KETONAL®

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

Composition:

Active ingredient: ketoprofen;

1 g of cream contains ketoprofen 50 mg;

Excipients: methylparaben (methyl p-hydroxybenzoate) (E 218), propylparaben (propyl p-hydroxybenzoate) (E 216), propylene glycol, isopropyl myristate, white soft paraffin, copolymer of polyethylene glycol 45 and lauryl glycol, glycerol sorbitan oleostearate, magnesium sulfate heptahydrate, purified water.

Pharmaceutical form. Cream.

Main physicochemical properties: homogeneous cream of white or almost white color.

Pharmacotherapeutic group.

Agents used locally for joint and muscle pain. Topical non-steroidal anti-inflammatory drugs. ATC code M02A A10.

Pharmacological properties.

Pharmacodynamics.

Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) exerting analgesic and anti-inflammatory effects. Ketoprofen inhibits the activity of cyclooxygenase-1 and cyclooxygenase-2, thereby reducing the synthesis of prostaglandins, which play a key role in the pathogenesis of inflammation and pain. The anti-inflammatory mechanism of action of ketoprofen is not fully understood. It reduces oxygen metabolism in neutrophils and the release of lysosomal enzymes, inhibits macrophage migration, and exhibits anti-bradykinin activity. These properties allow for a reduction in the second phase of the inflammatory response by decreasing the migration of macrophages and granulocytes into the synovial membrane and formation of cellular exudates.

Pharmacokinetics.

When applied topically, absorption of ketoprofen is minimal, resulting in a local effect and absence of systemic effects. The bioavailability of ketoprofen in the form of cream is approximately 5%. Plasma protein binding is 99%. The active substance is detected in synovial fluid at therapeutic concentrations; plasma concentrations are negligible.

After three applications of 70–80 mg ketoprofen in cream form to the knee surface, the maximum plasma concentration (0.0182 ± 0.118 μg/mL) is reached 6 hours after administration. Twelve hours after the last application of the cream to the knee skin, ketoprofen concentrations in joint tissues are as follows: adipose tissue – 4.7 ± 3.87 μg/g, joint capsule – 2.35 ± 2.41 μg/g, synovial fluid – 1.31 ± 0.89 μg/g.

Ketoprofen is metabolized in the liver to form conjugates, which are slowly excreted primarily in urine. The metabolism of ketoprofen is not altered in elderly patients or in those with severe renal impairment or hepatic cirrhosis.

Clinical characteristics.

Indications.

Post-traumatic pain in muscles and joints, tendon inflammation.

Contraindications.

Hypersensitivity to ketoprofen or to other excipients of the medicine, salicylates, or other nonsteroidal anti-inflammatory drugs (NSAIDs). Known hypersensitivity reactions, such as bronchial asthma, allergic rhinitis, or urticaria, following administration of ketoprofen, other NSAIDs, acetylsalicylic acid, fenofibrate, or tiaprofenic acid. Any history of photosensitization reactions. Skin manifestations of allergy previously observed during treatment with ketoprofen, other excipients of the medicine, fenofibrate, tiaprofenic acid, ultraviolet (UV) light blockers, or perfumed products. Exposure to sunlight (even on cloudy days), including indirect sunlight and UV irradiation in solariums, during the entire treatment period and for 2 weeks after discontinuation of the medicine. Exacerbation of gastric or duodenal ulcer; gastrointestinal bleeding in medical history; chronic dyspepsia (discomfort and pain in the upper abdomen); severe renal insufficiency. Skin damage, rashes, skin injuries, irritation, itching, skin infections, acne, burns. Pediatric age; third trimester of pregnancy; breastfeeding period. The cream must not be applied to damaged skin (eczema, dermatoses, open or infected wounds). Occlusive dressings must not be used.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of other topical medicinal products containing ketoprofen or other NSAIDs is not recommended, as this may enhance their effect as well as the adverse reactions they cause.

