COMPOSITION:

active substance: lornoxicam;

1 tablet contains 4 mg or 8 mg of lornoxicam;

Excipients:

Lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate, Оpadry white 03F58750.

*Оpadry white 03F58750:

Talc, polyethylene glycol, hydroxypropyl methylcellulose, titanium dioxide (E 171).

INDICATIONS:

– Treatment of mild or severe pain syndrome.

– Symptomatic treatment of pain and inflammation at inflammatory and degenerative rheumatic diseases.

DOSAGE:

At mild or severe pain syndrome recommended dose is 8 – 16 mg per day split into 2 – 3 intakes.

At inflammatory and degenerative rheumatic diseases recommended initial dose is 12 mg split into 2 – 3 intakes.

Maximum daily dose should not exceed 16 mg per day.

Larfix® tablets should be taken before meals with water following.

Daily dose and duration of therapy are determined individually according to the nature and state of disease.

Elderly patients (over 65 years) do not require dose adjustment but should administer Larfix® drug carefully due to the risk of gastrointestinal adverse reactions occurrence.

Maximum daily dose should not exceed 16 mg per day.

For patients with mild and severe renal failure and severe liver failure recommended daily dose is 12 mg split into 2 – 3 intakes.

ADVERSE REACTIONS:

It is recognized that about 20% of patients may have adverse reactions. The most frequent are those common for all other non-steroidal anti-inflammatory drugs associated with gastrointestinal tract disorders: gastrointestinal ulcers with enterobrosia that can be severe; nausea, vomiting with blood; diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease. There were rare cases of gastritis.

Undesirable effects that may occur at Larfix® drug administration are classified into following groups depending of their frequency rate: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1 000, < 1/100), rare (> 1/10 000, < 1/1 000), very rare (1/10 000).

Infections and invasions.

Rare:

Pharyngitis. Haemopoiesis and lymphatic system disorders.

Rare:

Anemia, thrombocytopenia, eosinophilia, leukopenia, impaired coagulation, pancytopenia.

Very rare:

Ecchymosis. Some records show that NSAIDs may cause severe hematologic disorders, namely neutropenia, agranulocytosis, hypoplastic and hemolytic anemia.

Immune system disorders.

Rare:

Hypersensitivity reactions, fever, shivering, anaphylactoid reactions, anaphylaxis.

Metabolic disorders.

Uncommon:

Appetite loss, body weight changes.

Endocrine system disorders.

Rare:

Hypernatremia.

Psychiatric disorders.

Uncommon:

insomnia, depression.

Rare:

Anxiety, mental confusion, hypererethism, impaired concentration, attention disorders, cognitive abnormalities.

Central nervous system disorders.

Common:

Moderate short-term headache, dizziness.

Rare:

Somnolence, paresthesia, dysgeusia, tremor, migraine, hyperkinesia, hypesthesia.

Very rare:

Aseptic meningitis in patients with systemic lupus erythematosus and mixed connective tissue diseases.

Vision disorders.

Uncommon:

Conjunctivitis.

Rare:

Visual impairments, including blurred vision, color perception disorders, visual field defects, scotoma, amblyonia, diplopia, iridocyclitis.

Ear and labyrinth disorders.

Uncommon:

Vertigo, tinnitus.

Cardiovascular system disorders.

Uncommon:

Irregular heartbeat, tachycardia, edemas, fluid retention, heart failure, flush.

Rare:

Arterial hypertension, fluxions, congestions, vasculitis, hematomas.

Respiratory system, chest organs and mediastinal disorders.

Uncommon:

Rhinitis.

Rare:

Dyspnoea, cough, bronchospasm.

Gastrointestinal tract disorders.

Common:

Nausea, stomach pain, dyspepsia, diarrhea, vomiting.

Uncommon:

Constipation, flatulence, eructation, dry mouth, gastritis, peptic ulcers, abdominal pain, bleeding gums, ulcerative stomatitis.

Rare:

Melena, vomiting with blood, stomatitis, esophagitis, gastroesophageal reflux disease, dysphagia, aphthous stomatitis, glossitis, peptic ulcers perforations, hemorrhoid, gastrointestinal bleedings.

Hepatobiliary system disorders.

