Dexpro

Order of the Ministry of Health of Ukraine
No. 56 of January 13, 2022
Marketing Authorisation
No. UA/17373/02/01

INSTRUCTION
for Medical Use
Dexpro®

Composition:

active substance: dexketoprofen;

Each single-dose sachet contains 36.90 mg dexketoprofen trometamol, which is equivalent to 25 mg dexketoprofen;

excipients: ammonium glycyrrhizinate, acesulfame potassium, lemon flavour, sucrose, colloidal anhydrous silica.

Pharmaceutical form .Granules for oral solution.

Main physicochemical properties: white or off-white granules.

Pharmacotherapeutic group. Non-steroid anti-inflammatory and antirheumatic products. propionic acid derivatives. Dexketoprofen. ATC code M01A E17.

Pharmacological properties.

Pharmacodynamic properties.

Dexketoprofen trometamol is the tromethamine salt of S-(+)-2-(3-benzoylphenyl)propionic acid, an analgesic, anti-inflammatory and antipyretic drug, which belongs to the non-steroidal anti-inflammatory group of drugs.

Mechanism of action

The mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is related to the reduction of prostaglandin synthesis by the inhibition of cyclooxygenase pathway. Specifically, NSAIDs inhibit the transformation of arachidonic acid into cyclic endoperoxides, PGG₂ and PGH₂, which produce prostaglandins PGE₁, PGE₂, PGF_2α, PGD₂, and PGI₂ (prostacyclin) and thromboxanes TxA₂ and TxB₂. Furthermore, the inhibition of the synthesis of prostaglandins could affect other inflammation mediators such as kinins, causing an indirect action.

Pharmacodynamic effects

Dexketoprofen has been demonstrated to be an inhibitor for cyclooxygenase-1 and cyclooxygenase-2 activities in animals and humans.

Clinical efficacy and safety

Clinical studies performed on several pain models demonstrated effective analgesic activity of dexketoprofen. The onset of the analgesic activity was obtained in some studies at 30 minutes post-administration. The analgesic effect persists for 4 to 6 hours.

Pharmacokinetic properties.

Absorption.

Dexketoprofen trometamol is rapidly absorbed after oral administration, after administration in the form of granules, the maximum plasma concentration is reached in 0.25 to 0.33 hours. Comparison of dexketoprofen tablets with standard release times and granules with dosages of 12.5 and 25 mg has shown that these two forms are biologically equivalent in terms of bioavailability (AUC). Peak concentrations (C_max) after taking the granules were approximately 30% higher than after taking the tablets.

When administered concomitantly with food, the AUC does not change, however, the C_max of dexketoprofen trometamol decreases and its absorption rate is delayed (increased t_max).

Distribution.

The distribution half-life and elimination half-life values of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. As with other drugs with a high plasma protein binding (99%), its volume of distribution has a mean value below 0.25 l/kg.

Biotransformation and elimination,

The main elimination route for dexketoprofen is glucuronide conjugation followed by renal excretion.

After administration of dexketoprofen trometamol only the S-(+) enantiomer is obtained in urine, demonstrating that no conversion to the R-(−) enantiomer occurs in humans.

In multiple-dose pharmacokinetic studies, it was observed that the AUC after the last administration is not different from that obtained following a single dose, indicating that no drug accumulation occurs.

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and immunopharmacology. The chronic toxicity studies carried out in mice and monkeys gave a No Observed Adverse Effect Level (NOAEL) at doses 2-fold higher than maximum recommended human dose. In monkeys, at higher doses, the main adverse effect observed were blood in faeces, decreased body weight gain and, at the highest dose, erosive gastrointestinal lesions. These effects appeared at doses determining a drug exposure 14-18 fold higher than that at the maximum recommended human dose. There are not studies on the carcinogenic potential in animals.

As it has been recognised for all NSAIDs, dexketoprofen may cause changes of embryo-foetal survival in animal models, both indirectly, through the gastrointestinal toxicity on the pregnant mothers, and directly upon the development of the foetus.

Clinical particulars.

Therapeutic indications.

Symptomatic treatment of pain of mild to moderate intensity, such as musculo-skeletal pain, dysmenorrhoea, dental pain.