Despite the low degree of absorption of ketoprofen through the skin, its concomitant use with high doses of methotrexate is not recommended due to reduced methotrexate excretion, which significantly increases methotrexate toxicity. Ketoprofen may slightly inhibit the excretion of methotrexate and lithium salts and reduce the efficacy of certain diuretics, such as thiazides and furosemide.

Since plasma concentrations of the drug are extremely low, interactions with other medicines (as well as symptoms associated with systemic administration) are possible only with frequent and prolonged use:

• with methotrexate, cardiac glycosides, lithium salts, cyclosporine – increased toxicity due to reduced excretion;
• with anticoagulants, antithrombotic agents, acetylsalicylic acid or other NSAIDs, glucocorticoids, oral hypoglycemic agents, phenytoin – enhanced effect of the aforementioned agents;
• concomitant use of the medicine with other topical formulations (ointments, gels) containing ketoprofen or other NSAIDs is not recommended;
• with antihypertensive agents, diuretics, mifepristone – reduced efficacy of the aforementioned agents. An interval of 8 days must elapse between the end of mifepristone treatment and the initiation of ketoprofen therapy.

Concomitant use of acetylsalicylic acid and ketoprofen reduces the protein binding of ketoprofen in plasma.

Concomitant use of probenecid and ketoprofen leads to reduced plasma clearance of ketoprofen and decreased extent of its protein binding.

Monitoring is recommended for patients taking coumarins.

Special precautions for use.

The medicinal product is intended for topical use only. If the time for applying the cream has been missed, do not double the dose at the next application.

Although systemic adverse effects of ketoprofen with topical application are practically absent, the cream should be used with caution in patients with impaired renal, cardiac, or hepatic function, with a history of peptic ulcer, intestinal inflammation, cerebrovascular hemorrhage, or hemorrhagic diathesis. Isolated cases of systemic adverse reactions related to renal impairment have been reported.

Do not apply the cream to mucous membranes, the anal or genital area, large areas of skin, under occlusive dressings, or to the skin around the eyes. Avoid contact of the cream with the eyes.

Do not apply on damaged skin areas (e.g., eczema, acne, infectious processes, or open wounds).

The cream should not be used simultaneously with other topical agents on the same skin areas. The recommended dose and duration of treatment should not be exceeded, as the risk of contact dermatitis and photosensitization reactions increases over time.

Areas of skin treated with the product must be protected from sunlight (including UV radiation in solariums) during treatment and for 2 weeks after its completion to minimize any risk of photosensitization. Skin areas where the cream is applied should be covered with clothing to protect from sunlight.

The product should be discontinued immediately if any skin reactions occur, including skin reactions following concomitant use with products containing octocrylene (used to prevent photodegradation in certain cosmetic and hygiene products such as shampoos, shaving gels, shower gels, creams, lipsticks, anti-aging creams, makeup removers, hair sprays, to which octocrylene is added).

Hands must be thoroughly washed after each application of the cream. If prolonged rubbing of the cream into the skin is required, surgical gloves should be used.

Topical application of large amounts of cream may provoke systemic effects, including bronchial asthma attacks and hypersensitivity reactions such as contact dermatitis, urticaria, and bronchospasm.

The cream contains methylparaben (E 218) and propylparaben (E 216), which may cause immediate-type hypersensitivity reactions (e.g., urticaria, bronchospasm) or delayed-type reactions (e.g., contact dermatitis). The cream contains propylene glycol, which may cause skin irritation.

Patients with bronchial asthma associated with chronic rhinitis, chronic sinusitis, and/or nasal polyps have a higher risk of developing aspirin and/or nonsteroidal anti-inflammatory drug (NSAID) allergy than the general population.

Use during pregnancy or breastfeeding.

There are no clinical data on the use of topical forms of Ketonal during pregnancy. Even though systemic exposure is lower compared to oral administration, it is unknown whether systemic exposure to Ketonal achieved after topical application could be harmful to the embryo/fetus. Ketonal should not be used during the first and second trimesters of pregnancy except in cases of extreme necessity. If used, the dose should be as low as possible and the duration of treatment as short as possible.

