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:

decrease 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

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 physic-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.