Contraindications.

• Hypersensitivity to the active substance, to any other NSAID, or to any of the excipients.
• Patients in whom substances with a similar action, e.g. acetylsalicylic acid, or other NSAIDs, precipitate attacks of asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria or angioneurotic oedema.
• Known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates.
• History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
• Active peptic ulcer/ gastrointestinal haemorrhage or any history of gastrointestinal bleeding, ulceration or perforation.
• Chronic dyspepsia.
• Active bleedings or bleeding disorders.
• Crohn’s disease or ulcerative colitis.
• Severe heart failure.
• Moderate to severe renal impairment (creatinine clearance ≤59 ml/min).
• Severely impaired hepatic function (Child-Pugh score 10-15).
• Haemorrhagic diathesis and other coagulation disorders.
• Severe dehydration (caused by vomiting, diarrhoea or insufficient fluid intake)
• During the third trimester of pregnancy and lactation period (see the section “Fertility, pregnancy and lactation”).

Interaction with other medicinal products and other forms of interaction.

The following interactions apply to non-steroidal anti-inflammatory drugs (NSAIDs) in general.

Inadvisable combinations:

• Other NSAIDs including cyclooxygenase-2 selective inhibitors and high doses of salicylates (≥ 3 g/day): administration of several NSAIDs together may increase the risk of gastrointestinal ulcers and bleeding, via a synergistic effect.
• Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin, due to the high plasma protein binding of dexketoprofen and the inhibition of platelet function and damage to the gastroduodenal mucosa. If the combination cannot be avoided, close clinical observation and monitoring of laboratory values should be carried out.
• Heparins: increased risk of haemorrhage (due to the inhibition of platelet function and damage to the gastroduodenal mucosa). If the combination cannot be avoided, close clinical observation and monitoring of laboratory values should be carried out.
• Corticosteroids: there is an increased risk of gastrointestinal ulceration or bleeding.
• Lithium preparations: NSAIDs (described with concomitant use with several NSAIDs) increase blood lithium levels, which may reach toxic values due to decreased renal excretion of lithium. This parameter, therefore, requires monitoring during the initiation, adjustment and withdrawal of treatment with dexketoprofen.
• Methotrexate, used at high doses (15 mg/week or more): increased haematological toxicity of methotrexate via a decrease in its renal clearance by anti-inflammatory agents in general.
• Hydantoines and sulphonamides: the toxic effects of these substances may be increased.

Combinations requiring precautions:

• Diuretics, ACE inhibitors, antibacterial aminoglycosides, and angiotensin II receptor antagonists: Dexketoprofen may reduce the effect of diuretics and antihypertensive drugs. In some patients with compromised renal function (e. g. dehydrated patients or elderly patients with compromised renal function), the coadministration of agents that inhibit cyclo-oxygenase and ACE inhibitors, angiotensin II receptor antagonists or antibacterial aminoglycosides may result in further deterioration of renal function, which is usually reversible. In case of combined prescription of dexketoprofen and a diuretic, it is essential to ensure that the patient is adequately hydrated and to monitor renal function at the start of the treatment and periodically after it. Concomitant use of dexketoprofen and potassium-sparing diuretics may lead to hyperkalaemia. It is necessary to control the concentration of potassium in the blood.
• Methotrexate, used at low doses (less than 15 mg/week): increased haematological toxicity of methotrexate via a decrease in its renal clearance by anti-inflammatory agents in general. Weekly monitoring of blood count during the first weeks of the combination. Increased surveillance in the presence of even mildly impaired renal function, as well as in the elderly.
• Pentoxyfilline: increased risk of bleeding. Perform clinical monitoring and check bleeding time.
• Zidovudine: risk of increased erythropoiesis toxicity by zidovudine (toxic action on reticulocytes), with severe anaemia occurring one week after the NSAID is started. Check complete blood count and reticulocyte count one to two weeks after starting treatment with the NSAID.
• Sulfonylureas: NSAIDs can increase the hypoglycaemic effect of sulfonylureas by displacement from plasma protein binding sites.

