1. NAME OF THE MEDICINAL PRODUCT

MIG Junior 40 mg/ml oral suspension MIG Junior 40 mg/ml oral suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of oral suspension contains 40 mg of ibuprofen.

Excipients with known effect: liquid maltitol 0.5 g/ml and 5.79 mg sodium per 1 ml oral suspension.

For the full list of excipients, see section 6.1.

3. MEDICINAL FORM

Oral suspension

White or off-white viscous suspension.

4. CLINICAL DATA

1. Therapeutic indications

MIG Junior is used for the short-term symptomatic treatment of:

• mild to moderate pain
• fever

MIG Junior is indicated for children weighing more than 10 kg (aged 1 year), adolescents and adults.

4.2 Dosage and method of administration

Dosage

The dosage is in accordance with the table below. In children and adolescents, the dose of MIG Junior is determined depending on body weight, generally from 7 to 10 mg/kg

body weight as a single dose, up to a maximum of 30 mg/kg body weight as a total daily dose.

The interval between individual doses is in accordance with the symptoms and the maximum daily dose

dose. It should not be less than 6 hours. The recommended maximum dose should not be exceeded.

If children and adolescents need to use this medicinal product for more than 3 days, or if symptoms worsen, a doctor should be consulted.

If adults need to use this product for more than 3 days in case of high fever or for more than 4 days to treat pain or if symptoms worsen, a doctor should be consulted.

The package contains a dosing syringe for oral administration of MIG Junior.

The oral syringe is graduated in 0.25 ml increments to a full volume of 5 ml.

5 ml of oral suspension corresponds to 200 mg of ibuprofen. The bottle should be shaken well before use.

MIG Junior 40 mg/ml:

Adverse reactions can be minimized by using the lowest effective dose for the shortest time to control symptoms (see section 4.4).

Special populations

Elderly population:

No special dose adjustment is required in elderly patients. Due to the possible adverse reaction profile (see section 4.4), elderly patients should be monitored with particular care.

Renal impairment:

No dose reduction is required in patients with mild to moderate impairment of renal function (for patients with severe renal insufficiency, see section 4.3).

Liver damage (see section 5.2):

No dose reduction is required in patients with mild to moderate renal impairment

liver function (for patients with severe liver failure, see section 4.3).

Pediatric population:

MIG Junior is not recommended for use in children under the age of 1 year or with a body weight of less than 10 kg.

Application method

For oral use and for short-term use only. The bottle should be shaken well before use.

The oral suspension can be taken without regard to food. For patients with a sensitive stomach, it is recommended that MIG Junior be taken during meals.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in point 6.1.

History of bronchospasm, asthma, rhinitis, angioedema or urticaria associated with the use of acetylsalicylic acid (ASA) or other non-steroidal anti-inflammatory drugs (NSAIDs).

Unexplained disorders in hematopoiesis.

Active or history of recurrent peptic ulcer/haemorrhage (two or more separate episodes of proven ulcer or haemorrhage).

History of gastrointestinal bleeding or perforation related to previous NSAID treatment.

Cerebrovascular or other active hemorrhage.

Severe hepatic insufficiency, severe renal insufficiency, or severe heart failure (NYHA Class IV).

Severe dehydration (caused by vomiting, diarrhea or insufficient fluid intake). Pregnant patients in the last three months of pregnancy.

4.4 Special warnings and precautions for use

Adverse reactions can be minimized if the lowest effective dose is administered for the shortest time to control symptoms (see gastrointestinal risks and

the cardiovascular system below). Gastrointestinal safety

Concomitant use of MIG Junior oral suspension with NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided.

Old age:

Elderly patients have an increased incidence of adverse reactions to NSAIDs, particularly gastrointestinal haemorrhage and perforation, which may be fatal (see section 4.2).

Gastrointestinal haemorrhage, ulcer and perforation:

Gastrointestinal haemorrhage, ulceration or perforation, which may be fatal, have been reported with all NSAIDs at any time of treatment, with or without warning symptoms or a previous history of serious gastrointestinal events.

