleeding increases with high-dose NSAID use in patients with a history of peptic ulcer, particularly if associated with bleeding or perforation (see section "Contraindications"), as well as in elderly patients. These patients should receive the lowest effective dose. For such patients, and for patients requiring concomitant use of low-dose acetylsalicylic acid (aspirin) or other agents with negative effects on the gastrointestinal tract, concomitant therapy with protective agents (e.g., misoprostol or proton pump inhibitors) may be required (see section "Interaction with other medicinal products and other forms of interaction").

Patients with gastrointestinal disorders, including the elderly, should report any unusual GI symptoms (particularly signs of GI bleeding), especially at the beginning of treatment. Particular caution is required in patients who are concurrently taking medications that increase the risk of bleeding or ulcers, such as systemic corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (such as acetylsalicylic acid) (see section "Interaction with other medicinal products and other forms of interaction").

If peptic ulceration or GI bleeding occurs in a patient receiving Zerodol, treatment should be discontinued.

Cardiovascular and cerebrovascular effects

Patients with mild to moderate hypertension and/or congestive heart failure require appropriate monitoring and special caution, as fluid retention and edema have been reported with NSAID use. There are insufficient data to exclude this risk with aceclofenac.

Clinical trials and epidemiological data indicate that some NSAIDs (particularly at high doses and with prolonged use) are associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Particular caution is required when administering aceclofenac to patients with congestive heart failure (NYHA functional class I) and those with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking). Since the adverse cardiovascular effects increase with higher doses and longer treatment duration, the lowest effective daily dose for the shortest possible duration should be used. The need for continued symptomatic treatment and the efficacy of therapy should be reviewed periodically.

Aceclofenac should be used with caution and under close medical supervision in patients with a history of cerebrovascular hemorrhage.

Aceclofenac should be used with caution and under close medical supervision in patients with the following conditions (due to the risk of exacerbation) (see section "Adverse reactions"):

− symptoms indicating gastrointestinal disease, including upper and lower GI tract involvement;

− history of gastrointestinal ulcer, bleeding, or perforation;

− ulcerative colitis;

− Crohn’s disease;

− predisposition to bleeding, systemic lupus erythematosus (SLE), porphyria, and disorders of hematopoiesis and hemostasis.

Effects on liver and kidneys

NSAID use may cause dose-dependent reduction in prostaglandin synthesis and acute renal failure. The importance of prostaglandins in maintaining renal blood flow should be considered when using the drug in patients with cardiac, renal, or hepatic impairment, patients receiving diuretics, patients after surgery, and elderly patients.

Caution should be exercised when administering the drug to patients with mild to moderate hepatic or renal impairment, as well as in patients with other conditions associated with fluid retention. In these patients, NSAID use may lead to impaired renal function and fluid retention. Caution is also required when using Zerodol in patients taking diuretics or in those at increased risk of hypovolemia. The lowest effective dose should be used, and regular medical monitoring of renal function is necessary. Renal adverse effects are usually reversible upon discontinuation of aceclofenac.

Aceclofenac treatment should be discontinued if liver function test abnormalities persist or worsen, if clinical symptoms of liver disease develop, or if other signs appear (e.g., eosinophilia, rash). Hepatitis may develop without prodromal symptoms. NSAID use in patients with hepatic porphyria may trigger an attack.

Systemic lupus erythematosus (SLE) and mixed connective tissue disease

Patients with SLE and mixed connective tissue diseases have an increased risk of developing aseptic meningitis (see section "Adverse reactions").

Hypersensitivity and skin reactions

Like other NSAIDs, Zerodol may cause allergic reactions, including anaphylactic/anaphylactoid reactions, even upon first administration. Severe skin reactions (some of which may be fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely following NSAID use (see section "Adverse reactions"). The highest risk of these reactions occurs at the beginning of treatment, and most cases develop within the first month of therapy. Zerodol should be discontinued at the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity.

In rare cases, complications such as serious skin and soft tissue infections may occur during varicella (chickenpox). The role of NSAIDs in worsening these infections cannot currently be excluded. Therefore, Zerodol should be avoided during varicella.

Hematological disorders

Zerodol may cause reversible inhibition of platelet aggregation (see section “Interaction with other medicinal products and other forms of interaction”).

Respiratory system disorders

The drug should be used with caution in patients with bronchial asthma or a history of this condition, as NSAID use may provoke sudden bronchospasm in such patients.

Elderly patients

Caution should be exercised when using the drug in elderly patients (aged 65 years and older), as they are more likely to experience adverse effects (particularly GI bleeding and perforation) with NSAID use. Complications may be fatal. Elderly patients also more frequently suffer from renal, hepatic, or cardiovascular diseases.

Long-term use

All patients undergoing long-term treatment with NSAIDs should be under close medical supervision (including complete blood count, liver function tests, and renal function tests).

Excipients

Zerodol contains hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy or breastfeeding. Breastfeeding should be discontinued during treatment with aceclofenac.

Impairment of fertility in women.

Aceclofenac may impair fertility in women. This drug is not recommended for women attempting to conceive. Women experiencing difficulty conceiving or undergoing infertility investigations should discontinue Zerodol.

