Lornado

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LORNADO (LORNADO)

Composition:

Active substance: lornoxicam;

One film-coated tablet contains 4 mg or 8 mg of lornoxicam;

Excipients: lactose monohydrate; sodium croscarmellose; microcrystalline cellulose; povidone K-25; magnesium stearate; Opadry white 03F180011 (hypromellose, titanium dioxide (E 171), macrogol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: elongated, film-coated tablets of white color, with engraving «L04» on one side for 4 mg tablets and «L08» for 8 mg tablets.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic drugs. Oxicams. ATC code M01A C05.

Pharmacological Properties

Pharmacodynamics.

Lornoxicam is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and anti-inflammatory properties, belonging to the oxicam class. Its mechanism of action is primarily related to inhibition of prostaglandin synthesis (inhibition of the enzyme cyclooxygenase), leading to desensitization of peripheral nociceptors and suppression of inflammation. A central effect on nociceptors, unrelated to anti-inflammatory activity, is also presumed. Lornoxicam does not affect vital parameters (such as body temperature, respiratory rate, heart rate, arterial blood pressure, ECG, spirometry).

The analgesic properties of lornoxicam have been successfully demonstrated in several clinical studies during its development.

Due to gastrointestinal irritation and systemic ulcerogenic effects associated with inhibition of prostaglandin synthesis, the use of lornoxicam, like other NSAIDs, frequently leads to the development of gastrointestinal complications.

Pharmacokinetics.

Absorption.

After oral administration, lornoxicam is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration (C_max) is reached within 1–2 hours (T_max) after administration. Absolute bioavailability of lornoxicam is 90–100%. No first-pass effect has been observed. When lornoxicam is taken simultaneously with food, C_max decreases by approximately 30%, and T_max increases from 1.5 to 2.3 hours. Absorption of lornoxicam (calculated based on the area under the plasma concentration-time curve (AUC)) may be reduced by 20%.

Distribution.

In plasma, lornoxicam is present in unchanged form and as its inactive hydroxylated metabolite. Plasma protein binding of lornoxicam is 99% and is independent of its concentration.

Metabolism.

Lornoxicam is actively metabolized in the liver via hydroxylation, primarily to its inactive metabolite, 5-hydroxy-lornoxicam. Lornoxicam undergoes biotransformation involving cytochrome CYP2C9. Due to genetic polymorphism, individuals with either slow or extensive metabolism of this enzyme exist, which may result in a significant increase in plasma lornoxicam levels in individuals with slow metabolism. The hydroxylated metabolite has no pharmacological activity. Lornoxicam is completely metabolized. Approximately two-thirds are excreted via the liver and one-third via the kidneys as inactive compounds. In animal models, lornoxicam did not induce hepatic enzymes. Clinical studies provided no evidence of lornoxicam accumulation after repeated administration of recommended doses. The absence of accumulation was confirmed by safety and efficacy monitoring data from studies lasting up to 1 year.

Elimination.

The elimination half-life of the parent compound is 3–4 hours. After oral administration, approximately 50% is excreted in feces and 42% via the kidneys, mainly as 5-hydroxy-lornoxicam. The elimination half-life of 5-hydroxy-lornoxicam is approximately 9 hours after parenteral administration once or twice daily.

Special patient populations.

Elderly patients.

In elderly patients (aged 65 years and older), clearance is reduced by 30–40%. Apart from this reduction in clearance, there are no significant changes in the kinetic profile of lornoxicam in elderly patients.

Patients with hepatic and/or renal impairment.

There is no significant change in the kinetic profile of lornoxicam in patients with renal or hepatic impairment, except for accumulation observed in patients with chronic liver disease after 7 days of therapy with daily doses of 12 mg and 16 mg.

Clinical characteristics.

Indications.

• Short-term treatment of mild to moderate acute pain.
• Symptomatic relief of pain and inflammation in osteoarthritis.
• Symptomatic relief of pain and inflammation in rheumatoid arthritis.

Contraindications.

• Hypersensitivity to the active substance and/or to excipients of the medicinal product.
• Hypersensitivity (symptoms similar to those observed with asthma, rhinitis, angioneurotic edema, or urticaria) to other NSAIDs, including acetylsalicylic acid.
• Gastrointestinal bleeding, cerebrovascular or other bleeding.
• History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
• Active recurrent gastric ulcer/bleeding or history of recurrent gastric ulcer/bleeding (two or more distinct documented episodes of ulceration or bleeding).
• Thrombocytopenia.
• Severe heart failure.
• Severe hepatic impairment.
• Severe renal impairment (plasma creatinine level > 700 µmol/L).
• Third trimester of pregnancy (see section "Use in pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction.

