for medical use
1 tabletcontains lornoxicam 4 mgor 8 mg;
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).
Pharmaceutical form. Film coated tablets.
Main physicochemical properties:
tablets 4 mg:oval-shaped, white to off-white, oblong coated tablets, smooth on both sides;
tablets 8 mg:oval-shaped, white to off-white, oblong coated tablets, embossed with “L8” on one side and smooth on the other side.
Pharmacotherapeuticgroup. Non-steroidal anti-inflammatory and antirheumatic agents.
ATC code M01AC05.
Lornoxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicams with anti-inflammatory and analgesic properties.
Mode of action. Lornoxicam inhibits the prostaglandin synthesis (inhibition of the cyclooxygenase enzyme) leading to desensitization of peripheral nociceptors and inhibition of inflammation. Lornoxicam also has a central effect on nociceptors which seems to be independent from anti-inflammatory action. Lornoxicam has no effect on vital signs (e.g. body temperature, respiratory rate, heart rate, blood pressure, ECG, spirometry).
Absorption. Lornoxicam is absorbed rapidly and almost completely from the gastrointestinal tract. Maximum blood plasma concentrations (Cmax) are achieved in approximately 1-2 hours after drug administration. The absolute bioavailability of lornoxicam is 90-100 %. No first-pass effect has been observed. The mean half-life is 3-4 hours.
Simultaneous intake of lornoxicam with food reduces Cmax by approximately 30% and Tmax increases from 1.5 to 2.3 hours. The absorption of lornoxicam (calculated on the area under the “concentration-time” curve (AUC) can be reduced to 20 %.
Distribution.Lornoxicam is found in blood plasma in unchanged form and as inactive form of its hydroxylated metabolite. The plasma protein binding of lornoxicam is 99 % and is not concentration dependent.
Biotransformation. Lornoxicam is extensively metabolized in the liver by hydroxylation, primarily to the inactive 5–hydroxylornoxicam. CYP2C9 is involved in biotransformation of lornoxicam. Due to genetic polymorphism, poor and extensive metabolizers exist for this enzyme which could result in markedly increased plasma levels of lornoxicam in poor metabolizers. The hydroxylated metabolite exhibits no pharmacological activity. Lornoxicam is metabolized completely. Approximately 2/3 is eliminated via the liver and 1/3 via the kidneys as inactive substance.
Lornoxicam did not induce liver enzymes in preclinical studies. There is no data on accumulation of lornoxicam after repeated administrations, when given according to recommended dosage.
Elimination. The elimination half-life of the parent compound is 3 to 4 hours. After oral administration about 50% is excreted in the faeces and 42% through the kidneys, mainly as 5-hydroxylornoxicam. The elimination half-life of 5-hydroxylornoxicam is about 9 hours after a parenteral single or twice daily doses.
In elderly patients (above 65) the clearance is reduced by 30-40 %. Apart from this reduced clearance there are no significant changes in the kinetic profile of lornoxicam in elderly patients.
There is no significant change in the kinetic profile of lornoxicam in patients with renal or hepatic failure, except for accumulation in patients with chronic liver disease after 7 days of treatment with daily doses of 12 and 16 mg.
- Short term treatment of mild to moderate acute pain.
- Symptomatic treatment of pain and inflammation in osteoarthritis.
- Symptomatic treatment of pain and inflammation in rheumatoid arthritis.
- Hypersensitivity to lornoxicam, or any of drug excipients.
- Hypersensitivity (symptoms, such as asthma, rhinitis, angioedema or urticaria) to other NSAIDs, including acetylic salicylic acid.
- Severe heart failure.
- Gastrointestinal bleedings, cerebrovascular bleedings or other blood coagulation disorders.
- History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
- Active or history of recurrent peptic ulceration/hemorrhage (two or more distinct episodes of proven ulceration or bleeding).
- Severe hepatic impairment.
- Severe renal impairment (serum creatinine > 700 µmol/l).
- The third trimester of pregnancy (see section «Use during pregnancy and lactation»).
Interaction with other medicinal products and other forms of interaction
Exposure of other medicinal products to lornoxicam.
Cimetidine: increased blood plasma concentrations of lornoxicam (no interaction between lornoxicam and ranitidine, or lornoxicam and antacids has been demonstrated).
Exposure of lornoxicam to other medicinal products.
Anticoagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section «Peculiarities of use»). Careful monitoring of international normalization ratio should be undertaken.
Phenprocoumon: decreased effect of phenprocoumon treatment.
ACE inhibitors: may reduce the ACE inhibitors action.
Diuretics: decreased diuretic and antihypertensive effect of loop, thiazide and potassium sparing diuretics.
Beta-adrenergic blockers: decreased antihypertensive efficacy.
Angiotensin II receptor blockers: decreased antihypertensive efficacy.
Methotrexate: increased blood serum concentration of methotrexate that results in an increase in its toxicity. When concomitant therapy has to be used careful monitoring should be undertaken.
Digoxin: decreased renal clearance of digoxin.
Lithium: NSAIDs inhibit renal clearance of lithium, thus the serum concentration of lithium may increase above toxicity limits. Therefore serum lithium levels require monitoring, especially during treatment initiation, adjustment and withdrawal of treatment.