Ability to affect reaction speed when driving or operating machinery.

Patients experiencing symptoms such as weakness, dizziness, vertigo, or other central nervous system effects during NSAID therapy should refrain from driving or operating machinery.

Method of Administration and Dosage

Zerodol, film-coated tablets, is intended for oral administration and should be taken with at least ½ glass of liquid. Zerodol is preferably taken with food.

Adverse effects can be minimized by keeping the duration of treatment as short as possible, necessary to control symptoms (see section "Special Instructions").

Adults

The maximum recommended dose is 200 mg per day, administered as two doses of 100 mg each (1 tablet in the morning and 1 tablet in the evening).

Elderly Patients

Careful monitoring of these patients is required, as they more frequently experience impaired renal or hepatic function, cardiovascular disorders, and are more likely to receive concomitant therapy for other conditions, which increases the risk of serious adverse reactions. If NSAIDs are necessary, they should be administered at the lowest effective doses and for the shortest possible duration. Dose reduction is generally not required. Patients should be closely monitored for gastrointestinal bleeding during NSAID therapy, and recommendations described in the section "Special Instructions" should be followed.

Hepatic Impairment

For patients with mild to moderate hepatic impairment, the dose of aceclofenac should be reduced. The recommended initial dose is 100 mg daily (see section "Special Instructions").

Renal Impairment

There is insufficient data to recommend dose adjustment of aceclofenac in patients with mild renal impairment; however, caution should be exercised when administering the drug to these patients (see section "Special Instructions").

Children

The medicinal product is contraindicated in children.

Overdose

There are no reported cases of aceclofenac overdose in humans.

Possible symptoms

Headache, nausea, vomiting, stomach pain, dizziness, drowsiness, gastrointestinal irritation, gastrointestinal bleeding, diarrhea, disorientation, excitation, coma, tinnitus, arterial hypotension, respiratory depression, loss of consciousness, seizures. In severe cases, acute renal failure and hepatic dysfunction may occur.

Treatment

Management of acute NSAID poisoning includes administration of antacids (if necessary) and other supportive and symptomatic therapies for complications such as arterial hypotension, renal failure, seizures, gastrointestinal mucosal irritation, and respiratory depression.

In cases of aceclofenac overdose, treatment includes prevention of drug absorption by gastric lavage and administration of activated charcoal (repeated doses) as soon as possible after ingestion. Forced diuresis, dialysis, or hemoperfusion may be insufficiently effective for removing NSAIDs due to their high degree of plasma protein binding and extensive metabolism.

Adverse Reactions

Gastrointestinal tract: The most frequently reported adverse reactions were gastrointestinal (GI) in nature. Gastrointestinal ulcers, perforation, or gastrointestinal bleeding, sometimes fatal, may occur during NSAID therapy, particularly in elderly patients (see section "Special precautions"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease have been reported with NSAID use (see section "Special precautions"). Gastritis has been observed less frequently. Pancreatitis has been reported very rarely.

Cardiovascular system: Edema, hypertension, and heart failure have been reported in association with NSAID use.

Aceclofenac has structural and metabolic similarities to diclofenac, which, according to extensive clinical and epidemiological data, is associated with a slightly increased risk of major arterial thrombotic events (e.g., myocardial infarction or stroke), especially with high-dose or long-term use.

Epidemiological data also suggest an increased risk of acute coronary syndrome and myocardial infarction associated with aceclofenac use (see sections "Contraindications" and "Special precautions").

Hypersensitivity and skin reactions: Hypersensitivity reactions have been reported with NSAIDs. These may include non-specific allergic reactions presenting as anaphylactic reactions, respiratory tract reactivity including asthma, worsening of asthma, bronchospasm, or dyspnea, and various skin reactions, including rashes of different types, pruritus, urticaria, purpura, and angioedema. Less frequently, exfoliative and bullous dermatitis (including epidermal necrolysis and erythema multiforme) have been reported.

Neurological disorders and sensory organ disorders: Optic neuritis, cases of aseptic meningitis (particularly in patients with autoimmune disorders such as systemic lupus erythematosus and mixed connective tissue disease) have been reported, with symptoms including neck stiffness (rigidity), headache, nausea, vomiting, fever, disorientation, confusion, hallucinations, malaise, and somnolence (see section "Special precautions").

Hematological disorders: Agranulocytosis, aplastic anemia.

The table below lists adverse events reported in clinical trials and during post-marketing use of the medicinal product Zerodol, grouped by organ system and frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000).

Other adverse effects observed during the use of NSAIDs

Rare:

Renal and urinary tract disorders: interstitial nephritis.

Skin and subcutaneous tissue disorders: bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), photosensitization.

In exceptional cases, severe skin infections and soft tissue infections have been observed during the use of NSAIDs in patients with varicella (chickenpox) (see also sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister, 1 or 3 blisters in a carton.

Prescription category. Prescription only.

Manufacturer.

Ipca Laboratories Limited.

Manufacturer's address and place of business.

Plot No. 255/1, Village – Atal, U.T. Dadra and Nagar Haveli, 396230 Silvassa, India.