Arketal Rompharm (Solution) Instructions for Use

Marketing Authorization Holder

S.C. Rompharm Company S.R.L. (Romania)

ATC Code

M01AE03 (Ketoprofen)

Active Substance

Ketoprofen (Rec.INN registered by WHO)

Dosage Form

Arketal Rompharm

Solution for infusion and intramuscular administration 50 mg/1 ml: amp. 2 ml 10 pcs.

Dosage Form, Packaging, and Composition

Solution for infusion and intramuscular administration transparent, colorless or pale yellow.

Excipients: ethanol 96% – 100 mg, propylene glycol – 400 mg, benzyl alcohol – 20 mg, sodium hydroxide – 8.5 mg, sodium hydroxide solution 10% or hydrochloric acid – to pH 7.2±0.2, water for injection – to 1 ml.

2 ml – dark glass ampoules (5) – blister packs (2) – cardboard cartons.

Clinical-Pharmacological Group

NSAID

Pharmacotherapeutic Group

NSAID

Pharmacological Action

NSAID. It has anti-inflammatory, analgesic, and antipyretic effects. Ketoprofen blocks the action of the enzyme COX-1 and COX-2 and, partially, lipoxygenase, which leads to suppression of prostaglandin synthesis (including in the CNS, most likely in the hypothalamus).

It stabilizes lysosomal membranes in vitro and in vivo, and at high concentrations in vitro, it suppresses the synthesis of bradykinin and leukotrienes. Ketoprofen does not have a negative effect on the condition of the articular cartilage.

Pharmacokinetics

With intravenous administration of ketoprofen, the average plasma concentration 5 minutes after the start of infusion and up to 4 minutes after its cessation is 26.4±5.4 µg/ml. Bioavailability is 90%.

With a single intramuscular injection at a dose of 100 mg, Ketoprofen is detected in blood plasma 15 minutes after the start of the injection, and C_max (1.3 µg/ml) is reached after 2 hours. Bioavailability increases linearly with increasing dose.

The plasma clearance of ketoprofen is approximately 0.08 l/kg/h.

The binding of ketoprofen to plasma proteins is 99%, mainly to the albumin fraction. V_d is 0.1 l/kg. Ketoprofen penetrates into the synovial fluid. With intravenous administration of 100 mg, after 3 hours its concentration reaches 1.5 µg/ml, which is 50% of the concentration in blood plasma (about 3 µg/ml). After 9 hours, the concentration in the synovial fluid is 0.8 µg/ml, and in blood plasma – 0.3 µg/ml, which means that Ketoprofen penetrates into the synovial fluid more slowly and is eliminated from it more slowly. After a single intramuscular injection of 100 mg of ketoprofen, it is detected in the cerebrospinal fluid, as well as in the blood serum, after 15 minutes.

Ketoprofen undergoes intensive metabolism under the action of liver microsomal enzymes. T_1/2 is less than 2 hours. Ketoprofen binds to glucuronic acid and is excreted from the body as a glucuronide. There are no active metabolites of ketoprofen. Up to 80% of ketoprofen is excreted by the kidneys within 24 hours, mainly in the form of ketoprofen glucuronide.

Indications

Symptomatic therapy of pain syndrome, including in inflammatory processes of various origins: rheumatoid arthritis; seronegative arthritis: ankylosing spondylitis (Bekhterev’s disease), psoriatic arthritis, reactive arthritis (Reiter’s syndrome); gout, pseudogout; degenerative diseases of the musculoskeletal system, including osteoarthritis; mild, moderate, and severe pain syndrome in headache, migraine, tendinitis, bursitis, myalgia, neuralgia, radiculitis; post-traumatic and postoperative pain syndrome, including accompanied by inflammation and fever; pain syndrome in oncological diseases; algodysmenorrhea.

ICD codes

Dosage Regimen

Administer Arketal Rompharm by intravenous infusion or intramuscular injection.

Set the dosage regimen individually based on the severity of pain and the patient’s clinical condition.

The single dose is 100 mg to 200 mg.

Do not exceed the maximum daily dose of 200 mg.

For intramuscular administration, inject deeply into the gluteal muscle.

For intravenous administration, administer as a short-term infusion.

Dilute the required dose in 100-500 ml of 0.9% sodium chloride solution or 5% glucose solution.

Infuse over a period of 30 minutes to 8 hours, depending on the total volume.

Use the lowest effective dose for the shortest possible duration to control symptoms.

Re-evaluate the need for continued parenteral therapy regularly.

Monitor patients for signs of gastrointestinal bleeding or renal impairment, especially with prolonged use.

Adjust the dose or discontinue treatment if adverse reactions occur.

Combine parenteral administration with other ketoprofen dosage forms (tablets, suppositories) if necessary.