Combinations needing to be taken into account:

• β-blockers: may decrease their antihypertensive effect via inhibition of prostaglandin synthesis.
• Cyclosporin and tacrolimus: nephrotoxicity may be enhanced by NSAIDs via renal prostaglandin mediated effects. During combination therapy, renal function has to be measured.
• Thrombolytics: increased risk of bleeding.
• Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.
• Probenecid: plasma concentrations of dexketoprofen may be increased; this interaction can be due to an inhibitory mechanism at the site of renal tubular secretion and of glucuronoconjugation and requires adjustment of the dose of dexketoprofen.
• Cardiac glycosides: may increase plasma glycoside concentration.
• Mifepristone: There is a theoretical risk that prostaglandin synthetase inhibitors may alter the efficacy of mifepristone. Limited evidence suggests that co-administration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of mifepristone or the prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy.
• Quinolone antibiotics: Animal data indicate that high doses of quinolones in combination with NSAIDs can increase the risk of developing convulsions.
• Tenofovir: concomitant use with NSAID can increase plasma urea nitrogen and creatinine, renal function should be monitored in order to control a potential synergic influence on renal function.
• Deferasirox: concomitant use with NSAIDs can increase the risk of gastrointestinal toxicity and requires close clinical monitoring.
• Pemetrexed: concomitant use with NSAIDs may decrease pemetrexed elimination, therefore caution should be made when administering higher doses of NSAIDs. In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min), the concomitant administration of pemetrexed with NSAIDs doses should be avoided for 2 days before and 2 days following pemetrexed administration.

Special warnings and precautions for use.

Administer with caution in patients with a history of allergic conditions.

The use of the product with concomitant other NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

Gastrointestinal safety.

Gastrointestinal bleeding, ulceration or perforation which can be fatal, have been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. When gastrointestinal bleeding or ulceration occurs in patients receiving dexketoprofen, the treatment should be withdrawn.

The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly.

Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal. These patients should commence treatment on the lowest dose available.

As with all NSAIDs, any history of oesophagitis, gastritis and/or peptic ulcer must be sought in order to ensure their total cure before starting treatment with dexketoprofen. Patients with gastrointestinal symptoms or history of gastrointestinal disease should be monitored for digestive disturbances, especially gastrointestinal bleeding during treatment with dexketoprofen.

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.

Combination therapy with protective agents, e.g. misoprostol or proton pump inhibitors, should be considered for these patients, and also for patients requiring concomitant low dose acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk.

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

Caution should be advised in patients receiving concomitant medications, which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid.

Renal Safety.

Caution should be exercised in patients with impairment of renal functions. In these patients, the use of NSAIDs may result in deterioration of renal function, fluid retention and oedema. Caution is also required in patients receiving diuretic therapy or those who could develop hypovolaemia as there is an increased risk of nephrotoxicity.

Adequate fluid intake should be ensured during treatment to prevent dehydration and possibly associated increased renal toxicity.

As with all NSAIDs, it can increase plasma urea nitrogen and creatinine. As with other inhibitors of prostaglandin synthesis, it can be associated with adverse effects on the renal system, which can lead to glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome, and acute renal failure.

Elderly patients are more likely to be suffering from impaired renal function.

Liver Safety.

Caution should be exercised in patients with impairment of hepatic functions. As with other NSAIDs, it can cause transient small increases in some liver parameters, and also significant increases in aspartate aminotransferase and alanine aminotransferase. In case of a relevant increase in such parameters, therapy must be discontinued.

Elderly patients are more likely to be suffering from impaired hepatic function.

Cardiovascular and cerebrovascular safety.

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate heart failure. Special caution should be exercised in patients with a history of cardiac disease, in particular those with previous episodes of heart failure as there is an increased risk of triggering heart failure, since fluid retention and oedema have been reported in association with NSAIDs therapy. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for dexketoprofen. Consequently, patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with dexketoprofen after careful consideration. Similar consideration should be made before initiating longer-term treatment of the patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

All non-selective NSAIDs can inhibit platelet aggregation and prolong bleeding time via inhibition of prostaglandin synthesis. Therefore, the use of dexketoprofen in patients who are receiving other therapy that interferes with haemostasis, such as warfarin or other coumarins or heparins is not recommended. Elderly patients are more likely to be suffering from impaired cardiovascular function.