The risk of gastrointestinal haemorrhage, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulceration, especially if complicated by haemorrhage or perforation (see section 4.3) and in the elderly. These patients should be started on the lowest possible dose. In these patients, as well as in patients in whom it is necessary

concomitant use of low-dose acetylsalicylic acid or other drugs that increase gastrointestinal risk, combined treatment with protective agents (eg misoprostol or proton pump inhibitors) should be considered (see below and section 4.5).

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

Caution is advised in patients receiving concomitant treatment that may increase the risk of ulceration and bleeding, such as oral corticosteroids, anticoagulants, such as

warfarin, selective serotonin reuptake inhibitors or antithrombotic agents such as acetylsalicylic acid (see section 4.5).

If gastrointestinal bleeding or ulceration occurs in patients receiving MIG Jr., treatment should be discontinued.

NSAIDs should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as these conditions may be exacerbated (see section 4.8. Adverse drug reactions).

Cardiovascular and cerebrovascular effects

Caution (consultation with a physician or pharmacist) is required before starting treatment in patients with a history of hypertension and/or heart failure, as fluid retention, hypertension and edema have been reported in association with NSAID treatment.

Clinical studies have shown that the use of ibuprofen, especially in high doses (2400 mg/day) may be associated with a slightly increased risk of arterial thrombotic events (eg, myocardial infarction or stroke). In general, epidemiological studies do not

showed that low doses of ibuprofen (eg, £1200 mg/day) were associated with an increased risk of arterial thrombotic events.

Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischemic heart disease, peripheral arterial disease and/or cerebral

vascular disease should be treated with ibuprofen only after careful consideration and high doses (2400 mg/day) should be avoided.

Careful consideration should also be given to initiation of long-term treatment in patients with risk factors for cardiovascular events (ie, hypertension, hyperlipidemia, diabetes mellitus, smoking), especially with high doses of ibuprofen (2400 mg/day).

Severe skin reactions

Severe skin reactions, some of which are fatal, including exfoliative dermatitis,

Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients are at the highest risk of these reactions early in the course of treatment: the onset of the reaction in most cases is within the first month of treatment. Acute generalized exanthematous pustulosis (AGEP) has been reported in association with products containing ibuprofen. The reception of MIG Junior should be stopped at the first manifestation of

skin rash, mucosal lesions or any other sign of hypersensitivity.

Exceptionally, chicken pox may underlie serious infectious complications of the skin and soft tissues. At this point, the role of NSAIDs cannot be ruled out

worsening of these infections. Therefore, it is recommended to avoid the use of MIG Jr. in cases of chickenpox.

Other information:

MIG Junior should be used only after careful consideration of the benefit/risk ratio in:

• congenital disorders of porphyrin metabolism (e.g. acute intermittent porphyria),
• in systemic lupus erythematosus (SLE) and mixed connective tissue disease – increased risk of aseptic meningitis (see section 4.8).

Particularly careful follow-up by a doctor is required in the following cases:

• with impaired renal function (as acute deterioration of renal function may occur in patients with pre-existing renal disease);
• in dehydration
• in liver dysfunction;
• immediately after major surgical procedures;
• in patients who suffer from hay fever, nasal polyps, chronic edema of the nasal mucosa or chronic obstructive respiratory diseases, as they have an increased risk of developing allergic reactions. Such reactions

may manifest in the form of asthmatic attacks (so-called analgesic asthma), angioedema or urticaria;

• in patients who react allergically to other substances, as they have an increased risk of hypersensitivity reactions when using MIG Junior.

Severe acute hypersensitivity reactions (eg anaphylactic shock) have been observed very rarely. At the first signs of a hypersensitivity reaction after ingestion of MIG Junior, treatment should be stopped. In accordance with the symptoms, medical measures should be taken by specialized personnel.

Respiratory disorders: Caution is required when MIG Jr. is administered to patients who suffer from or have a history of bronchial asthma, as NSAIDs have been reported to exacerbate bronchospasm in these patients.

Ibuprofen, the active substance in MIG Jr., can temporarily inhibit platelet function (platelet aggregation). Therefore, patients with bleeding disorders should be carefully monitored.

With long-term use of ibuprofen (MIG Jr.), regular monitoring of liver values, renal function and blood counts is required.

Caution should be exercised in patients already taking other pain-relieving or antipyretic drugs or antibiotics.