Uncommon:

Increase of liver enzymes levels (ALT, AST).

Very rare:

Toxic effect on liver that may result in liver failure, hepatitis, jaundice, and cholestasis.

Disorders of skin and subcutaneous tissues.

Uncommon:

Rash, itching, hyperhidrosis, erythematous rashes, urticaria, angioneurotic edema, alopecia.

Rare:

dermatitis, eczema, maculopapular rash, purpura.

Very rare:

Edema and bullous reactions, changes in nail structure, psoriasis, erythema multiforme, Stevens – Johnson syndrome, toxic epidermal necrolysis.

Disorders of muscular-skeletal system and connective tissues.

Uncommon:

Arthralgia.

Rare:

Bones and back pain, muscle spasms, muscle weakness, myalgia, synovitis.

Kidneys and urinary system disorders.

Rare:

Nocturia, urinary disorders, increase of urea nitrogen and creatinine blood levels.

Very rare:

Lornoxicam may cause acute renal failure in patients having kidney diseases. There are registered cases of nephritis, nephrotic syndrome, and renal papillary necrosis development due to NSAIDs administration.

General disorders.

Uncommon:

General uneasiness, facial edema.

Rare:

Asthenia.

Drug interactions:

– Cimetidine:

Increase of serum lornoxicam concentration (no interaction of lornoxicam and ranitidine, or lornoxicam and antacids has been demonstrated).

– Anticoagulating agents:

Non-steroidal anti-inflammatory drugs may cause increased effect of anticoagulating agents (namely, warfarin, anisindione, dicoumarol, phenedione) that leads to bleeding time increasing.

– Phenprocoumon:

Efficacy of phenprocoumon therapy is decreased.

– Heparin:

Non-steroidal anti-inflammatory drugs used with heparin increase spinal epidural hematoma occurrence risk at spinal or epidural anesthesia.

– ATE inhibitors:

May decrease effect of ATE inhibitors.

– Diuretics:

Lessening of diuretic and hypotensive effect of loop, thiazide, and potassium-sparing diuretics.

– β-adrenoreceptor blockers:

Aecrease of hypotensive effect.

– Angiotensin II receptor blockers:

decrease of hypotensive effect.

– Digoxin:

decreased renal clearance of digoxin.

– Corticosteroids:

elevated risk of gastrointestinal ulcers and bleedings;

– Quinolone antibacterial drugs:

increased risk of epileptic events occurrence.

– Antiplatelet drugs:

increased risk of gastrointestinal bleedings.

– Other NSAIDs:

increased risk of gastrointestinal bleedings.

– Methotrexate:

elevated serum methotrexate concentration, causing its toxicity increasing. At concomitant use meticulous monitoring is required.

– Serotonin reuptake inhibitors:

increased risk of gastrointestinal bleedings.

– Lithium drugs:

non-steroidal anti-inflammatory drugs may decrease renal lithium clearance with further elevation of its serum concentration. It is necessary to control serum lithium level, specifically at treatment beginning, dose adjustment, and therapy cessation stages.

– Cyclosporine:

elevated serum cyclosporine concentration, cyclosporine nephrotoxicity increasing is possible. At combined therapy renal function control is necessary.

– Sulfonylurea drugs (for example, glibenclamide):

hypoglycemic effect increasing is possible.

– Lornoxicam

(like other NSAIDs metabolized by cytochrome system CYP2C9) interacts with common inductors and inhibitors of CYP2C9 isoenzymes (namely, tranylcypromine and rimphamycine).

– Tacrolimus:

concomitant use of NSAIDs and tacrolimus may increase nephrotoxicity risk consequent to renal prostacyclin synthesis decreasing. At such combined therapy thorough renal function control is necessary.

– Pemetrexed:

NSAIDs may decrease renal pemetrexed clearance that leads to increased renal and gastrointestinal toxicity, along with myelosuppression.

Pregnancy and lactation:

Administration of drug is not recommended for pregnant women in III trimester. There is no clinical data as for Larfix® administration in I – II trimesters and its excretion in breast milk at lactation, therefore drug is not used during pregnancy or breastfeeding.

Children:

Drug is contraindicated in children (under 18 years) with reference of insufficient clinical data as for its efficacy and safety.

