Ultrafastin

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

Composition:

Active substance: ketoprofen;

1 tablet contains 100 mg of ketoprofen;

Excipients:

Tablet core: microcrystalline cellulose, colloidal anhydrous silicon dioxide, crospovidone, magnesium stearate;

Coating: hypromellose, lactose monohydrate, triacetin, titanium dioxide (E 171), macrogol 3000, quinoline yellow (E 104), yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pale-yellow, round, biconvex tablets.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and anti-rheumatic drugs. Propionic acid derivatives. Ketoprofen. ATC code M01AE03.

Pharmacological Properties

Pharmacodynamics

Ketoprofen, a derivative of phenylpropionic acid, belongs to the group of nonsteroidal drugs with anti-inflammatory and anti-rheumatic effects.

The mechanism of action is due to inhibition of cyclooxygenase, the enzyme responsible for prostaglandin synthesis. Ketoprofen is also a bradykinin antagonist. It inhibits leukotriene synthesis, reduces platelet aggregation, and affects lysosomal membranes.

In women, ketoprofen reduces symptoms of primary dysmenorrhea due to inhibition of prostaglandin synthesis.

Pharmacokinetics

Absorption. Ketoprofen is well absorbed from the gastrointestinal tract. Maximum plasma concentration is reached approximately 60–90 minutes after oral administration. The bioavailability of ketoprofen is 90% and is directly proportional to the administered dose. Food does not affect the bioavailability of the drug, but it reduces the rate of absorption and the maximum plasma concentration.

Distribution. Ketoprofen is 99% bound to plasma proteins, primarily to albumins. Ketoprofen penetrates into the synovial fluid and joint cavity: joint capsule, synovial membrane, and periartricular tissues. Ketoprofen penetrates into cerebrospinal fluid and crosses the placental barrier. After repeated administration, ketoprofen does not accumulate in the body. The concentration of ketoprofen in synovial fluid persists for up to 30 hours, thus providing prolonged reduction of pain and joint stiffness. A steady-state concentration of ketoprofen in plasma is achieved within 24 hours after administration of oral formulations.

Elimination. The elimination half-life of the drug from plasma is approximately 2 hours. Ketoprofen is metabolized in the liver primarily via conjugation with glucuronic acid and partially by hydroxylation. Ketoprofen and its metabolites are excreted predominantly in the urine.

Clinical characteristics.

Indications.

• Rheumatoid arthritis; seronegative spondyloarthritides (ankylosing spondylitis, psoriatic arthritis, reactive arthritis); gout, pseudogout; osteoarthritis; extra-articular rheumatism (tendinitis, bursitis, shoulder capsulitis);
• Pain syndrome of various etiologies, mild to moderate (lumbago; post-traumatic pain in joints, muscles);
• Algomenorrhea.

Contraindications.

• Hypersensitivity to ketoprofen or to any of the excipients;
• Contraindicated in patients in whom the use of ketoprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs (NSAIDs) induces bronchospasm, asthmatic attacks, urticaria, angioneurotic edema, acute rhinitis, or other allergic reactions;
• Active phase or relapse of peptic ulcer disease of the stomach and/or duodenum;
• History of gastrointestinal bleeding/perforation/ulcers, cerebrovascular or other bleeding;
• Patients prone to hemorrhage;
• Severe hepatic or renal insufficiency;
• Severe heart failure;
• Postoperative pain treatment following coronary artery bypass graft (CABG) surgery;
• Chronic dyspepsia in medical history.

Interaction with other medicinal products and other types of interactions.

Risk of hyperkalemia.

Some medicinal products, such as potassium salts, diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus, trimethoprim, may cause hyperkalemia.

The development of hyperkalemia may depend on the presence of additional factors. The risk of hyperkalemia increases when the above-mentioned medicinal products are used concomitantly.

Risk associated with the use of antiplatelet agents.

A number of medicinal products cause interactions due to their inhibitory effect on platelet aggregation. These include acetylsalicylic acid and nonsteroidal anti-inflammatory drugs, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, iloprost.

Concomitant use of antiplatelet agents increases the risk of bleeding, as does concomitant administration of heparin, oral anticoagulants, and thrombolytic agents. In such cases, clinical monitoring of the patient and laboratory tests are required.