Prolonged use of any type of headache pain reliever can make it worse. If this occurs or is suspected, consultation with

physician and discontinuation of treatment. The diagnosis of drug overdose headache should be considered in patients who frequently or daily have headaches despite (or because of) regular use of headache medications.

In general, the regular use of pain relievers, especially a combination of several

painkillers, may lead to persistent kidney damage with risk of kidney failure (analgesic nephropathy).

With the simultaneous use of alcohol with NSAIDs, the adverse reactions associated with the active substance, especially with regard to the gastrointestinal tract or the central nervous system, may increase.

NSAIDs can mask the symptoms of infection and high fever. Pediatric population

There is a risk of kidney damage in dehydrated children and adolescents.

This medicinal product contains liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

This medicinal product contains up to 2.52 mmol (or 57.9 mg) sodium per dose. Consider in patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Ibuprofen (like other NSAIDs) should be used with caution in combination with the following medicinal substances:

Other non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid:

The simultaneous use of two or more NSAIDs can lead to an increased risk of

gastrointestinal ulcers and hemorrhages due to a synergistic effect. Therefore, the simultaneous administration of ibuprofen with other NSAIDs should be avoided (see section 4.4).

Acetylsalicylic acid :

Concomitant use of ibuprofen and acetylsalicylic acid is generally not recommended due to the possibility of increased adverse effects.

Experimental data show that ibuprofen can competitively inhibit the effect of low doses of acetylsalicylic acid on platelet aggregation when administered simultaneously. Although there are uncertainties regarding the extrapolation of these data to

clinical cases, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. There is no clinically significant effect that can be considered likely with the occasional use of ibuprofen (see section 5.1).

Digoxin, Phenytoin, Lithium:

Concomitant administration of MIG Jr. with digoxin, phenytoin, or lithium may increase the serum levels of these medicinal products. With proper administration (maximum 4 days), it is generally not necessary to monitor the serum levels of lithium, digoxin and

phenytoin.

Diuretics, ACE-inhibitors, beta-receptor blockers and angiotensin-II antagonists:

NSAIDs can reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the simultaneous administration of ACE inhibitors, beta-receptor blockers or angiotensin II antagonists and

agents that inhibit cyclooxygenase can lead to additional damage to

renal function, including possible acute renal failure, which is usually reversible. That is why the combination should be used with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of combination therapy and periodically thereafter.

The simultaneous use of MIG Jr. and potassium-sparing diuretics can lead to hyperkalemia.

Corticosteroids:

Increased risk of gastrointestinal ulceration and hemorrhage (see section 4.4).

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs):

Increased risk of gastrointestinal bleeding (see section 4.4).

Anticoagulants :

NSAIDs may enhance the effects of anticoagulants such as warfarin (see section 4.4).

Methotrexate :

The administration of MIG Junior 24 hours before or after the administration of methotrexate can lead to an increased concentration of methotrexate and to an increase in its toxic effect.

Sulfonylureas:

Clinical studies have shown interactions between NSAIDs and antidiabetic drugs (sulfonylureas). Although so far they haven't

reported interactions between ibuprofen and sulfonylureas, monitoring of blood sugar values is recommended as a precaution when they are used simultaneously.

Zidovudine :

Concomitant administration of MIG Jr. Oral Suspension may increase the risk of joint bleeding and bruising in HIV-positive patients suffering from

hemophilia.

Cyclosporine :

The risk of a nephrotoxic effect caused by cyclosporine is increased by the simultaneous use of certain NSAIDs. This effect cannot be ruled out also in

the combination of cyclosporine and ibuprofen.

Tacrolimus :

The risk of nephrotoxicity increases with simultaneous administration of this medicinal product with MIG Jr. oral suspension.

Probenecid and sulfinpyrazone:

Medicinal products that contain probenecid and sulfinpyrazone may delay the excretion of ibuprofen.

Quinolone antibiotics:

Animal data indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may increase the risk of seizures.

