Alfort stick

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALFORT STICK

Composition:

Active substance: dexketoprofen;

1 sachet (10 ml) contains 36.90 mg of dexketoprofen trometamol, equivalent to 25 mg of dexketoprofen;

Excipients: sucrose; macrogol 400; methyl 4-hydroxybenzoate (E 218); neohesperidin dihydrochalcone (E 959); ammonium glycyrrhizinate; sodium saccharin; povidone; sodium dihydrogen phosphate dihydrate; disodium hydrogen phosphate anhydrous; natural lemon flavor (containing 69% ethanol, 31% lemon essential oil); purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear yellowish solution with a citrus odor.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. Dexketoprofen. ATC code M01AE17.

Pharmacological properties.

Pharmacodynamics.

Dexketoprofen trometamol is the tromethamine salt of (S)-(+)-2-(3-benzoylphenyl) propionic acid. It is an analgesic, anti-inflammatory, and antipyretic medicinal product belonging to the group of non-steroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

The mechanism of action of NSAIDs involves reduction of prostaglandin synthesis by inhibition of cyclooxygenase activity. Specifically, NSAIDs inhibit the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2, which form prostaglandins PGE1, PGE2, PGF2α, and PGD2, as well as prostacyclin PGI2 and thromboxanes TxA2 and TxB2. In addition, inhibition of prostaglandin synthesis may affect other mediators of inflammation, such as kinins, providing not only direct but also indirect effects.

Pharmacodynamic effects

In animal studies and human trials, dexketoprofen has demonstrated inhibition of both cyclooxygenase-1 and cyclooxygenase-2 activity.

Clinical efficacy and safety

Clinical studies conducted in various pain models have shown that dexketoprofen trometamol exerts a pronounced analgesic effect. In some studies, the analgesic effect began within 30 minutes after administration. The duration of analgesia lasts 4–6 hours.

Pharmacokinetics.

Absorption

Dexketoprofen is rapidly absorbed after oral administration. Following administration of the oral solution, maximum plasma concentration (Cmax) is reached within 15 minutes (range – 10–40 minutes).

A comparison of 25 mg tablets and oral solution of dexketoprofen showed that these two dosage forms are bioequivalent in terms of bioavailability (AUC). Cmax after administration of the solution was approximately 20% higher than after administration of tablets.

When the drug is taken with food, the area under the plasma concentration-time curve (AUC) remains unchanged, but the Cmax of dexketoprofen is reduced and the rate of absorption is decreased (increased time to reach maximum concentration (tmax)).

Distribution

The distribution half-life and elimination half-life of dexketoprofen are 0.35 and 1.65 hours, respectively. Similar to other drugs with a high degree of plasma protein binding (99%), the volume of distribution of dexketoprofen averages less than 0.25 L/kg. Multiple-dose pharmacokinetic studies have shown that AUC after the last dose does not differ from values after single administration, indicating absence of drug accumulation.

Biotransformation

After administration of dexketoprofen, only the S-(+) enantiomer is detected in urine, indicating absence of transformation of the drug into the R-(-) optical isomer in the human body.

Excretion

Excretion of dexketoprofen occurs mainly via conjugation with glucuronic acid followed by renal excretion.

Clinical characteristics.

Indications.

Alfort Stick is indicated in adults for short-term symptomatic treatment of mild to moderate acute pain, such as acute musculoskeletal pain, painful menstruation (dysmenorrhea), and toothache.

Contraindications.