PRECAUTIONS:

Patients with renal failure (serum creatinine level is 150 – 300 mcmol/l) and moderate renal failure (serum creatinine level is 300 – 700 mcmol/l) should administer drug exceptionally after meticulous benefits / risks assessment. In case of kidney function decrease, therapy should be stopped.

Patients after extensive surgical interference with heart failure administering diuretics or drugs that may lead to kidneys damaging should have careful renal function control.

Patients with impaired coagulation should pass intensive clinical examination and laboratory figures assessment (in particular, partial thrombin time test) since lornoxicam inhibits thrombocyte aggregation, thus increasing blood coagulation time.

Patients with liver failure (for example, liver cirrhosis) upon drug administration in the dose of 12 – 16 mg per day are recommended to pass laboratory tests in view of lornoxicam body accumulation possibility (increasing of AUC). However, there were no pharmacokinetic characteristics abnormalities in patients with liver failure, compared to healthy volunteers.

At long-term therapy (above 3 months), it is recommended to evaluate blood condition (hemoglobin estimation), renal function (creatinine estimation) and liver enzymes.

Elderly patients (over 65 years) are recommended to control kidneys and liver functioning and be careful when administering Larfix® after surgical interference.

It is desired to avoid concomitant lornoxicam use with other NSAIDs, in particular with selective cyclooxygenase-2 inhibitors.

Undesirable reactions can be minimized by administering the lowest effective dose of the drug.

Administration of NSAIDs can be associated with gastrointestinal bleedings, ulcers and perforations having lethal outcome. Patients with ulcers in anamnesis complicated by bleedings or perforations, as well as elderly patients, should take special precautions at starting Larfix® therapy with the lowest therapeutical doses.

Larfix® should be carefully used in patients concomitantly administering drugs that increase ulcer and bleedings occurrence risk (see part “Drug interactions and other types of interactions”). Patients requiring such conjoint therapy can have treatment in the setting of proton pump inhibitors concomitant use, along with meticulous monitoring.

Elderly patients may have increased adverse reactions occurrence risk at NSAIDs administration, in particular gastrointestinal bleedings and perforation. In case of any gastrointestinal adverse reactions, it is necessary to seek medical attention immediately.

Patients with arterial hypertension and/or heart failure should carefully administer Larfix® with obligatory prior thorough analysis since NSAIDs may cause edemas and fluid retention in the body.

Patients with uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, cerebrovascular disorders, increased risk factors of cardiovascular diseases (arterial hypertension, hyperlipidemia, diabetes mellitus, and smoking) should start treatment exceptionally after intensive analysis.

Concomitant use of NSAIDs and heparin increases spinal epidural hematoma occurrence risk at spinal or epidural anesthesia.

Administration of NSAIDs, particular at the beginning of treatment, occasionally was associated with severe adverse skin reactions, namely exfoliative dermatitis, Stevens – Johnson syndrome, and toxic epidermal necrolysis. Therapy should be stopped at first symptoms occurrence (skin rash, blennosis, and other hypersensitivity symptoms).

Patients with bronchial asthma, including that in anamnesis, should carefully administer NSAIDs because of bronchospasm development cases.

Patients with systemic lupus erythematosus and mixed connective tissue diseases may have increased aseptic meningitis risk.

Lornoxicam inhibits thrombocyte aggregation, thus increasing blood coagulation time. Therefore, drug should be carefully indicated in patients predisposed to bleeding.

Concomitant indication of NSAIDs and tacrolimus may cause increased risk of nephrotoxicity consequent to renal prostacyclin synthesis decreasing. At such combined therapy thorough renal function control is necessary.

Like other NSAIDs, Larfix® may cause episodic increase of transaminases and bilirubin serum levels, as well as increase of urea nitrogen and creatinine blood levels. In case laboratory figures abnormalities are significant and last for a long time, treatment should be stopped and adequate examination should have place.

Patients with rare hereditary galactose intolerance, lactase deficiency, and glucose-galactose malabsorption should avoid drug administration.

Like other cyclooxygenase synthesis inhibitors, lornoxicam may suppress fertility. So it is not recommended in pregnancy planning women.

Patients with chicken pox should not administer the drug.