Avoid concomitant use with other NSAIDs.

Adverse Reactions

From the hematopoietic system rarely – hemorrhagic anemia, hemolytic anemia, leukopenia; frequency unknown – agranulocytosis, thrombocytopenia, bone marrow dysfunction.

From the immune system frequency unknown – anaphylactic reactions (including anaphylactic shock).

From the nervous system often – insomnia, depression, asthenia; infrequently – headache, dizziness, drowsiness; rarely – paresthesia, confusion or loss of consciousness, peripheral polyneuropathy; frequency unknown – convulsions, taste disturbance, emotional lability.

From the sensory organs rarely – blurred vision, tinnitus, conjunctivitis, dryness of the eye mucosa, eye pain, hearing loss; frequency unknown – optic neuritis.

From the cardiovascular system infrequently – tachycardia; frequency unknown – heart failure, increased blood pressure, vasodilation.

From the respiratory system rarely – exacerbation of bronchial asthma, nosebleeds, laryngeal edema; frequency unknown – bronchospasm (especially in patients with hypersensitivity to NSAIDs), rhinitis.

From the digestive system often – nausea, vomiting, dyspepsia, abdominal pain, NSAID-gastropathy; infrequently – constipation, diarrhea, flatulence, gastritis; rarely – peptic ulcer, stomatitis; very rarely – exacerbation of ulcerative colitis or Crohn’s disease, gingival, gastrointestinal, hemorrhoidal bleeding, melena, perforation of gastrointestinal organs; frequency unknown – gastrointestinal discomfort, stomach pain.

From the liver and biliary tract rarely – hepatitis, increased activity of liver enzymes in the blood, increased concentration of bilirubin in the blood.

From the urinary system rarely – cystitis, urethritis, hematuria; very rarely – acute renal failure, interstitial nephritis, nephrotic syndrome, abnormal values of kidney function indicators.

From the skin and subcutaneous tissues infrequently – skin rash, skin itching; frequency unknown – photosensitivity, alopecia, urticaria, exacerbation of chronic urticaria, angioedema, erythema, bullous rash, including Stevens-Johnson syndrome, toxic epidermal necrolysis, purpura.

Other infrequently – peripheral edema, fatigue; rarely – hemoptysis, menometrorrhagia, shortness of breath, thirst, muscle twitching.

Contraindications

Hypersensitivity to ketoprofen, as well as to salicylates or other NSAIDs; complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance to acetylsalicylic acid or other NSAIDs (including in history); peptic ulcer of the stomach or duodenum in the acute phase; ulcerative colitis, Crohn’s disease; hemophilia and other bleeding disorders; severe hepatic failure; severe renal failure (creatinine clearance less than 30 ml/min), confirmed hyperkalemia, progressive kidney diseases; decompensated heart failure; postoperative period after coronary artery bypass surgery; gastrointestinal, cerebrovascular and other bleedings (or suspicion of bleeding); chronic dyspepsia; third trimester of pregnancy; breastfeeding period; children and adolescents under 15 years of age.

With caution

History of peptic ulcer, presence of Helicobacter pylori infection; history of bronchial asthma; clinically significant cardiovascular, cerebrovascular diseases and peripheral artery diseases; dyslipidemia; moderate hepatic failure, hyperbilirubinemia, alcoholic cirrhosis of the liver; chronic renal failure (creatinine clearance 30-60 ml/min); chronic heart failure (NYHA class II-IV); arterial hypertension; blood diseases; dehydration; diabetes mellitus; smoking; elderly age; long-term use of NSAIDs, simultaneous use of anticoagulants (including warfarin), antiplatelet agents (including clopidogrel), oral corticosteroids (including prednisolone), selective serotonin reuptake inhibitors (including fluoxetine, paroxetine, citalopram, sertraline).

Use in Pregnancy and Lactation

Contraindicated in the third trimester of pregnancy. Use in the first and second trimesters of pregnancy is possible only if the expected benefit of therapy for the mother outweighs the existing risk to the fetus. In such a case, Ketoprofen should be used at the minimum effective dose for the shortest possible course.

Contraindicated during breastfeeding.

The use of ketoprofen may affect female fertility, so it is not recommended for use in patients with infertility (including those undergoing examination).

Use in Hepatic Impairment

Contraindicated in severe hepatic failure.

Should be prescribed with caution in hepatic insufficiency, hyperbilirubinemia, alcoholic cirrhosis of the liver.

Use in Renal Impairment

Contraindicated in severe renal failure (creatinine clearance less than 30 ml/min), confirmed hyperkalemia, progressive kidney diseases.

Should be used with caution in chronic renal failure (creatinine clearance 30-60 ml/min).