• Hypersensitivity to the active substance, to any other NSAID, or to any excipient of the medicinal product.
• Use in patients in whom substances with a similar mechanism of action, such as acetylsalicylic acid and other NSAIDs, induce attacks of bronchial asthma, bronchospasm, acute rhinitis, or lead to the development of nasal polyps, urticaria, or angioedema.
• Known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates.
• Bleeding or perforation in the gastrointestinal tract in medical history associated with the use of NSAIDs.
• Active phase of peptic ulcer/gastrointestinal bleeding or history of peptic ulcer, gastrointestinal bleeding, or perforation.
• Chronic dyspepsia in medical history.
• Other active bleeding or coagulation disorders.
• Crohn’s disease or ulcerative colitis.
• Severe heart failure.
• Moderate to severe renal impairment (creatinine clearance ≤59 ml/min).
• Severe hepatic impairment (Child-Pugh score 10–15 points).
• Hemorrhagic diathesis or other disorders of blood coagulation.
• Severe dehydration (as a result of vomiting, diarrhea, or insufficient fluid intake).
• Third trimester of pregnancy and breastfeeding period (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions.

Interactions typical for the class of NSAIDs

Not recommended combinations:

Other NSAIDs (including selective cyclooxygenase-2 inhibitors) and high-dose salicylates (more than 3 g/day). Concurrent use of multiple NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to synergistic effects.

Anticoagulants. NSAIDs may enhance the effects of anticoagulants, such as warfarin, due to the high degree of plasma protein binding of dexketoprofen, inhibition of platelet function, and damage to the gastric and duodenal mucosa. If this combination cannot be avoided, careful clinical monitoring of the patient and appropriate laboratory tests are required.

Heparins. Increased risk of bleeding (due to inhibition of platelet function and damage to the gastric and duodenal mucosa). If this combination cannot be avoided, careful clinical monitoring of the patient and appropriate laboratory tests are required.

Corticosteroids. Increased risk of peptic ulcers and gastrointestinal bleeding.

Lithium preparations (reported with several NSAIDs). NSAIDs increase lithium blood levels to toxic values (due to reduced renal excretion). Therefore, lithium blood levels should be monitored at the start of dexketoprofen treatment, during dose adjustment, or upon discontinuation of the drug.

Methotrexate when administered in high doses (15 mg/week or more). Increased hematological toxicity of methotrexate due to reduced renal excretion, which is typical for all NSAIDs.

Hydantoin derivatives and sulfonamides. Possible increase in toxicity of these substances.

Combinations requiring caution:

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists (ARBs). Dexketoprofen may reduce the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of drugs that inhibit cyclooxygenase with ACE inhibitors, ARBs, or aminoglycoside antibiotics may lead to further deterioration of renal function, which is usually reversible. When using dexketoprofen concomitantly with any diuretic, ensure the patient is not dehydrated and monitor renal function at the beginning of therapy and regularly during treatment. Concomitant use of the drug with potassium-sparing diuretics may lead to hyperkalemia; therefore, potassium concentration in blood should be monitored.

Methotrexate when administered in low doses (less than 15 mg/week). Possible increase in hematological toxicity of methotrexate due to reduced renal excretion, which is typical for all anti-inflammatory drugs. During the first weeks of using this combination, a complete blood count should be performed weekly. Particular caution is required even with mild renal impairment and in elderly patients.

Pentoxifylline. Increased risk of bleeding. Close clinical observation and more frequent monitoring of bleeding time are required.

Zidovudine. Risk of increased toxic effect of zidovudine on erythropoiesis (due to toxic effects on reticulocytes), potentially leading to severe anemia one week after starting NSAID therapy. Therefore, an extended complete blood count with reticulocyte count should be performed within one to two weeks after initiating NSAID treatment.

Sulfonylurea derivatives. NSAIDs may enhance the hypoglycemic effect of sulfonylurea drugs by displacing them from plasma protein binding sites.

Combinations requiring attention:

Beta-blockers. NSAIDs may reduce their antihypertensive effect due to inhibition of prostaglandin synthesis.

Cyclosporine and tacrolimus. NSAIDs may enhance the nephrotoxicity of these drugs via indirect effects on renal prostaglandins. Renal function should be monitored regularly when using this combination.

Thrombolytic agents. Increased risk of bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding.

Probenecid. May increase dexketoprofen plasma concentration. This interaction may be due to inhibition of renal tubular secretion and glucuronidation of dexketoprofen; in such cases, the dose of dexketoprofen should be adjusted.