The following interactions may occur when administered concomitantly with lornoxicam.

Cimetidine.

Concomitant use may increase plasma levels of lornoxicam (no interactions were observed between lornoxicam and ranitidine or between lornoxicam and antacids).

Anticoagulants.

Concomitant use may enhance the effect of anticoagulants, e.g., warfarin (see section "Special warnings and precautions for use"). Careful monitoring of the international normalized ratio (INR) is recommended when these medicinal products are used together.

Phenprocoumon.

Concomitant use reduces the effectiveness of phenprocoumon treatment.

Heparin.

Concomitant use may increase the risk of spinal or epidural hematoma during spinal or epidural anesthesia (see section "Special warnings and precautions for use").

Angiotensin-converting enzyme (ACE) inhibitors.

Concomitant use may reduce the effect of ACE inhibitors.

Diuretics.

Concomitant use may reduce the diuretic and antihypertensive effects of loop, thiazide, and potassium-sparing diuretics.

Beta-adrenergic blockers.

Concomitant use may reduce the antihypertensive effect of beta-blockers.

Angiotensin II receptor blockers.

Concomitant use may reduce the antihypertensive effect of angiotensin II receptor blockers.

Digoxin.

Concomitant use may reduce renal clearance of digoxin.

Corticosteroids.

Concomitant use may increase the risk of gastrointestinal ulcers or bleeding (see section "Special warnings and precautions for use").

Quinolone antibacterial agents.

Concomitant use may increase the risk of seizures.

Antiplatelet agents.

Concomitant use increases the risk of gastrointestinal bleeding (see section "Special warnings and precautions for use").

Other NSAIDs.

Concomitant use increases the risk of gastrointestinal bleeding.

Methotrexate.

Concomitant use increases methotrexate plasma levels, leading to increased toxicity. Careful monitoring of the patient is recommended when these medicinal products are used together.

Selective serotonin reuptake inhibitors (SSRIs).

Concomitant use increases the risk of gastrointestinal bleeding (see section "Special warnings and precautions for use").

Lithium preparations.

Concomitant use reduces renal clearance of lithium, potentially leading to plasma lithium concentrations exceeding the toxic threshold. Plasma lithium levels should be monitored when these medicinal products are used together, especially at the beginning of treatment, during dose adjustments, and upon discontinuation of treatment.

Cyclosporine.

Concomitant use may increase cyclosporine plasma levels and nephrotoxicity due to effects mediated by renal prostaglandins. Careful monitoring of renal function is recommended when these medicinal products are used together.

Sulfonylurea derivatives (e.g., glyburide).

Concomitant use increases the risk of hypoglycemia.

Known inducers and inhibitors of CYP2C9 isoenzymes.

Lornoxicam (like other NSAIDs metabolized by cytochrome P450 2C9 (CYP2C9 isoenzyme)) interacts with known inducers and inhibitors of CYP2C9 isoenzymes (see section "Metabolism").

Tacrolimus.

Concomitant use increases the risk of nephrotoxicity due to reduced renal prostacyclin synthesis. Monitoring of renal function is recommended when these medicinal products are used together (see section "Special warnings and precautions for use").

Pemetrexed.

Concomitant use may reduce pemetrexed renal clearance, thereby increasing renal, gastrointestinal toxicity, and myelosuppression.

Since food intake slows the absorption of lornoxicam, the medicinal product should not be taken with food when a rapid onset of therapeutic effect (pain relief) is required. Food intake reduces absorption by approximately 20% and increases Tmax.

Special precautions for use.

The medicinal product should be used only after careful assessment of the expected benefit of therapy and possible risk in the following conditions.

The medicinal product should be used with caution in patients with mild (plasma creatinine level 150–300 µmol/L) and moderate renal impairment (plasma creatidine level 300–700 µmol/L) due to the important role of prostaglandins in maintaining renal blood flow. In case of renal function impairment, the use of the medicinal product should be discontinued.

After extensive surgical procedures, patients with heart failure who are taking diuretics or medicinal products that may cause renal damage require careful monitoring of renal function.

During the use of the medicinal product in patients with coagulation disorders, careful clinical examination and assessment of laboratory parameters (e.g., activated partial thromboplastin time) are recommended.

During the use of the medicinal product at a dose of 12–16 mg per day in patients with hepatic impairment (e.g., liver cirrhosis), regular laboratory tests are recommended due to the possible accumulation of lornoxicam in the body (increased AUC). However, no deviations in pharmacokinetic parameters were observed in patients with hepatic impairment compared to healthy volunteers.