It is not recommended to use ketoprofen concomitantly with:

• other nonsteroidal anti-inflammatory drugs and salicylates, including selective cyclooxygenase-2 (COX-2) inhibitors;
• oral anticoagulants and parenterally administered heparin;
• lithium;
• methotrexate (at doses exceeding 15 mg/week). Severe, sometimes fatal, toxicity has occurred after concomitant use of ketoprofen with methotrexate (mainly high doses). This toxicity is due to increased and prolonged plasma concentration of methotrexate;
• mifepristone, as its effect may be reduced. Nonsteroidal anti-rheumatic agents should be taken 8–12 days after mifepristone administration.

Use of ketoprofen concomitantly with the following requires caution:

• diuretics, ACE inhibitors, and angiotensin II receptor blockers, as the risk of renal impairment increases. Ketoprofen may reduce the effects of antihypertensive agents and diuretics. Diuretics may increase the risk of NSAID-induced nephrotoxicity;
• methotrexate (at doses less than 15 mg/week);
• sulfonamides, anticoagulants, hydantoins, as dose adjustments may be needed to prevent increased plasma levels of these drugs due to competition for plasma protein binding;
• anticoagulants, e.g., warfarin, due to potentiation of their effect;
• oral antidiabetic and antiepileptic agents (phenytoin), due to potentiation of their effect;
• cardiac glycosides due to possible exacerbation of heart failure, decreased glomerular filtration rate, and increased plasma levels of glycosides;
• pentoxifylline due to possible increased risk of bleeding. Monitoring of the coagulation system is required.

Particular attention should be paid when using ketoprofen concomitantly with:

• other medicinal products that inhibit platelet aggregation (ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, iloprost), due to increased risk of bleeding; other medicinal products that may cause hyperkalemia (potassium salts, ACE inhibitors, angiotensin II receptor blockers, other NSAIDs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus, trimethoprim), due to the risk of hyperkalemia;
• beta-adrenergic blocking agents, due to the risk of reduced efficacy of these drugs (due to inhibition of prostaglandin synthesis, ketoprofen reduces their antihypertensive effect);
• cyclosporine, due to increased risk of nephrotoxicity, especially in elderly patients;
• possible reduction in the effectiveness of intrauterine contraceptives;
• oral hypoglycemic agents, as the hypoglycemic effect of the latter may be enhanced;
• corticosteroids, due to increased risk of gastrointestinal bleeding;
• probenecid, as concomitant use may lead to a significant reduction in plasma clearance of ketoprofen.

Ketoprofen may reduce glomerular filtration rate and increase serum concentration of cardiac glycosides.

Aluminum-containing compounds with neutralizing action do not reduce the absorption of ketoprofen.

Special precautions for use.

Adverse reactions can be minimized by using the lowest effective dose required to control symptoms for the shortest possible duration (see section "Dosage and administration").

Concomitant use of ketoprofen with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Elderly patients: Absorption of ketoprofen is not altered, but the elimination half-life is prolonged (by 3 hours), and renal and plasma clearance are reduced. In elderly patients, the risk of adverse reactions increases, particularly gastrointestinal bleeding and perforations, which may be fatal (see section "Dosage and administration"). If NSAID therapy is necessary, the lowest effective dose should be used for as short a duration as possible. Regular monitoring for gastrointestinal bleeding should also be performed during NSAID therapy.

In patients with bronchial asthma, chronic rhinitis, chronic sinusitis, and/or nasal polyps, there is an increased risk of hypersensitivity to acetylsalicylic acid and other NSAIDs. Ketoprofen may provoke asthma attacks or bronchospasm in such individuals, especially in those with known hypersensitivity to acetylsalicylic acid and other NSAIDs.

In isolated cases, severe allergic reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported during NSAID use. The risk of such reactions is highest at the beginning of treatment (most cases occur within the first months of therapy). Ketoprofen must be discontinued at the first signs of skin rash, mucosal lesions, or other symptoms of hypersensitivity.

