INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BlokMAX® Rapid (BlokMAX® Rapid)

Composition:

Active ingredient: ibuprofen;

One film-coated tablet contains ibuprofen lysinate 684 mg (equivalent to 400 mg of ibuprofen);

Excipients: microcrystalline cellulose silicified, copovidone, sodium starch glycolate (type A), magnesium stearate;

Coating: Opadry 200 Series White 200F280000 [polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), talc, macrogol 4000, methacrylic acid or ethyl acrylate copolymer, sodium bicarbonate].

Dosage form. Film-coated tablets.

Main physicochemical characteristics: elongated, biconvex, film-coated tablets of white to creamy color, with a score line on one side.

The score line is intended only to facilitate breaking the tablet for easier swallowing and does not ensure equal dose division.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. ATC code M01AE01.

Pharmacological Properties.

Pharmacodynamics.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that exerts targeted effects against pain, fever, and inflammation in humans by inhibiting the synthesis of prostaglandins—mediators of pain and inflammation. In addition, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that concomitant use of ibuprofen may reduce the effect of low-dose acetylsalicylic acid on platelet aggregation.

Some pharmacodynamic studies show that when single 400 mg doses of ibuprofen are administered within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg), a reduction in the effect of acetylsalicylic acid on thromboxane formation or platelet aggregation may occur. However, the limited nature of these data and uncertainty regarding extrapolation of ex vivo findings to clinical situations do not allow definitive conclusions to be drawn regarding regular use of ibuprofen; effects are considered unlikely with occasional use of ibuprofen.

After oral administration, ibuprofen lysine is broken down into ibuprofen acid and lysine. Lysine does not influence the pharmacotherapeutic activity of the medicinal product. The pharmacodynamic properties of ibuprofen lysine are similar to those of ibuprofen acid.

Pharmacokinetics.

Most pharmacokinetic data obtained after administration of ibuprofen acid also apply to ibuprofen lysine.

Ibuprofen is rapidly absorbed in the gastrointestinal tract and binds to plasma proteins. Ibuprofen penetrates into breast milk.

After administration with food, maximum plasma concentration is reached within 1–2 hours. Following administration in the form of ibuprofen lysine, absorption of ibuprofen occurs more rapidly.

After fasting administration, maximum plasma concentration is reached within 38 minutes.

Ibuprofen is metabolized in the liver into two main metabolites, which are almost entirely excreted by the kidneys either unchanged or as conjugated compounds, with a negligible amount of unchanged ibuprofen. Elimination of the drug via the kidneys is complete and rapid.

The elimination half-life is approximately 2 hours.

No significant differences in pharmacokinetic profile have been observed in elderly patients.

Clinical characteristics.

Indications.

Symptomatic treatment of headache, migraine, toothache, menstrual pain, rheumatic pain, muscle pain and back pain.

Symptomatic treatment of signs of cold, influenza, and fever.

Contraindications.

Hypersensitivity to ibuprofen or to any of the excipients of the medicinal product.
History of hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, or urticaria) following the administration of acetylsalicylic acid or other NSAIDs.
Active peptic ulcer/hemorrhage or history of recurrent episodes (two or more documented episodes of peptic ulcer or bleeding).
Gastrointestinal bleeding or perforation related to previous NSAID therapy.
Severe hepatic insufficiency, severe renal insufficiency, severe heart failure (NYHA Class IV).
Cerebrovascular or other active bleeding.
Coagulation disorders or hemorrhagic diathesis.
Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of ibuprofen, as with other NSAIDs, with the following drugs should be avoided:

Acetylsalicylic acid (low-dose)

Concomitant use of ibuprofen and low-dose acetylsalicylic acid is generally not recommended due to the potential for increased adverse effects, except when a physician prescribes low-dose acetylsalicylic acid (not exceeding 75 mg daily).

Study data indicate that concomitant use of ibuprofen may interfere with the antiplatelet effect of low-dose acetylsalicylic acid. However, the limited nature of these data and uncertainty regarding the translation of ex vivo findings into clinical practice mean that no definitive conclusion can be drawn regarding a clinically significant effect of ibuprofen with regular or occasional use.

Other NSAIDs, including salicylates

The synergistic effect of concomitant use of multiple NSAIDs may increase the risk of adverse reactions. Therefore, concomitant use of ibuprofen with other NSAIDs should be avoided.

Ibuprofen should be used with caution in combination with the following drugs:

Cardiac glycosides

NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of glycosides.

Corticosteroids

Concomitant use with corticosteroids may increase the risk of adverse reactions, particularly gastrointestinal (e.g., development of ulcers or gastrointestinal bleeding).