Cardiac glycosides. NSAIDs may increase plasma concentrations of cardiac glycosides.

Mifepristone. There is a theoretical risk that prostaglandin synthesis inhibitors may alter the effectiveness of mifepristone.

Limited data indicate that NSAID use on the day of prostaglandin administration does not alter the effects of mifepristone or prostaglandins on cervical ripening or uterine contractions and does not reduce the clinical efficacy of medical abortion.

Quinolone antibiotics. Animal studies have shown that high-dose quinolone use in combination with NSAIDs may increase the risk of seizures.

Tenofovir. Concomitant use with NSAIDs may increase blood urea nitrogen and creatinine levels; therefore, renal function should be monitored to control potential synergistic effects on renal function.

Deferasirox. Concomitant use with NSAIDs may increase gastrointestinal toxicity and requires careful clinical monitoring.

Pemetrexed. Concomitant use with NSAIDs may reduce pemetrexed elimination; therefore, caution should be exercised when administering higher NSAID doses. Patients with mild to moderate renal impairment (creatinine clearance 45–79 ml/min) should avoid NSAID use for 2 days before and 2 days after pemetrexed administration.

Special precautions for use.

The drug should be used with caution in patients with a history of allergic reactions.

Concomitant use of Alfort Stick with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms.

Gastrointestinal (GI) effects

Gastrointestinal bleeding, ulceration, or perforation (in some cases, fatal) have been reported during treatment with all NSAIDs at any stage of therapy, regardless of the presence of preceding symptoms or a history of serious GI disorders. If GI bleeding or ulceration occurs in patients receiving Alfort Stick, treatment should be discontinued.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation, and in elderly patients.

The incidence of adverse reactions in elderly patients is higher, and gastrointestinal bleeding and perforation may be fatal. Treatment of such patients should begin with the lowest possible dose.

As with all NSAIDs, a history of esophagitis, gastritis, and/or peptic ulcer should be considered, and such conditions should be fully resolved prior to initiating treatment with dexketoprofen. Patients with GI symptoms or a history of GI disorders should be monitored for GI complications, including gastrointestinal bleeding.

The drug should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn’s disease), as exacerbation may occur.

For such patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase GI risk, consideration should be given to using combination therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors).

Patients with a history of gastrointestinal toxicity, particularly elderly patients, should report any unusual abdominal symptoms (including episodes of gastrointestinal bleeding), especially during the initial stages of treatment.

Patients should be cautious when using other drugs that may increase the risk of ulcer formation or perforation (e.g., oral corticosteroids, anticoagulants (warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents such as acetylsalicylic acid).

Renal effects

The drug should be administered with caution in patients with impaired renal function. In such patients, NSAID use may lead to deterioration of renal function, fluid retention, and edema. Due to the increased risk of nephrotoxicity, the drug should also be used cautiously in patients receiving diuretics or those at risk of hypovolemia.

During treatment, adequate fluid intake should be maintained to prevent dehydration, which may exacerbate the drug’s nephrotoxic effects.

Like all NSAIDs, this drug may increase plasma urea and creatinine levels. Similar to other prostaglandin synthesis inhibitors, its use may be associated with renal adverse reactions, including glomerulonephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome, and acute renal failure.

Renal dysfunction occurs more frequently in elderly patients.

Hepatic effects

The drug should be administered with caution in patients with impaired liver function.

Similar to other NSAIDs, the drug may cause transient and minor elevations in some liver function tests, as well as significant increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. Therapy should be discontinued if such increases occur.

Liver dysfunction occurs more frequently in elderly patients.

Cardiovascular and cerebrovascular effects

Patients with a history of hypertension and/or mild to moderate heart failure require appropriate monitoring and medical advice. Particular caution is required when treating patients with a history of heart disease, especially those with prior episodes of heart failure, as fluid retention and edema have been reported after NSAID use.

Clinical trial data and epidemiological evidence suggest that the use of certain NSAIDs (particularly at high doses and during long-term therapy) may be associated with an increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Sufficient data to exclude such risk with dexketoprofen use are lacking.