Ketoprofen use may cause gastrointestinal bleeding, peptic ulceration of the stomach and/or duodenum, or perforation, which may occur even in the absence of prodromal symptoms. Ketoprofen should be prescribed with caution in patients with a history of gastrointestinal disorders. The risk of gastrointestinal bleeding is higher in elderly patients, those predisposed to such bleeding, patients with low body weight, and individuals with impaired platelet function or those taking anticoagulants or antiplatelet agents. If gastrointestinal bleeding or symptoms of peptic ulcer disease occur, the drug should be discontinued immediately. In cases of mild gastrointestinal symptoms, agents that neutralize gastric acid or coat the gastric mucosa may be used. These patients should start treatment with the lowest possible dose. Concomitant therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) is recommended for such patients.

Masking symptoms of underlying infections: Ultrastin may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby worsening disease progression. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Ultrastin is used for fever or pain relief during infection, monitoring for infectious disease progression is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Ketoprofen should be prescribed with caution in patients with gastrointestinal disorders, with careful monitoring for conditions such as gastritis and/or duodenitis, ulcerative colitis, and Crohn's disease.

The drug should be used cautiously in patients with coagulation disorders, hemophilia, von Willebrand disease, severe thrombocytopenia, renal or hepatic impairment, and in individuals taking anticoagulants (coumarin derivatives and heparins, particularly low-molecular-weight heparins).

Careful monitoring of diuresis and renal function is required in patients with hepatic impairment, those receiving diuretics, and in patients with hypovolemia following major surgery, particularly in the elderly.

Ketoprofen should be used with caution in individuals with alcoholism.

The drug should be used cautiously in patients taking concomitant medications that may increase the risk of bleeding or ulceration, such as oral corticosteroids, anticoagulants (warfarin), selective serotonin reuptake inhibitors, and antiplatelet agents (acetylsalicylic acid).

Careful monitoring is also required in patients with a history of photosensitivity or phototoxicity during ketoprofen use. In elderly patients and individuals with heart failure, hepatic impairment, chronic renal insufficiency, or fluid imbalance (e.g., dehydration due to diuretic use, postoperative hypovolemia), ketoprofen may impair renal function due to inhibition of prostaglandin synthesis.

During the initial treatment period in such patients, urine output and other renal function parameters should be closely monitored. Impaired renal function may lead to edema and increased serum non-protein nitrogen levels.

In patients with heart failure, particularly in the elderly, fluid and sodium retention may exacerbate adverse reactions. Cardiac and renal function should be monitored in these patients.

Appropriate monitoring and medical advice are required for patients with a history of arterial hypertension and mild to moderate heart failure, as fluid retention and edema have been reported with NSAID use.

Evidence suggests that the use of certain NSAIDs (particularly at high doses and long-term) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction, stroke).

Ketoprofen may be used in patients with uncontrolled arterial hypertension, chronic heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only with careful monitoring. Patients with risk factors such as hyperlipidemia, diabetes, or smoking should undergo thorough evaluation before initiating long-term treatment.

Patients with hepatic impairment require close monitoring (periodic assessment of transaminase activity) and individual dose adjustment.

Ketoprofen should be prescribed with particular caution in elderly patients, especially those with hepatic or renal impairment; such patients require dose reduction. During prolonged ketoprofen therapy, blood morphology, liver, and kidney function should be monitored.

Patients with hepatic dysfunction or a history of liver disease (hepatitis, jaundice) should undergo liver function monitoring, periodic transaminase measurements, and individual dose adjustment, especially during long-term treatment.

During prolonged ketoprofen therapy, particularly in elderly patients, blood counts, as well as liver and kidney function, should be monitored. Dose adjustment of ketoprofen is required when creatinine clearance is below 0.33 mL/s (20 mL/min).

The drug should be discontinued prior to major surgical procedures.

Ketoprofen may adversely affect female fertility; therefore, it should not be used in women planning pregnancy. Women experiencing infertility or undergoing fertility investigations should discontinue ketoprofen.

Administration of the drug at the lowest effective dose for the shortest duration necessary to relieve symptoms reduces the risk of adverse effects and minimizes impact on the gastrointestinal tract and cardiovascular system.

Patients with systemic lupus erythematosus and systemic connective tissue diseases have an increased risk of developing aseptic meningitis.

The product contains lactose and therefore should not be administered to patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Patients with renal impairment: Renal and plasma clearance are reduced, and elimination half-life is prolonged proportionally to the severity of renal insufficiency.