During prolonged use of the medicinal product (more than 3 months), blood status (hemoglobin determination), renal function (creatinine determination), and liver enzymes should be monitored.

During the use of the medicinal product in elderly patients, renal and hepatic function should be monitored. The medicinal product should be used with caution in such patients after surgical procedures.

Avoid concomitant use of the medicinal product with other NSAIDs, including selective cyclooxygenase-2 inhibitors.

Adverse reactions can be minimized by using the lowest effective dose of lornoxicam for the shortest duration necessary to control disease symptoms.

During the use of any NSAID (including lornoxicam) at any time during treatment, gastrointestinal bleeding, ulceration, or perforation (with or without warning symptoms or history of serious gastrointestinal disorders) may occur, which can be fatal.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses in patients with a history of peptic ulcers, especially those complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Initiation of treatment in such patients should be done with particular caution and at the lowest therapeutic doses.

The medicinal product should be used with caution in the above-mentioned patient groups and in patients who are concurrently taking low-dose acetylsalicylic acid or other drugs that increase the risk of gastrointestinal complications (see section "Interaction with other medicinal products and other forms of interaction").

For patients requiring such concomitant therapy, treatment may be administered with concomitant use of protective agents, such as misoprostol or proton pump inhibitors (see section "Interaction with other medicinal products and other forms of interaction"). Clinical monitoring at regular intervals is recommended.

During the use of the medicinal product in patients with a history of gastrointestinal toxicity, especially elderly patients, they should be informed about any unusual abdominal symptoms (particularly gastrointestinal bleeding) at the initial stages of treatment.

The medicinal product should be used with particular caution in patients who are concurrently taking drugs that may increase the risk of ulceration or bleeding, e.g., oral corticosteroids, anticoagulants – warfarin, SSRIs, or antiplatelet agents such as acetylsalicylic acid (see section "Interaction with other medicinal products and other forms of interaction").

In case of gastrointestinal bleeding or ulceration in patients taking lornoxicam, the use of the medicinal product should be discontinued.

The medicinal product should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn's disease), as their condition may worsen (see section "Side effects").

In elderly patients, the frequency of adverse reactions during NSAID use increases, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "Contraindications").

The medicinal product should be used with caution in patients with a history of arterial hypertension and/or heart failure, as edema and fluid retention may occur due to NSAID use.

Patients with a history of arterial hypertension and/or mild to moderate chronic heart failure require monitoring during the use of the medicinal product, as NSAID treatment may be associated with fluid retention and edema.

Clinical studies and epidemiological data suggest that the use of some NSAIDs (especially long-term therapy and high doses) may be associated with a small increased risk of arterial thrombotic events (myocardial infarction or stroke). There are insufficient data to exclude such a risk with lornoxicam use.

The medicinal product should be used only after careful assessment of indications in patients with uncontrolled arterial hypertension, chronic heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disorders. Assessment is also required before prolonged use of the medicinal product in patients with risk factors for cardiovascular diseases (e.g., hypertension, hyperlipidemia, diabetes, smoking).

Concomitant use of lornoxicam with heparin increases the risk of spinal/epidural hematoma during spinal or epidural anesthesia (see section "Interaction with other medicinal products and other forms of interaction").

During the use of lornoxicam, severe skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, may very rarely occur, sometimes with fatal outcomes (see section "Side effects"). The risk of such reactions is highest at the beginning of treatment: most cases occur within the first month of lornoxicam use. The use of the medicinal product should be discontinued at the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity.

The medicinal product should be used with caution in patients with bronchial asthma or a history of this condition, as NSAIDs have been reported to provoke bronchospasm in such patients.

During the use of lornoxicam in patients with systemic lupus erythematosus or mixed connective tissue disease, the risk of aseptic meningitis may increase.

Lornoxicam inhibits platelet aggregation, thereby prolonging blood clotting time. The medicinal product should be used with caution in patients with a tendency to bleeding.

Concomitant use of lornoxicam with tacrolimus may increase the risk of nephrotoxicity due to reduced prostacyclin synthesis in the kidneys. In case of such combination therapy, renal function should be carefully monitored.

During the use of lornoxicam, transient elevations in plasma transaminases and bilirubin, increased plasma urea and creatinine levels, and other laboratory parameter deviations from normal may occur. If laboratory abnormalities are significant and persistent, the use of the medicinal product should be discontinued and appropriate investigations performed.