CYP2C9 inhibitors:

Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase

exposure to ibuprofen (a CYP2C9 substrate). In a study with voriconazole and fluconazole (CYP2C9 inhibitors), increased exposure to S(+)-ibuprofen by about 80 to 100% was demonstrated. A reduction in the dose of ibuprofen should be considered when potent CYP2C9 inhibitors are co-administered, especially if high doses of ibuprofen are administered with voriconazole and fluconazole.

4.6 Fertility, pregnancy and breastfeeding

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development.

Data from epidemiological studies show an increased risk of spontaneous abortions and

cardiac malformations and gastroschisis after the use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformation increased from less than 1% to approximately 1.5%. The risk is thought to increase with dose and duration of therapy.

In animals, administration of prostaglandin synthesis inhibitors results in increased pre- and post-implantation losses and embryo-fetal lethality. In addition, an increased incidence of various malformations, including cardiovascular, has been reported in animals

which are inhibitors of prostaglandin synthesis administered during the period of organogenesis.

During the first and second trimesters of pregnancy, MIG Junior should not be used unless absolutely necessary. If ibuprofen (MIG Jr.) is taken by women who are trying to become pregnant or during the first and second trimesters of

pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors can lead to exposure

• of the fruit of:
  • cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
  • renal dysfunction that may progress to renal failure and oligohydroamnion;
• of the mother and the newborn, at the end of the pregnancy, of:
  • possible increased bleeding time, an anticoagulant effect that can occur even at very low doses;
  • suppression of uterine contractions, resulting in delayed or prolonged labor.

Therefore, MIG Junior is contraindicated during the third trimester of pregnancy (see section 4.3).

Breastfeeding

Ibuprofen and its metabolites pass into breast milk in small amounts. As there are no known harmful effects in the infant so far, in general short-term use of ibuprofen at the recommended doses does not require discontinuation of

breastfeeding (see item 4.2).

Fertility

There is evidence that drugs that inhibit cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation. This is reversible on discontinuation of treatment.

4.7 Effects on the ability to drive and use machines

MIG Junior has a minor influence on the ability to drive and use machines.

When applying MIG Junior, side effects such as fatigue and dizziness may occur. As a result, in individual cases, the ability to react may change and the ability to actively participate in road traffic and operate machinery may be impaired. This applies to a greater extent when interacting with alcohol.

4.8 Adverse drug reactions

The list of adverse drug reactions below covers all the adverse reactions known to date for ibuprofen, including those reported when high doses are used for a long time in patients with rheumatism. The indicated frequencies, with the exception of reports of very rare frequency, refer to short-term administration of daily doses up to a maximum of 1200 mg ibuprofen (30 ml MIG Jr. oral suspension,

maximum daily dose for adults and adolescents over 12 years of age) for oral forms and a maximum of 1800 mg for suppositories.

The evaluation of adverse drug reactions is based on the following frequency classification:

It should be noted that the following side effects are dose-dependent and vary from patient to patient.

The most frequently observed side effects are gastrointestinal in origin. Peptic ulcers, perforation or gastrointestinal haemorrhage may occur, sometimes fatal, especially in the elderly (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melena, haematemesis, ulcerative colitis have been reported after administration.

stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4). Gastritis has been observed less frequently.

Edema, hypertension and heart failure have been reported in association with NSAID treatment.

Clinical studies have shown that the use of ibuprofen, especially in high doses (2400 mg/day) may be associated with a slightly increased risk of arterial thrombotic events (eg, myocardial infarction or stroke) (see 4.4).

Infections and infestations

Very rare: Exacerbation of infectious inflammation (e.g. development of necrotizing fasciitis) associated with systemic administration of non-steroidal anti-inflammatory drugs has been described. This is most likely related to the mechanism of action of nonsteroidal anti-inflammatory drugs.

If signs of infection appear or worsen during the administration of MIG Junior, it is recommended that the patient immediately visit a doctor. Whether this is an indication for anti-infective/antibiotic therapy should be considered.

Disorders of the blood and lymphatic system

Very rare: Blood formation problems (anaemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis).

The first signs can be fever, sore throat, superficial sores in the mouth, flu-like complaints, severe fatigue, bleeding from the nose and skin. In these

cases the patient should be advised to immediately stop the drug and avoid self-medication with analgesics or antipyretics and consult a doctor.

Blood counts should be monitored regularly during long-term treatment.