Patients with hepatic insufficiency: Plasma clearance and elimination half-life are unchanged; however, the amount of unbound drug increases almost twofold.

Use during pregnancy or breastfeeding.

During the first and second trimesters of pregnancy, the drug may be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus, using the lowest effective dose for the shortest possible duration. Like other NSAIDs, the drug is contraindicated in the third trimester of pregnancy (due to possible inhibition of uterine contractility and premature closure of the fetal ductus arteriosus).

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and/or congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%.

The risk may increase with higher doses and longer duration of treatment. From the 20th week of pregnancy, use of Ultrastin tablets may cause oligohydramnios due to fetal renal dysfunction. Renal impairment may occur shortly after treatment initiation and is usually reversible upon discontinuation of ibuprofen. Additionally, narrowing of the ductus arteriosus has been reported after second-trimester treatment, which resolved after treatment cessation.

Antenatal monitoring for oligohydramnios and ductus arteriosus narrowing may be advisable after several days of ibuprofen use starting from the 20th week of pregnancy. Ketoprofen should be discontinued if signs of oligohydramnios or ductus arteriosus narrowing are detected.

Animal studies have shown that administration of prostaglandin synthesis inhibitors leads to increased pre- and post-implantation loss and embryonic/fetal mortality.

Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular malformations, has been observed. If the drug is used in women attempting to conceive or during the first trimester of pregnancy, the dose should be as low as possible and treatment duration as short as possible.

Use of ketoprofen during the third trimester of pregnancy and during breastfeeding is contraindicated.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus as follows:

• Cardio-pulmonary toxicity (with premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• Renal dysfunction, which may progress to renal failure with oligohydramnios (see above).

Effects on the mother and newborn, particularly at the end of pregnancy:

• Possible prolongation of bleeding time, anti-aggregatory effect, which may occur even at very low doses;
• Inhibition of uterine contractions, leading to delayed or prolonged labor.

There are no data on the excretion of ketoprofen in breast milk; therefore, ketoprofen is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Until individual response to the drug is established (possible visual disturbances, dizziness, drowsiness, or other central nervous system effects), caution is recommended when driving or operating machinery.

Dosage and Administration

Dosage should be individually adjusted depending on the patient's condition and response to treatment.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section "Special Warnings and Precautions for Use").

The recommended dose for adults is 1 tablet twice daily.

The recommended dose for the treatment of rheumatoid arthritis and osteoarthritis is 1 tablet twice daily.

The recommended dose for mild to moderate pain and dysmenorrhea is 1 tablet once daily.

The duration of treatment depends on the severity and course of the disease; however, adverse reactions may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

The maximum daily dose of ketoprofen is 200 mg. Before prescribing the maximum daily dose of 200 mg, the risk/benefit ratio should be carefully considered. Higher doses are not recommended.

Tablets should be taken during meals with water. Tablets should be swallowed whole, without chewing.

To prevent the negative effects of ketoprofen on the gastrointestinal mucosa, antacid agents may be taken concomitantly.

Use in elderly patients.

In elderly patients, the risk of adverse reactions increases. If NSAID therapy is necessary, the lowest effective dose should be used for the shortest possible duration. During NSAID therapy, regular monitoring for signs and symptoms of gastrointestinal bleeding is recommended.

Children.

The safety of ketoprofen use in children has not been established; therefore, the drug should not be administered to children.

Overdose.

Symptoms. In cases of ketoprofen overdose, the following symptoms have been observed: headache, drowsiness, nausea, vomiting, diarrhea, abdominal pain, reduced renal function, and renal impairment. In cases of significant overdose: arterial hypotension or arterial hypertension, dyspnea, respiratory depression, impaired consciousness, gastrointestinal bleeding; rarely – coma, convulsions, acute renal failure.

Treatment. In case of overdose, administration of the drug should be immediately discontinued. If less than 1 hour has passed since the overdose, gastric lavage should be performed and activated charcoal administered at a dose of 60–100 g for adults and 1–2 g/kg body weight for children. Symptomatic treatment aimed at supporting vital functions should be initiated. Forced diuresis may be indicated. In case of renal failure, hemodialysis may be used to remove the drug from the body. H2-receptor antagonists, proton pump inhibitors, and prostaglandins may help alleviate the harmful gastrointestinal effects of ketoprofen. There is no specific antidote.