Lornoxicam, like other agents that inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility; therefore, it is not recommended for use in women attempting to conceive. Women experiencing difficulty in becoming pregnant or undergoing infertility evaluation should discontinue the use of the medicinal product.

In rare cases, severe skin and soft tissue infections may develop in the presence of chickenpox. The influence of NSAIDs on worsening the course of such infections cannot be excluded. The use of the medicinal product is not recommended in patients with active chickenpox.

The medicinal product contains lactose; therefore, it should not be used in patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

The medicinal product is contraindicated during the third trimester of pregnancy. There are no clinical data on the use of lornoxicam during the first and second trimesters of pregnancy and during labor; therefore, the medicinal product is not recommended during this period.

There are insufficient data on the use of lornoxicam in pregnant women. Animal studies have shown reproductive toxicity.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital heart defects with the use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with higher doses and longer duration of therapy. In animals, prostaglandin synthesis inhibitors cause increased pre- and post-implantation loss and embryofetal mortality.

Prostaglandin synthesis inhibitors should not be used during the first and second trimesters of pregnancy. Use is possible only if absolutely necessary.

From the 20th week of pregnancy, the use of lornoxicam may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after the start of treatment and is usually reversible after discontinuation of therapy. Additionally, there have been reports of arterial duct constriction after treatment during the second trimester, most of which resolved after discontinuation of therapy. It is recommended to avoid the use of NSAIDs from the 20th week of pregnancy onwards.

If NSAID use is necessary between the 20th and 28th weeks of pregnancy, the lowest effective dose of the medicinal product for the shortest possible duration is recommended.

Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after lornoxicam exposure for several days starting from the 20th gestational week. The use of the medicinal product should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, the use of any prostaglandin synthesis inhibitors may have the following effects on the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with the development of oligohydramnios (see above).

The pregnant woman and the fetus near term may be affected by the use of prostaglandin synthesis inhibitors as follows:

• possible prolongation of bleeding time;
• inhibition of uterine contractility, which may lead to delayed or prolonged labor.

Therefore, the use of the medicinal product is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Period of breastfeeding.

There are no data on the excretion of lornoxicam into human breast milk. High concentrations of lornoxicam are excreted into the milk of lactating rats. The medicinal product should not be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

If dizziness and/or drowsiness occur after using the medicinal product, driving or operating machinery should be avoided.

Dosage and Administration.

The medicinal product is intended for oral use. Tablets should be taken orally with sufficient amount of water.

Adverse reactions can be minimized by using the lowest effective dose of lornoxicam for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

For all patients, the appropriate dosage regimen should be based on individual response to treatment.

Pain.

The medicinal product should be administered at a dose of 8–16 mg daily, divided into 2–3 doses. The maximum recommended daily dose is 16 mg.

Osteoarthritis and rheumatoid arthritis.

The medicinal product should be initiated at a dose of 12 mg daily, divided into 2–3 doses. The maintenance dose should not exceed 16 mg daily.

Elderly patients.

Elderly patients, except those with hepatic or renal impairment, do not require dose adjustment; however, the medicinal product should be used with caution in these patients due to the increased likelihood of gastrointestinal adverse reactions.

Patients with renal impairment.

For patients with mild to moderate renal impairment, the maximum recommended daily dose of lornoxicam is 12 mg, divided into 2–3 doses.

Patients with hepatic impairment.

For patients with moderate hepatic impairment, the maximum recommended daily dose of lornoxicam is 12 mg, divided into 2–3 doses (see section "Special Warnings and Precautions for Use").

Children.

The medicinal product is not recommended for use in children under 18 years of age due to insufficient data on efficacy and safety of lornoxicam.

Overdose.

Currently, there are no data on lornoxicam overdose that would allow determination of its consequences or suggest specific treatment. However, symptoms of lornoxicam overdose may include: nausea, vomiting, central nervous system symptoms (dizziness, visual disturbances); in severe cases – ataxia progressing to coma and seizures; liver and kidney damage, and possible impairment of blood coagulation.

In case of actual or suspected overdose, administration of the medicinal product should be discontinued. Due to the short elimination half-life, lornoxicam is rapidly eliminated from the body. It is not dialyzable. There is no specific antidote available. Standard emergency measures should be initiated, including gastric lavage. According to general principles, only activated charcoal, if administered immediately after lornoxicam overdose, may reduce its absorption. For management of gastrointestinal disturbances, for example, a prostaglandin analogue or ranitidine may be used.