Anticoagulants

NSAIDs may potentiate the effects of anticoagulants such as warfarin.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs)

Concomitant use increases the risk of gastrointestinal bleeding.

Lithium

Concomitant use of ibuprofen and lithium may increase serum lithium concentrations.

Diuretics, ACE inhibitors, beta-blockers, and angiotensin II receptor antagonists

NSAIDs may attenuate the effects of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of ACE inhibitors, beta-blockers, or angiotensin II receptor antagonists with cyclooxygenase inhibitors may lead to further deterioration of renal function, including potentially reversible acute renal failure. Therefore, such combinations should be used with caution, particularly in elderly patients. When such combinations are used, adequate hydration should be ensured and monitoring of renal function should be considered at the start of treatment and periodically thereafter.

MTX (methotrexate)

Potential for increased plasma methotrexate levels.

Cyclosporine

Increased risk of nephrotoxicity.

Tacrolimus

Risk of nephrotoxicity is increased with concomitant use.

Zidovudine

Concomitant use of NSAIDs with zidovudine increases the risk of hematotoxicity. Evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant zidovudine and ibuprofen.

Quinolone antibiotics

Animal studies indicate that concomitant use of NSAIDs and quinolone antibiotics may increase the risk of seizures. Patients receiving NSAIDs concomitantly with quinolones have an increased risk of developing seizures.

Mifepristone

NSAIDs should not be used earlier than 8–12 days after mifepristone administration, as NSAIDs reduce the efficacy of mifepristone.

Sulfonylurea derivatives and phenytoin

Potential for enhanced effects of these drugs.

Special precautions for use.

Adverse reactions associated with the use of ibuprofen and NSAIDs in general can be minimized by using the lowest effective dose required to treat symptoms, for the shortest necessary duration.

Caution should be exercised when treating patients with:

systemic lupus erythematosus and mixed connective tissue disease;
gastrointestinal disorders and chronic inflammatory bowel diseases (ulcerative colitis, Crohn’s disease);
arterial hypertension and/or heart failure;
impaired kidney function;
impaired liver function;
coagulation disorders (ibuprofen may prolong bleeding time).

Elderly patients have an increased frequency of adverse reactions during NSAID therapy, particularly gastrointestinal bleeding and perforations, which may be fatal.

Respiratory effects

Bronchospasm may occur in patients suffering from bronchial asthma or allergic conditions, or with a history of such diseases.

Other NSAIDs

Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, increases the risk of adverse reactions and should therefore be avoided.

Systemic lupus erythematosus and mixed connective tissue diseases

Ibuprofen should be used with caution in patients with systemic lupus erythematosus or mixed connective tissue diseases due to an increased risk of aseptic meningitis.

Renal effects

Renal impairment, as kidney function may deteriorate.

There is a risk of kidney damage in dehydrated children and adolescents.

Hepatic effects

Impaired liver function.

Cardiovascular and cerebrovascular effects

Patients with a history of arterial hypertension and/or moderate to severe congestive heart failure should begin long-term treatment cautiously (medical consultation required), as fluid retention, arterial hypertension, and edema have been reported during therapy with ibuprofen and other NSAIDs.

Clinical trial data and epidemiological evidence indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), and prolonged treatment may lead to a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, epidemiological data do not suggest that low-dose ibuprofen (e.g., ≤1200 mg per day) increases the risk of myocardial infarction.

Patients with uncontrolled arterial hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful assessment of the clinical condition. High doses (2400 mg per day) should be avoided.

Careful consideration is also required before initiating long-term treatment in patients with risk factors for cardiovascular disease (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high doses of ibuprofen (2400 mg per day) are required.

Cases of Kounis syndrome have been reported in patients taking ibuprofen. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, which may potentially lead to myocardial infarction.

Effect on female fertility

Limited data suggest that medicinal products which inhibit cyclooxygenase/prostaglandin synthesis may affect the process of ovulation. This effect is reversible upon discontinuation of treatment. This medicinal product should not be used in women experiencing difficulties in becoming pregnant or undergoing infertility investigations.

Gastrointestinal effects

NSAIDs should be used with caution in patients with chronic inflammatory bowel diseases (ulcerative colitis, Crohn’s disease), as these conditions may worsen. Cases of gastrointestinal bleeding, perforation, and ulcers, some of which were fatal, have been reported during NSAID therapy, occurring at any stage of treatment regardless of prior warning symptoms or history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, perforation, and ulcers increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. These patients should start treatment at the lowest possible dose. Caution should be exercised when treating patients receiving concomitant medications that may increase the risk of gastotoxicity or bleeding, such as oral corticosteroids or anticoagulants (e.g., warfarin) or antiplatelet agents (e.g., acetylsalicylic acid).