Disorders of the immune system:

Uncommon : Hypersensitivity reactions with skin rashes and itching, as well as asthmatic attacks (with a possible drop in blood pressure).

The patient should be instructed to notify a physician immediately and stop taking MIG Jr. in this case.

Very rare: Signs of aseptic meningitis, such as headache, nausea, vomiting, high fever, neck stiffness or confusion. It appears that patients with certain disorders of the immune system (systemic lupus erythematosus or mixed

connective tissue disease) are at higher risk.

Severe generalized hypersensitivity reactions. Signs may include: swelling of the face, tongue and inside of the larynx with narrowing of the airways, shortness of breath,

palpitations, drop in blood pressure to life-threatening shock.

If any of these symptoms appear, which may occur even with the first application, immediate medical attention is required.

Mental disorders

Very rare: Psychotic reactions, depression.

Disorders of the nervous system

Uncommon: Central nervous system disorders such as headache, dizziness, insomnia, agitation, anxiety, irritability or lethargy.

Eye disorders

Uncommon : Visual disturbances. In this case, the patient should be instructed to notify a physician and discontinue the use of ibuprofen.

Disorders of the ear and labyrinth

Rare : Tinnitus.

Heart disorders

Very rare: Palpitations, heart failure, myocardial infarction.

Vascular disorders

Very rare: Arterial hypertension, vasculitis.

Respiratory, thoracic and mediastinal disorders

Very rare: Asthma, bronchospasm, dyspnoea and wheezing.

Gastrointestinal disorders

Common: Gastrointestinal complaints such as heartburn, abdominal pain, nausea, vomiting, flatulence, diarrhoea, constipation and mild gastrointestinal bleeding, which may exceptionally lead to anaemia.

Uncommon: Stomach or intestinal ulcers, sometimes with hemorrhage and perforation. Ulcerative stomatitis, exacerbation of colitis or Crohn's disease (see section 4.4), gastritis.

Very rare: Esophagitis, pancreatitis, formation of intestinal membrane-like structures.

Administration of MIG Jr. should be stopped if the patient experiences significant upper abdominal pain, vomits blood, has blood in the stool, or black stools.

Hepatobiliary disorders

Very rare: Liver function disorders, liver damage, especially with long-term treatment, liver failure, acute hepatitis.

Disorders of the skin and subcutaneous tissue

Uncommon: Various skin rashes

Very rare : Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), alopecia.

Not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP)

Exceptionally, severe skin infections and soft-tissue complications can occur with chickenpox (see also "Infections and Parasitosis").

Renal and urinary disorders

Rare : Damage to kidney tissue (papillary necrosis), especially with long-term use, increased serum concentrations of uric acid in the blood.

Very rare: Decreased urinary excretion and edema formation, especially in patients with

arterial hypertension or with renal failure, nephrotic syndrome, interstitial nephritis, which may be accompanied by acute renal failure.

The application of MIG Jr. should be stopped if these symptoms occur or worsen.

Reporting of suspected adverse reactions

Post-marketing reporting of suspected adverse reactions is important. This allows

to continue monitoring the benefit/risk ratio of the medicinal product. From the medical professionals

are required to report any suspected adverse reaction through the national reporting system:

Executive Agency for Medicines, 8 Damyan Gruev Street

1303 Sofia

tel.: +359 28903417

website: www.bda.bg

4.9 Overdose

Symptoms of overdose

Central nervous system disorders such as headache, dizziness,

dizziness, loss of consciousness (in children and myoclonic seizures), as well as abdominal pain, nausea and vomiting. In addition, gastrointestinal bleeding, a violation of

renal function and impaired liver function. In addition, hypotension, respiratory depression and cyanosis may occur. In severe poisoning, metabolic acidosis may occur.

Treatment

There is no specific antidote for ibuprofen.

Therapeutic options for the treatment of intoxication are guided by the degree, stage and clinical symptoms according to the general measures of intensive care.

5. PHARMACOLOGICAL PROPERTIES

1. Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory and anti-rheumatic products, non-steroidal; propionic acid derivatives

ATC code: M01AE01

Mechanism of action:

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), which in

conventional animal experiments on inflammatory models, has proven effective by inhibiting the synthesis of prostaglandins. In humans, ibuprofen reduces the associated

inflammation pain, swelling and high temperature. In addition, ibuprofen reversibly inhibits ADP- and collagen-induced platelet aggregation.