Therefore, Alfort Stick should be initiated in patients with uncontrolled hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful assessment of the potential benefits and risks. Similarly, careful consideration should be given to initiating long-term therapy in patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking).

All non-selective NSAIDs may inhibit platelet aggregation and prolong bleeding time by suppressing prostaglandin synthesis. Therefore, dexketoprofen is not recommended in patients receiving other drugs affecting hemostasis, such as warfarin or other coumarins, or heparins.

Cardiovascular dysfunction occurs more frequently in elderly patients.

Dermatological effects

Serious, sometimes fatal, skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported with NSAID use. The risk of such reactions is highest at the beginning of therapy and typically occurs within the first month of treatment. Alfort Stick should be discontinued at the first sign of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Other information

Particular caution is required when prescribing the drug to patients:

• with inherited porphyrin metabolism disorders (e.g., acute intermittent porphyria);
• with dehydration;
• immediately after major surgical procedures.

If prolonged use of dexketoprofen is considered necessary by the physician, regular monitoring of liver and kidney function, as well as complete blood counts, is recommended.

Very rarely, severe hypersensitivity reactions (e.g., anaphylactic shock) have been observed. If signs of severe hypersensitivity occur after Alfort Stick administration, treatment must be discontinued immediately. Medical personnel should provide appropriate emergency medical care depending on the symptoms.

Patients with bronchial asthma in combination with chronic rhinitis, chronic sinusitis, and/or nasal polyps have a higher risk of developing allergy to acetylsalicylic acid and/or NSAIDs compared to other patients. Use of this drug may trigger asthma attacks or bronchospasm, especially in patients allergic to acetylsalicylic acid or NSAIDs.

In rare cases, severe skin and soft tissue infections may develop during varicella. To date, data sufficient to completely exclude the role of NSAIDs in exacerbating this infectious process are lacking. Therefore, the use of dexketoprofen is not recommended during varicella.

Alfort Stick should be used with caution in patients with blood dyscrasias, systemic lupus erythematosus, and mixed connective tissue diseases.

Like other NSAIDs, dexketoprofen may mask symptoms of infectious diseases.

This medicinal product may cause allergic reactions (possibly delayed), as it contains methylparahydroxybenzoate.

The product contains 2 g of sucrose per dose, which should be taken into account when treating patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency, as well as in patients with diabetes mellitus.

This medicinal product contains a small amount of ethanol (alcohol), less than 100 mg per dose.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is practically sodium-free.

Pediatric population

Safety and efficacy in children and adolescents have not been established.

Use during pregnancy or breastfeeding.

Alfort Stick is contraindicated during pregnancy and breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data raise concerns about an increased risk of miscarriage, cardiac malformations, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increases from nearly 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of treatment. Animal studies have demonstrated that prostaglandin synthesis inhibitors cause pre- and post-implantation loss and embryonic/fetal death.

Furthermore, increased incidences of various malformations, including cardiovascular, have been reported in animals administered prostaglandin synthesis inhibitors during the organogenetic period. Starting from the 20th week of pregnancy, use of Alfort Stick may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation. Dexketoprofen trometamol should not be used during the first and second trimesters of pregnancy unless clearly necessary. If dexketoprofen is used by women attempting conception or during the first or second trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

Prenatal monitoring for oligohydramnios should be considered after several days of Alfort Stick exposure starting from the 20th week of pregnancy. Alfort Stick should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

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

the fetus:

• cardiopulmonary toxicity (with premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function, potentially leading to renal failure with oligohydramnios;

the mother and newborn (when used near term):

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

Breastfeeding period

It is unknown whether dexketoprofen passes into human breast milk; therefore, the drug is contraindicated during breastfeeding.

Fertility

Similar to other NSAIDs, dexketoprofen may impair female fertility and is therefore not recommended for women attempting to conceive. For women who are infertile or undergoing fertility investigations, discontinuation of dexketoprofen therapy should be considered.