Adverse Reactions

The most common adverse reactions associated with NSAIDs are gastrointestinal in nature. Peptic ulcers, perforation, or gastrointestinal bleeding may occur during NSAID therapy, sometimes resulting in fatal outcomes, particularly in elderly patients (see section "Special Warnings and Precautions for Use"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and Crohn’s disease have been reported during treatment with NSAIDs. Gastritis has been observed less frequently.

It is estimated that approximately 20% of patients treated with lornoxicam may experience adverse reactions. The most commonly reported adverse reactions include nausea, dyspepsia, digestive disorders, abdominal pain, vomiting, and diarrhea. These symptoms were generally observed in less than 10% of patients participating in clinical trials.

Edema, arterial hypertension, and heart failure have been reported during NSAID therapy.

Clinical trials and epidemiological data suggest that the use of certain NSAIDs, especially at high doses and during long-term treatment, may be associated with an increased risk of arterial thrombotic events such as myocardial infarction or stroke (see section "Special Warnings and Precautions for Use").

Very rarely, severe skin and soft tissue infections have been reported during varicella (chickenpox) infection.

Adverse reactions are classified by frequency as follows: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations:

Rare – pharyngitis.

Blood and lymphatic system disorders:

Rare – anemia, thrombocytopenia, leukopenia, prolonged bleeding time; very rare – ecchymosis. NSAIDs may cause potentially serious hematological disorders specific to this class of drugs, such as neutropenia, agranulocytosis, aplastic anemia, and hemolytic anemia.

Immune system disorders:

Rare – hypersensitivity reactions, anaphylactoid reactions, and anaphylaxis.

Metabolism and nutrition disorders:

Uncommon – loss of appetite, changes in body weight.

Psychiatric disorders:

Uncommon – insomnia, depression; rare – confusion, nervousness, agitation.

Nervous system disorders:

Common – mild and transient headache, dizziness; rare – somnolence, paraesthesia, taste disturbances (dysgeusia), tremor, migraine; very rare – aseptic meningitis in patients with systemic lupus erythematosus (SLE) or mixed connective tissue disease (see section "Special Warnings and Precautions for Use").

Eye disorders:

Uncommon – conjunctivitis; rare – visual disturbances.

Ear and labyrinth disorders:

Uncommon – vertigo, tinnitus.

Cardiovascular disorders:

Uncommon – palpitations, tachycardia, edema, heart failure, facial flushing; rare – hypertension, hot flushes, hemorrhage, bruising.

Respiratory, thoracic and mediastinal disorders:

Uncommon – rhinitis; rare – dyspnea, cough, bronchospasm.

Gastrointestinal disorders:

Common – nausea, abdominal pain, dyspepsia, diarrhea, vomiting; uncommon – constipation, flatulence, belching, dry mouth, gastritis, gastric ulcer, upper abdominal pain, duodenal ulcer, oral mucosal ulceration; rare – melena, vomiting blood, stomatitis, esophagitis, gastroesophageal reflux, dysphagia, aphthous stomatitis, glossitis, peptic ulcer perforation, gastrointestinal hemorrhage.

Hepatobiliary disorders:

Uncommon – increased liver enzymes (ALT, AST); very rare – hepatotoxicity, which may lead to liver failure, hepatitis, jaundice, cholestasis.

Skin and subcutaneous tissue disorders:

Uncommon – rash, pruritus, increased sweating, erythematous rash, urticaria, angioneurotic edema, alopecia; rare – dermatitis, eczema, purpura; very rare – edema and bullous reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders:

Uncommon – arthralgia; rare – bone pain, muscle spasms, myalgia.

Renal and urinary disorders:

Rare – nocturia, urinary disorders, increased plasma urea and creatinine levels; very rare – lornoxicam may cause acute renal failure in patients with conditions dependent on renal prostaglandins, which play an important role in maintaining renal blood flow (see section "Special Warnings and Precautions for Use"). Nephrotoxicity in various forms, including nephritis and nephrotic syndrome, is an effect specific to NSAIDs.

General disorders and administration site conditions:

Uncommon – malaise, facial swelling; rare – asthenia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life

3 years.

Storage conditions

Store at temperatures not exceeding 25°C, in a place inaccessible to children.

Packaging

Film-coated tablets, 4 mg: 10 tablets per blister; 1, 2, 5, or 10 blisters per cardboard box.

Film-coated tablets, 8 mg: 10 tablets per blister; 1, 2, 5, or 10 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

WORLD MEDICINE ILAC SAN. VE TIC. A.S.
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and place of business

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey

Marketing Authorization Holder

WORLD MEDICINE, LLC, Ukraine