Skin reactions.

Serious skin reactions (some of them fatal) including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment.

The medicinal product should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Masking of symptoms of underlying infections.

Dexketoprofen can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community-acquired pneumonia and bacterial complications to varicella. When dexketoprofen is administered for pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.

Other information.

Particular caution is required when prescribing this medicinal product in patients with:

- congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria)

- dehydration

- directly after major surgery

If the physician considers long-term dexketoprofen therapy to be necessary, hepatic and renal function and the blood count should be regularly checked.

Severe acute hypersensitivity reactions (anaphylactic shock, for example) have been observed on very rare occasions. Treatment must be discontinued at the first signs of severe hypersensitivity reactions following intake of dexketoprofen. Depending on the symptoms, any medically required procedures must be initiated by specialist healthcare professionals.

Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyposis have a higher risk of allergy to acetylsalicylic acid and/or NSAIDs than the rest of the population. Administration of this medicinal product can cause asthma attacks or bronchospasm, particularly in subjects allergic to acetylsalicylic acid or NSAIDs.

Exceptionally, varicella can be at the origin of serious cutaneous and soft tissues infectious complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of dexketoprofen in case of varicella.

The medicinal product should be administered with caution to patients suffering from haematopoietic disorders, systemic lupus erythematosus or mixed connective tissue disease.

Paediatric population

The safe use in children and adolescents has not been established.

Important information about the excipients.

This medicinal product contains sucrose. This should be taken into account by patients with diabetes.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not take this medicinal product.

Fertility, pregnancy and lactation.

The medicinal product is contraindicated during the third trimester of pregnancy and lactation.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy.

The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. Nevertheless, animal studies with dexketoprofen haven’t shown reproductive toxicity. During the first and second trimester of pregnancy, dexketoprofen should not be given unless clearly necessary. If dexketoprofen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity, e.g. premature closure of the ductus arteriosus and pulmonary hypertension;
• renal impairment, which may progress to renal failure with oligo-hydroamniosis;

the mother and the neonate, at the end of pregnancy, to:

• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;
• inhibition of uterine contractions resulting in delayed or prolonged labour.

Breast-feeding

It is not known whether dexketoprofen is excreted in human milk. Dexketoprofen is contraindicated during breast-feeding.

Fertility

As with other NSAIDs, the use of Dexketoprofen may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of dexketoprofen should be considered.

Effects on ability to drive and use machines.

Dexketoprofen may cause undesirable effects such as dizziness, visual disturbances or drowsiness. The ability to react and the ability to take part actively in road traffic and to operate machines may be impaired in these cases.

Posology and method of administration.

Posology.

The lowest effective dose should be used for the shortest duration necessary to control symptoms (see the section “Special warnings and precautions for use”).

Adults.

According to the nature and severity of pain, the recommended dosage is generally 25 mg every 8 hours. The total daily dose should not exceed 75 mg.

The medicinal product is not intended for long-term use and the treatment must be limited to the symptomatic period.

Elderly. In elderly patients, it is recommended to start the therapy at the lower end of the dosage range. The daily dose is 50 mg. The dosage may be increased to the usual one only after good general tolerance has been ascertained. Elderly patients should be closely monitored by a physician due to the risk of adverse reactions.

Hepatic impairment

Patients with mild to moderate hepatic impairment should start therapy at the lower end of the dosage range and under close medical supervision. The daily dose is 50 mg. Dexketoprofen should not be used in patients with severe hepatic impairment.

Renal impairment

The initial dosage should be reduced to 50 mg total daily dose in patients with mildly impaired renal function (creatinine clearance 60-89 ml/min). Dexketoprofen should not be used in patients with moderate to severe renal impairment (creatinine clearance ≤ 59 ml / min).

Method of administration

Before use, dissolve the entire contents of one sachet in a glass of water and mix well for better dissolution. The resulting solution should be taken immediately after preparation. Concomitant administration with food delays the absorption rate of the drug (see the section “Pharmacokinetic properties”), thus in case of acute pain, it is recommended that administration is at least 15 minutes before meals.