Ability to affect reaction speed when driving or operating machinery.

Alfort Stick may cause adverse reactions such as dizziness, visual disturbances, or somnolence. In such cases, reaction speed and the ability to drive or operate machinery may be impaired.

Method of Administration and Dosage

Method of Administration

For oral use. The oral solution can be taken directly from the sachet or after mixing the contents of the sachet in a glass of water.

After opening the sachet, its contents should be used immediately.

Concomitant administration with food slows down drug absorption (see section "Pharmacokinetics"); therefore, in acute pain, it is recommended to take the medication at least 15 minutes before eating.

Dosage

Adults:

Depending on the type and intensity of pain, the recommended dose is usually 25 mg every 8 hours. The maximum daily dose should not exceed 75 mg.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms.

Alfort Stick is intended only for short-term use required to alleviate symptoms.

Elderly patients:

Elderly patients should start treatment with the lowest doses (maximum daily dose of 50 mg). Only if the drug is well tolerated may the initial dose be increased to the recommended dose.

Due to the risk of adverse reactions (see section "Special Warnings and Precautions for Use"), elderly patients should be under particularly careful monitoring.

Hepatic impairment:

Patients with mild to moderate hepatic impairment should start treatment with reduced doses (maximum daily dose of 50 mg) and under close medical supervision. The drug is contraindicated in patients with severe hepatic impairment.

Renal impairment:

Patients with mild renal impairment (creatinine clearance 60–89 mL/min) should have their initial dose reduced to 50 mg per day. Alfort Stick is contraindicated in patients with moderate to severe renal dysfunction (creatinine clearance ≤ 59 mL/min).

Children.

This medicinal product should not be used in children, as safety and efficacy have not been established (no studies have been conducted in pediatric populations).

Overdose.

Symptoms of overdose are unknown. Similar medicinal products may cause gastrointestinal disturbances (vomiting, anorexia, abdominal pain) and nervous system effects (drowsiness, vertigo, disorientation, headache).

In case of accidental overdose or ingestion of an excessive amount of the drug, symptomatic treatment appropriate to the patient's clinical condition should be initiated immediately. If an adult or child has ingested a dose exceeding 5 mg/kg body weight, activated charcoal should be administered within 1 hour.

Dexketoprofen trometamol is eliminated from the body via dialysis.

Adverse reactions.

Adverse reactions reported during clinical trials (in tablet form) that had at least a probable relationship to the use of dexketoprofen, as well as those identified during the post-marketing period (in oral solution sachet form), are listed below in tabular form and classified by system organ classes, and ordered by frequency of occurrence.

Since plasma Cmax levels of dexketoprofen after administration of the oral solution are higher than those after tablet administration, there is a potentially increased risk of gastrointestinal adverse reactions.

Gastrointestinal adverse reactions are the most commonly observed. For instance, peptic ulceration, perforation, or gastrointestinal hemorrhage may occur, sometimes leading to fatal outcomes, particularly in elderly patients (see section "Special precautions for use"). Following administration of the drug, cases of nausea, vomiting, diarrhea, abdominal distension, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn's disease have been reported. Gastritis has been observed less frequently. Edema, arterial hypertension, and heart failure have also been reported during NSAID therapy.

As with other NSAIDs, the following adverse reactions may occur: aseptic meningitis, which primarily occurs in patients with systemic lupus erythematosus or mixed connective tissue disorders, and blood system disorders (purpura, aplastic and hemolytic anemia, rarely agranulocytosis and bone marrow hypoplasia).

Very rarely, bullous reactions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Clinical trial data and epidemiological evidence suggest that the use of certain NSAIDs (particularly at high doses and during long-term therapy) may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are obliged to report any suspected adverse reactions through the national reporting system.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging.

10 ml in sachets, 20 sachets in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

SAG MANUFACTURING, S.L.U.

Manufacturer's address and location of business activity.

Ctra. N-I, Km 36, San Agustín de Guadalix, 28750 Madrid, Spain.