Clinical efficacy and safety:

Experimental data show that ibuprofen can competitively inhibit the effect of low doses of acetylsalicylic acid on platelet aggregation when administered simultaneously. Some pharmacodynamic studies show that when using

a single dose of 400 mg ibuprofen within 8 hours before or up to 30 minutes after administration of the immediate-release form of acetylsalicylic acid (81 mg), a reduction in the effect of acetylsalicylic acid on thromboxane formation or on platelet aggregation was observed. Although there are uncertainties about

extrapolation of these data to clinical cases, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. There is no clinically significant effect to be considered likely with infrequent use of ibuprofen (see section 4.5).

5.2 Pharmacokinetic properties

Absorption:

After oral administration, ibuprofen is partially absorbed in the stomach and then completely in the small intestine. Maximum plasma levels with oral administration of dosage forms with normal release are reached after 1-2 hours.

Distribution:

Plasma protein binding is about 99%. The elimination half-life in healthy individuals, as well as in those with liver and kidney disease, is 1.8 – 3.5 hours.

Biotransformation:

Ibuprofen is metabolized in the liver (hydroxylation, carboxylation).

Elimination:

Pharmacologically inactive metabolites are completely eliminated, mainly through the kidneys (90

%), but also through the bile.

Kidney damage

Increased levels of unbound (S)-ibuprofen, higher AUC values for unbound (S)-ibuprofen, and increased AUC of the S/R enantiomers compared to healthy subjects have been reported in patients with mild renal impairment.

In patients with end-stage renal disease who are on hemodialysis, the average

the free fraction of ibuprofen was 3% versus 1% in healthy volunteers. Severe impairment of renal function may lead to accumulation of ibuprofen metabolites. Is not

the significance of this effect is clear. Metabolites can be eliminated by hemodialysis (see sections 4.2, 4.3 and 4.4).

Liver damage

In patients with cirrhosis and moderate hepatic impairment (Child Pugh's score 6-10) treated with racemic ibuprofen, an average 2-fold increase in half-life and AUC enantiomeric ratio (S/R) was significantly lower compared to healthy subjects

controls, suggesting impaired conversion of the metabolite (R)-ibuprofen to the active (S)-enantiomer (see sections 4.2, 4.3 and 4.4).

Linearity:

At doses of 200 to 400 mg, ibuprofen has been reported to exhibit linear kinetics. At higher doses, the drug shows non-linear kinetics.

5.3 Preclinical safety data

The subchronic and chronic toxicity of ibuprofen in animal experiments is manifested mainly in the form of lesions and ulcers in the gastrointestinal tract.

In vitro and in vivo studies do not provide clinically relevant data that ibuprofen has

mutagenic effects. There was no evidence of carcinogenic effects of ibuprofen in studies in rats and mice.

Ibuprofen inhibits ovulation in rabbits and causes impaired implantation in various animal species (rabbit, rat, mouse). Experimental studies in rats and rabbits show that ibuprofen crosses the placenta. After administration of maternally toxic doses, an increased incidence of malformations (ventricular septal defects) was observed in the rat offspring.

6. PHARMACEUTICAL DATA

1. List of excipients

Sodium benzoate (E211), Citric acid, anhydrous, Sodium citrate,

Saccharin sodium, Sodium chloride, Hypromellose,

Xanthan gum, Maltitol, liquid, Glycerol (E422), Thaumatin (E957),

Strawberry flavor (natural flavors, corn maltodextrin, triethyl citrate (E-1505), propylene glycol (E-1520) and benzyl alcohol),

Purified water.

6.2 Incompatibilities

Not applicable

6.3 Expiry Date

3 years.

After first opening: 6 months

6.4 Special storage conditions

This medicinal product does not require special storage conditions. After first opening: Store below 30ºС.

6.5 Type and contents of packaging

Dark polyethylene terephthalate (PET) bottles of 30 ml, 100 ml, 150 ml and 200 ml, with a child-resistant cap and a low density polyethylene stopper.