Paediatric Population

Dexketoprofen has not been studied in children. Therefore, the safety and efficacy in children and adolescents have not been established and the product should not be used in children and adolescent

Overdose.

The symptomatology following overdose is not known. Similar medicinal products have produced gastrointestinal (vomiting, anorexia, abdominal pain) and neurological (somnolence, vertigo, disorientation, headache) disorders.

In case of accidental or excessive intake, immediately institute symptomatic therapy according to the patient’s clinical condition. Activated charcoal should be administered if more than 5 mg/kg has been ingested by an adult or a child within an hour. Dexketoprofen trometamol may be removed by dialysis.

Undesirable effects.

The adverse events reported as at least possibly related with dexketoprofen (as tablets) in clinical trials, as well as the adverse reactions reported after the marketing of the product are presented below, classified by system organ class and ordered by frequency:

Because the plasma C_max level of dexketoprofen in the form of granules is higher than that in the form of tablets, an increased risk of adverse reactions (from the gastrointestinal tract) cannot be ruled out.

All undesirable effects are classified by system organ class and ordered by frequency: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1 000 – < 1/100), rare (≥ 1/10000 – < 1/1000), very rare (< 1/10 000), and not known (frequency cannot be estimated from the available data).

Eye disorders: very rare – blurred vision.

Ear and labyrinth disorders: uncommon – vertigo; very rare – tinnitus.

Respiratory, thoracic and mediastinal disorders: rare – bradypnoea; very rare – bronchospasm, dyspnoea.

Gastrointestinal disorders: common – nausea and/or vomiting, abdominal pain, diarrhoea, dyspepsia; uncommon – gastritis, constipation, dry mouth, flatulence; rare – peptic ulcer, peptic ulcer haemorrhage or peptic ulcer perforation; very rare – pancreatitis.

Hepatobiliary disorders: rare – hepatocellular injury.

Renal and urinary disorders: rare – polyuria, acute renal failure; very rare – nephritis or nephrotic syndrome.

Metabolism and nutrition disorders: rare – anorexia.

Nervous system disorders: uncommon – headache, dizziness, somnolence; rare – paraesthesia, syncope.

Psychiatric disorders: uncommon – insomnia, anxiety.

Cardiac disorders: uncommon – palpitations; very rare – tachycardia.

Vascular disorders: uncommon – flushing; rare – hypertension; very rare – hypotension.

Blood and lymphatic system disorders: very rare – neutropenia, thrombocytopenia.

Immune system disorders: rare – laryngeal oedema; very rare – anaphylactic reaction, including anaphylactic shock.

Skin and subcutaneous tissue disorders: uncommon – rash; rare – urticaria, acne, sweating increased; very rare – Stevens Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), angioedema, facial oedema, photosensitivity reaction, pruritus.

Musculoskeletal and connective tissue disorders: rare – back pain.

Reproductive system and breast disorders: rare – menstrual disorder, prostatic disorder.

General disorders: uncommon – fatigue, pain, asthenia, rigors, malaise; rare – peripheral oedema.

Investigations: rare – liver function test abnormal.

The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been observed. Oedema, hypertension, and cardiac failure have been reported in association with NSAIDs treatment.

Clinical trial and epidemiological data suggest that use of some NSAIDs, particularly at high doses and in long term treatment, may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

As with other NSAIDs the following undesirable effects may appear: aseptic meningitis, which might predominantly occur in patients with systemic lupus erythematosus or mixed connective tissue disease; haematological reactions (purpura, aplastic and haemolytic anaemia, and rarely agranulocytosis and medullar hypoplasia).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the state pharmacovigilance system.

Shelf life. 1.5 years.

Do not use this medicinal product after the expiry date stated on the package.

Storage conditions.

Store in the original package below 25 °C.

Keep out of reach of children.

Nature and contents of container.

10 single-dose sachets in a pack.

Prescription status. Upon prescription.

Manufacturer. PRJSC Pharmaceutical company Darnitsa

Manufacturer’s location and place of business.

13 Boryspilska Street, 02093, City of Kyiv, Ukraine