Side effects.

Classification of adverse effects by organ systems 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), including isolated reports.

Adverse effects are usually transient. Gastrointestinal disorders occur most frequently.

Gastrointestinal system: very common – dyspepsia; common – nausea, vomiting, diarrhea, constipation, abdominal pain, flatulence, anorexia, stomatitis; rarely observed – gastritis; very rare – colitis, intestinal perforation (as a complication of diverticulosis), melena, hematemesis, exacerbation of ulcerative colitis or Crohn's disease, enteropathy with perforation, stenosis. Peptic ulcers, perforation, or gastrointestinal bleeding may occur.

Enteropathy may be associated with mild bleeding and protein loss.

There have been reports of a case of rectal perforation in an elderly woman.

Ulceration, hemorrhage, or perforation may develop in 1% of patients within 3–6 months of treatment or in 2–4% of patients after 1 year of treatment with NSAIDs.

Blood system: uncommon – hemorrhagic anemia, hemolysis, purpura, thrombocytopenia, agranulocytosis, bone marrow failure. High doses of ketoprofen may inhibit platelet aggregation, thereby prolonging bleeding time, and may cause epistaxis and hematoma formation.

Immune system: exacerbation of asthma, bronchospasm, or dyspnea (especially in patients with hypersensitivity to acetylsalicylic acid and other NSAIDs); very rare – angioneurotic edema and anaphylaxis, hypersensitivity, anaphylactic reaction, including shock. Isolated cases of aseptic meningitis with symptoms such as nuchal rigidity, headache, nausea, vomiting, fever, or disorientation have been observed in patients with pre-existing autoimmune disorders (systemic lupus erythematosus, connective tissue diseases).

Psychiatric disorders: common – depression, nervousness, nightmares, somnolence; rare – delirium with visual and auditory hallucinations, disorientation, speech disturbances.

Nervous system: common – headache, asthenia, discomfort, fatigue, weakness, dizziness, paresthesia, mood changes, weight gain; rare – dysgeusia; very rare – isolated reports of cases of pseudotumor cerebri; uncommon – seizures.

Eye disorders: common – visual disturbances; very rare – conjunctivitis.

Ear disorders: common – tinnitus.

Cardiovascular system: common – edema; uncommon – heart failure, arterial hypertension, vasodilation.

Clinical studies and epidemiological data confirm that the use of certain NSAIDs (particularly at high doses and with long-term use) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction, stroke). Data on ketoprofen are insufficient to exclude such a risk.

Respiratory system: uncommon – hemoptysis, dyspnea, pharyngitis, rhinitis, bronchospasm, laryngeal edema (signs of anaphylactic reaction); rare – asthma attacks.

Hepatobiliary system: very rare – severe liver function disorders associated with jaundice and hepatitis, abnormal renal function tests.

Skin and subcutaneous tissue: common – skin rashes; uncommon – alopecia, eczema, purpura-like rashes, hyperhidrosis, urticaria, exfoliative dermatitis, pruritus; rare – photosensitivity, photoallergic dermatitis; very rare – bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Urinary system: very rare – acute renal failure, interstitial nephritis, nephrotic syndrome, acute pyelonephritis; frequency unknown – abnormalities in renal function tests.

Reproductive system: uncommon – menometrorrhagia.

Laboratory findings: very common – deviations from normal levels of liver transaminases, increased serum transaminase and bilirubin levels associated with diabetes-related disorders; uncommon – significant increases in ALT and AST levels during NSAID treatment.

Ketoprofen reduces platelet aggregation, thereby prolonging bleeding time.

Shelf life.

3 years.

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

Storage conditions.

Store in a dry, light-protected place at a temperature not exceeding 25°C.

Keep out of the reach of children.

Packaging.

10 tablets in a blister pack.

10 (1 blister), 20 (2 blisters), or 20 (1 blister) in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Pharmaceutical Factory "POLFArma" S.A.

Manufacturer's address and place of business.

Production unit in Nowa Dęba, ul. Metalowca 2, 39-460 Nowa Dęba, Poland.