Overdose:

Overdose of Larfix® drug may result in following symptoms occurrence:

Nausea, vomiting, cerebral symptoms (dizziness, visual disorders), ataxia leading to coma and convulsions; liver and kidneys functions changing is also possible; impaired coagulation.

In case of overdose it is necessary to stop drug administration. Due to its short elimination half-life, lornoxicam is rapidly eliminated. Lornoxicam is not dialyzable. At the present moment there is no specific antidote. General emergency measures are necessary to be taken, including gastric lavage. Based on common principles, intake of activated carbon shortly after Larfix® overdose may decrease drug absorption. Treatment is symptomatic.

Ability to influence reaction velocity while driving or operating any other mechanisms

In case of vertigo and/or somnolence upon drug administration it is recommended to avoid driving cars or operating other mechanisms.

CONTRAINDICATIONS:

– Hypersensitivity to lornoxicam or drug components;

– Thrombocytopenia;

– Hypersensitivity (symptoms are similar to those of bronchial asthma, rhinitis, angioneurotic edema, or urticaria) to other non-steroidal anti-inflammatory drugs including acetylsalicylic acid;

– Severe heart failure;

– Gastrointestinal bleedings, cerebrovascular bleedings or other hematological disorders;

– Gastrointestinal bleedings or perforations in anamnesis due to prior administration of non-steroidal anti-inflammatory drugs;

– Active peptic ulcer or recurrent peptic ulcer / bleedings in anamnesis (two or more proven cases of ulcer or bleeding);

– Severe liver failure;

– Severe renal failure (serum creatinine level >700 mcmol/l).

PHARMACOLOGICAL PROPERTIES:

Pharmacodynamics. Lornoxicam is non-steroidal anti-inflammatory drug of the oxicam class with analgesic and anti-inflammatory properties. Its mechanism of action is partially based on prostaglandins inhibition (cyclooxygenase inhibition). Cyclooxygenase inhibition does not cause enhanced leukotriene generation. Analgesic effect is not associated with narcotic action. Lornoxicam does not have opiate-like effect on CNS and opposed to narcotic analgesics does not inhibit breath and is not associated with drug dependence.

Pharmacokinetics. Lornoxicam is absorbed rapidly and almost completely from gastrointestinal tract. Maximum serum concentration Cmax is reached in 1 – 2 hours after drug administration. Absolute lornoxicam bioavailability equals 90 – 100%. First pass effect was not observed. Mean elimination half-life is 3 – 4 hours. At concomitant intake with food Cmax of lornoxicam is decreased by 30% and Tmax is increased from 1,5 hours to 2,3 hours. Lornoxicam absorption (calculated by area under concentration-time pharmacokinetic curve (AUC)) may decrease to 20%.

Lornoxicam is 99% bound to plasma proteins, irrespective to its concentration.

Serum lornoxicam is unchanged and has inactive form of its hydroxylated metabolite 5-hydroxylornoxicam with no pharmacological activity. Lornoxicam is metabolized by cytochrome system CYP2C9. Due to genetic polymorphism, there are persons with low and high metabolism, thus significant increase of serum lornoxicam level may occur in patients with low metabolism. Lornoxicam is completely metabolized. Approximately 2/3 of the drug is eliminated via the liver and 1/3 via the kidneys in the form of inactive compound.

Animal model trials did not show lornoxicam ability to induce liver enzymes. Clinical trials results did not present evidence of lornoxicam accumulation upon multiple administration of recommended doses.

Patients with renal and liver failures, as well as elderly patients, did not notice significant changes in lornoxicam pharmacokinetics. Elderly patients (over 65 years) may have decreased lornoxicam clearance by 30 – 40%.

PHARMACEUTICAL CHARACTERISTICS:

General physico-chemical properties: film coated capsule-shaped pink tablets with etching “500” or “750” on one side.

tablets 8 mg:

Oval-shaped, prolonged, colored from white to off-yellow, film-coated, debossed with “L8” on one side and plain on the other side.

Shelf-life:

2 years.

Storage:

Store at the temperature not more than 25°С. Keep out of reach of children.

Package:

10 tablets in blister. 3 or 10 blisters in carton pack.

Conditions of supply:

By prescription.