Patients with a history of gastrointestinal disorders, particularly elderly patients, should be advised to report any unusual gastrointestinal symptoms (especially bleeding), particularly gastrointestinal bleeding at the beginning of treatment. If gastrointestinal bleeding or ulceration occurs in patients taking ibuprofen, treatment should be discontinued immediately.

Serious skin adverse reactions

Very rare cases of severe skin adverse reactions, including fatal outcomes, have been reported with the use of ibuprofen, such as exfoliative dermatitis, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP) (see section "Adverse reactions"). Most of these reactions occurred within the first month of treatment. If signs or symptoms suggestive of these reactions appear, ibuprofen should be discontinued immediately and alternative therapy considered (if necessary).

Masking symptoms of underlying infections

Ibuprofen may mask the symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating the course of the illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When ibuprofen is used for fever or pain relief during infection, monitoring for signs of infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Use during pregnancy or breastfeeding

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following the use of prostaglandin synthesis inhibitors during early pregnancy. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy. From the 20th week of gestation, the use of ibuprofen may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of therapy. Additionally, there have been reports of arterial duct constriction following treatment in the second trimester, most of which resolved after stopping treatment. Therefore, ibuprofen should not be used during the first and second trimesters of pregnancy, except when absolutely necessary. If ibuprofen is used by a woman trying to conceive or during the first or second trimester of pregnancy, the lowest effective dose should be used for the shortest possible duration. Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after exposure to ibuprofen for several days starting from the 20th gestational week. Ibuprofen should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, use of any prostaglandin synthesis inhibitor may result in adverse effects on the fetus, such as cardiopulmonary toxicity (premature closure/constriction of the ductus arteriosus and pulmonary hypertension) and impaired renal function (see above). Ibuprofen is contraindicated during the third trimester of pregnancy due to the potential for inhibition of uterine contractility, which may lead to prolonged labor and increased bleeding time in both mother and child, even with very low doses.

In limited studies, ibuprofen has been detected in breast milk at very low concentrations. It is unlikely that ibuprofen has a negative effect on breastfed infants.

Ability to influence reaction speed when driving or operating machinery

No effect is expected at recommended doses and duration of therapy. Patients who experience dizziness, drowsiness, disorientation, or visual disturbances while taking NSAIDs should refrain from driving or operating machinery.

Dosage and Administration

For oral use only, for short-term use.

To relieve symptoms with short-term use, the lowest effective dose should be used (see section "Special Warnings and Precautions for Use"). If symptoms persist for more than 3 days from the start of treatment, the patient should consult a physician.

Adults, elderly patients, and children aged 12 to 18 years

Recommended single dose: 1 tablet. Administer orally with water, up to 3 times daily (if necessary). Repeated doses may be taken every 4 hours. Do not exceed 3 tablets (1200 mg) within 24 hours.

Elderly patients

No special dose adjustment is required.

Children

Not recommended for children under 12 years of age.

Overdose

In adults, dose-dependent effects are less pronounced than in children, in whom doses exceeding 400 mg/kg may cause symptoms of overdose. The half-life of ibuprofen in overdose is 1.5–3 hours.

Symptoms

In most patients, administration of clinically justified high doses of NSAIDs may cause nausea, vomiting, epigastric pain, and very rarely, diarrhea. Tinnitus, headache, and gastrointestinal bleeding may also occur.

NSAID poisoning may lead to toxic effects on the central nervous system, such as drowsiness, sometimes excitement, disorientation, or coma. Seizures may occasionally occur. In severe NSAID poisoning, metabolic acidosis may develop, and prothrombin time/international normalized ratio (INR) may be prolonged, possibly due to effects on blood coagulation factors. Acute renal failure and hepatic injury may also be observed. In patients with a history of bronchial asthma, disease exacerbation is possible.

Treatment

Symptomatic and supportive therapy should be administered, including maintenance of airway patency and monitoring of cardiovascular parameters and vital functions until the patient's condition stabilizes.

Oral administration of activated charcoal is recommended within 1 hour after ingestion of a potentially toxic amount of the drug.

For frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered.

Bronchodilators should be used for the treatment of bronchial asthma.

Adverse reactions.

The following list of adverse reactions refers to those observed with the use of ibuprofen at over-the-counter doses, up to the maximum daily dose of 1200 mg for short-term treatment.