Pediatric Use

Contraindicated for use in children and adolescents under 15 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

With long-term use of NSAIDs, it is necessary to periodically evaluate the complete blood count, as well as monitor kidney and liver function, especially in elderly patients (over 65 years of age), and perform a fecal occult blood test. It is necessary to exercise caution and monitor blood pressure more frequently when using ketoprofen to treat patients with arterial hypertension, cardiovascular diseases that lead to fluid retention in the body.

If visual disturbances occur, treatment should be stopped immediately.

Like other NSAIDs, Ketoprofen may mask the symptoms of infectious and inflammatory diseases. If signs of infection are detected or if the condition worsens during the use of the drug, the patient should immediately consult a doctor.

If there is a history of gastrointestinal contraindications (bleeding, perforation, peptic ulcer), in the case of long-term therapy and the use of ketoprofen in high doses, the patient should be under close medical supervision.

Due to the important role of prostaglandins in maintaining renal blood flow, special caution should be exercised when using ketoprofen in patients with heart or renal failure, as well as when treating elderly patients taking diuretics, and patients who, for any reason, have a reduced circulating blood volume (for example, after surgery).

Parenteral administration of ketoprofen can be combined with the use of other dosage forms of ketoprofen (tablets, capsules, rectal suppositories).

Effect on ability to drive vehicles and operate machinery

During treatment, drowsiness, dizziness, and other adverse reactions from the nervous system, including visual impairment, may occur. When using ketoprofen, patients should exercise caution when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

Concomitant use of ketoprofen with other NSAIDs (including selective COX-2 inhibitors and salicylates in high doses) is not recommended due to an increased risk of gastrointestinal bleeding and ulceration of the gastrointestinal mucosa.

Simultaneous use with anticoagulants (heparin, warfarin), antiplatelet agents (ticlopidine, clopidogrel) increases the risk of bleeding. If the use of such a combination is unavoidable, the patient’s condition should be carefully monitored.

With simultaneous use with lithium preparations, an increase in the concentration of lithium in the blood plasma up to toxic values is possible. The concentration of lithium in the blood plasma should be carefully monitored and the dose of lithium preparations should be adjusted in a timely manner during and after the use of NSAIDs.

Ketoprofen increases the hematological toxicity of methotrexate, especially when it is used in high doses (more than 15 mg/week). The time interval between the cessation or initiation of ketoprofen therapy and the intake of methotrexate should be at least 12 hours.

Against the background of ketoprofen therapy, patients taking diuretics, especially with the development of dehydration, have a higher risk of developing renal failure due to a decrease in renal blood flow caused by inhibition of prostaglandin synthesis. Before starting the use of ketoprofen in such patients, rehydration measures should be carried out. After the start of treatment, kidney function should be monitored.

Concomitant use of ketoprofen with ACE inhibitors and angiotensin II receptor antagonists (ARA II) in patients with impaired renal function (with dehydration, in elderly patients) may lead to worsening of renal function impairment, including the development of acute renal failure.

During the first weeks of simultaneous use of ketoprofen and methotrexate at a dose not exceeding 15 mg/week, a blood test should be monitored weekly. In elderly patients or if any signs of impaired renal function occur, the study should be performed more often.

Ketoprofen may weaken the hypotensive effect of antihypertensive drugs (beta-blockers, ACE inhibitors, diuretics).

Simultaneous use of ketoprofen with selective serotonin reuptake inhibitors (SSRIs) increases the risk of gastrointestinal bleeding.

Simultaneous use with thrombolytics increases the risk of bleeding.

Simultaneous use of ketoprofen with potassium salts, potassium-sparing diuretics, ACE inhibitors, ARA II, NSAIDs, low molecular weight heparins, cyclosporine, tacrolimus and trimethoprim increases the risk of hyperkalemia.

With simultaneous use with cyclosporine, tacrolimus, there is a risk of developing an additive nephrotoxic effect, especially in elderly patients.

Simultaneous use of several antiplatelet drugs (tirofiban, eptifibatide, abciximab, iloprost) increases the risk of bleeding.

Ketoprofen increases the plasma concentration of cardiac glycosides, slow calcium channel blockers, cyclosporine, methotrexate and digoxin.

Concomitant use of ketoprofen with corticosteroids, ethanol increases the risk of adverse reactions from the gastrointestinal tract.

Ketoprofen may enhance the effect of oral hypoglycemic and some anticonvulsant drugs (phenytoin).

Simultaneous use with probenecid significantly reduces the plasma clearance of ketoprofen.

NSAIDs may reduce the effectiveness of mifepristone. NSAIDs should be started no earlier than 8-12 days after discontinuation of mifepristone.

Ketoprofen is pharmaceutically incompatible with tramadol solution due to precipitation.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.