During the third trimester of pregnancy, systemic use of prostaglandin synthetase inhibitors, including Ketonal, may cause cardiopulmonary and renal toxicity in the fetus. Prolonged bleeding may occur in both mother and child near the end of pregnancy, and labor may be prolonged. Therefore, Ketonal is contraindicated during the last trimester of pregnancy (see section "Contraindications").

Ability to influence reaction rate when driving vehicles or operating machinery.

Data are lacking.

Method of Administration and Dosage

For external use only.

Apply the cream as a thin layer to the affected skin area twice daily and gently rub in. The amount of cream used depends on the size of the affected area. The product should generally be used for no more than 10 days. The cream may be used in combination with other dosage forms (capsules, tablets, suppositories). The total maximum daily dose must not exceed 200 mg of ketoprofen, regardless of the dosage form used.

The use of tight or occlusive dressings is not recommended. Hands should be washed after applying the cream, unless the hands themselves are the treated area.

Children

There is insufficient data available; therefore, the medicinal product is contraindicated in this patient group.

Overdose

Symptoms: irritation, erythema, itching, or worsening of other adverse reactions.

Since the amount of ketoprofen penetrating through the skin into the bloodstream is low, overdose is unlikely. Systemic adverse reactions may occur with prolonged use, application in high doses, or over large skin areas. If excessive amounts of cream have been applied, the skin should be washed with water.

In case of accidental oral ingestion, ketoprofen may cause drowsiness, dizziness, nausea, vomiting, and epigastric pain. These symptoms usually resolve with appropriate symptomatic treatment. High systemic doses of ketoprofen may lead to bradypnea, coma, convulsions, gastrointestinal bleeding, acute renal failure, and increased or decreased arterial blood pressure.

Treatment: There is no specific antidote. Symptomatic treatment and supportive care to maintain vital functions are recommended. Gastric lavage and administration of activated charcoal (the first dose should be given with sorbitol) are recommended, especially within the first 4 hours after overdose or if the ingested dose exceeds the recommended dose by 5–10 times.

Adverse Reactions

Adverse reactions are listed by frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be calculated from available data).

Immune system disorders: frequency not known – hypersensitivity reactions, anaphylactic reactions, including angioedema, and anaphylaxis, reported with systemic and topical use of ketoprofen.

Respiratory, thoracic and mediastinal disorders: frequency not known – bronchospasm, asthma attacks.

Skin and subcutaneous tissue disorders: uncommon – skin irritation, allergic skin reactions, hyperemia, pruritus, rash, burning sensation, swelling, erythema, eczema; rare – purpuric-like, bullous rash; increased sweating, urticaria, dermatitis (contact, exfoliative); photosensitivity, including severe skin reactions following sun exposure; frequency not known – vesicular, bullous and bullous-like eczema, which may spread and become generalized; purpura, erythema multiforme, lichenoid dermatitis, skin necrosis, Stevens-Johnson syndrome. There have been reports of local skin reactions extending beyond the application site, and of toxic epidermal necrolysis.

Gastrointestinal disorders: very rare – heartburn, peptic ulcer, gastrointestinal bleeding, nausea, vomiting, diarrhea or constipation (with prolonged use).

Renal and urinary disorders: very rare – a case of worsening renal function in a patient with chronic renal insufficiency after topical application of ketoprofen has been described. Interstitial nephritis has occurred in isolated cases.

Depending on the permeability of the active substance, the amount of cream applied, the size of the treated area, the integrity of the skin, the duration of use of the medicinal product, and the use of occlusive dressings, other adverse reactions such as hypersensitivity reactions, and adverse reactions affecting the gastrointestinal and urinary systems may occur. Elderly patients are more susceptible to adverse reactions when using nonsteroidal anti-inflammatory drugs.

Ketoprofen may provoke asthma attacks in patients with hypersensitivity to acetylsalicylic acid or its derivatives.

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach of children.

Packaging.

30 g of cream in a tube, 1 tube per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Solutas Pharma GmbH.

Manufacturer's address and place of business.

Production unit in Osterweddingen, Lange Herren 3, Sülzetal, OT Osterweddingen, Saxony-Anhalt, 39171, Germany.