Additional adverse reactions may occur during long-term treatment of chronic conditions.

Within each group, adverse reactions are listed in decreasing order of severity according to frequency of occurrence.

Very common (≥1/10).
Common (≥1/100 to <1/10).
Uncommon (≥1/1000 to <1/100).
Rare (≥1/10,000 to <1/1000).
Very rare (<1/10,000).
Frequency not known (frequency cannot be estimated from available data).

The most commonly observed adverse reactions are gastrointestinal in nature. Adverse effects are predominantly dose-dependent; in particular, the risk of gastrointestinal bleeding increases with higher dosage ranges and longer duration of treatment.

Blood and lymphatic system disorders

Very rare: hematological disorders, including anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, which may occur during prolonged treatment, with initial symptoms such as fever, sore throat, superficial mucosal ulcers in the oral cavity, flu-like symptoms, severe exhaustion, unexplained bleeding, and bruising.

Immune system disorders

Uncommon: hypersensitivity reactions, including urticaria and pruritus.

Very rare: severe hypersensitivity reactions, including facial, tongue, and throat swelling, dyspnea, tachycardia, and hypotension (anaphylaxis, angioedema, anaphylactic shock).

Hypersensitivity reactions may include: non-specific allergic reactions and anaphylaxis, respiratory tract reactivity including asthma, asthma exacerbation, bronchospasm, and dyspnea, or various skin reactions including pruritus, urticaria, purpura, angioedema, and less frequently, exfoliative and bullous dermatoses, including toxic epidermal necrolysis and erythema multiforme.

Psychiatric disorders

Rare: psychiatric disorders, depression, insomnia, excitement, hallucinations, confusion.

Eye disorders

Frequency not known: visual disturbances, optic neuritis, photosensitivity reactions may occur during prolonged treatment.

Ear and labyrinth disorders

Rare: tinnitus and dizziness may occur during prolonged treatment.

Nervous system disorders

Uncommon: headache.

Rare: vertigo.

Very rare: aseptic meningitis. The pathogenesis of drug-induced aseptic meningitis is not fully understood. Available data on aseptic meningitis associated with NSAIDs suggest a hypersensitivity reaction (based on temporal association with drug intake and resolution of symptoms after drug discontinuation). Isolated cases of symptoms of aseptic meningitis (nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) have been observed in patients with autoimmune diseases (systemic lupus erythematosus and mixed connective tissue disease).

Frequency not known: paresthesia, somnolence.

Cardiac disorders

Frequency not known: edema and heart failure have been reported during treatment with NSAIDs. According to results from clinical trials and epidemiological data, the use of ibuprofen (especially at high doses – 2400 mg per day) and long-term treatment may increase the risk of cardiovascular thrombotic events (myocardial infarction and stroke), Kounis syndrome.

Vascular disorders

Frequency not known: arterial hypertension, arterial thrombosis (myocardial infarction or stroke).

Respiratory system disorders

Frequency not known: respiratory tract reactivity, including asthma, bronchospasm, and dyspnea.

Gastrointestinal disorders

Uncommon: abdominal pain, dyspepsia, nausea.

Rare: diarrhea, flatulence, constipation, vomiting.

Very rare: peptic ulcer, perforation, or gastrointestinal hemorrhage, melena, hematemesis, sometimes fatal, especially in elderly patients. Ulcerative stomatitis, gastritis, pancreatitis.

Frequency not known: exacerbation of colitis and Crohn’s disease.

Hepatobiliary disorders

Very rare: liver function abnormalities.

Frequency not known: hepatitis and jaundice may occur during prolonged treatment.

Skin and subcutaneous tissue disorders

Uncommon: various types of skin rashes.

Very rare: severe skin adverse reactions such as bullous reactions, including Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, and exfoliative dermatitis.

Frequency not known: photosensitivity, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Renal and urinary disorders

Very rare: acute renal failure, especially with prolonged use of NSAIDs, associated with increased serum urea levels and edema; also including papillary necrosis, hypernatremia (sodium retention), oliguria.

Frequency not known: renal failure, nephrotoxicity, including interstitial nephritis and nephrotic syndrome.

General disorders

Malaise and fatigue, irritability.

Investigations

Very rare: decreased hemoglobin levels.

Reporting of adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: http://aisf.dec.gov.ua.

Shelf life.

3 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 1 or 2 blisters in a cardboard box.

Prescription status.

Over-the-counter.

Manufacturer.

ALKALOID AD Skopje.

Manufacturer's address and place of business.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.

Blockmax rapid