Cyclosporine: increased blood serum concentration of cyclosporine. Nephrotoxicity of cyclosporine may be enhanced via renal prostaglandin mediated effects. Renal function should be monitored during combined treatment.
Known inducers and inhibitors of CYP2C9 isoenzymes: lornoxicam (as other NSAIDs depending on the cytochrome P450 2C9 (CYP2C9 isoenzyme)) interacts with known inducers and inhibitors of CYP2C9 isoenzymes (see section «Pharmacological properties»).
Pemetrexed: NSAIDs may reduce renal clearance of pemetrexed resulting in increased renal and gastrointestinal toxicity, and myelosuppression.
Other important information.
Heparin: NSAIDs increase the risk of spinal/epidural hematoma when given concomitantly to heparin during the spinal or epidural anesthesia (see section «Peculiarities of use»).
Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section «Peculiarities of use»).
Quinolone antibacterial agents: increased risk of seizures.
Anti-platelet agents: increased risk of gastrointestinal bleeding (see section «Peculiarities of use»).
Other NSAIDs: increased risk of gastrointestinal bleeding.
Selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section «Peculiarities of use»).
Sulphonylureas (e.g. glibenclamide): increased risk of hypoglycemia.
Tacrolimus: increase the risk of nephrotoxicity owing to reduced synthesis of prostacyclin in the kidneys. During combined treatment renal function should be monitored (see section «Peculiarities of use»).
Other forms of interaction. Food intake.
Lornoxicam is absorbed slowly when given with food, therefore, Larfix tablets should not be taken with food when a quick onset of efficacy (relief of pain) is required. Food intake reduces the absorption by about 20% and increases Tmax.
Peculiarities of use.
The drug should be administered for the patients with the following disorders only after careful risk-benefit assessment:
Mild (serum creatinine 150-300 µmol/l) and moderate (serum creatinine 300 – 700 µmol/l) renal impairment. Lornoxicam should be administered with precaution due to the important role of prostaglandins in maintenance of renal blood flow. Treatment with lornoxicam should be discontinued if renal function deteriorates during treatment.
State after extensive surgical interference; heart failure; administration of diuretics or drugs that may lead to kidneys damaging. Renal function should be carefully controlled by lornoxicam administration.
Impaired coagulation. Intensive clinical examination and laboratory figures assessment (in particular, partial thrombin time test) are recommended since lornoxicam inhibits thrombocyte aggregation, thus increasing blood coagulation time. The drug should be administered with caution for the patients with a predisposition to bleeding.
Hepatic impairment (e.g. liver cirrhosis). Laboratory tests at regular intervals should be considered in patients with hepatic impairment as accumulation of lornoxicam (increase in AUC) may occur after treatment with daily doses of 12-16 mg. There are no data as for pharmacokinetic divergence in parameters in patients with hepatic impairment.
A long-term therapy
Undesirable reactions can be minimized by administering the lowest effective dose of the drug during the shortest time necessary to control disease symptoms. At long-term therapy (3 months and longer), it is recommended to evaluate blood condition (hemoglobin estimation), renal function (creatinine estimation) and liver enzymes.
Monitoring of renal and hepatic function is recommended in elderly patients (above 65 years) and precaution is advised in elderly postoperative patients.
Concomitant use with other NSAIDs.
The use of lornoxicam with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
Gastrointestinal tract disorders.
Gastrointestinal bleeding, ulceration or perforation, which can be fatal, may occur with all NSAIDs at any time during treatment. The risk of gastrointestinal bleedings, ulcerations or perforations is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with hemorrhage or perforation (see section “Contraindications”), and in the elderly patients. These patients should commence treatment on the lowest therapeutic doses with extreme caution.
NSAIDs should be used with caution for abovementioned patients, and also for patients requiring concomitant low doses of acetylsalicylic acid or other drugs likely to increase gastrointestinal disorders (see section “Interaction with other medicinal products and other forms of interaction”). Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients. Clinical monitoring at regular intervals is recommended.
Patients with a history of gastrointestinal tract toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) in the initial stages of treatment.
Special caution should be exercised when prescribing the drug in patients who concomitantly take medicinal products which may increase the risk of ulcer or bleeding, for instance, oral corticosteroids, anticoagulants – warfarin, selective serotonin reuptake inhibitors or antithrombotic drugs – acetylsalicylic acid (see section “Interaction with other medicinal products and other forms of interaction”).
In case of bleeding or ulceration of the gastrointestinal tract in patients taking lornoxicam treatment should be discontinued.
NSAIDs should be used with caution in patients with history of gastrointestinal diseases (ulcerative colitis, Crohn's disease) as their condition may deteriorate.
In elderly patients the incidence of adverse reactions increases during the use of NSAIDs, in particular gastrointestinal bleeding and perforation, which may lead to lethal outcome (see section “Contraindication”).
Caution should be exercised when using the drug in patients with arterial hypertension and/or heart failure in the anamnesis, since using NSAIDs may cause swelling and fluid retention in the body.
The patients with arterial hypertension and/or mild to moderate congestive heart failure in the anamnesis should be monitored, because NSAIDs therapy may be accompanied with such symptoms as fluid retention and swelling.
There are data that suggest that use of some NSAIDs (particularly long-term therapy and high doses) may be associated with a slight increase in the risk of arterial thrombotic events (e.g. myocardial infarction or stroke). There is not enough data to exclude such risk when taking lornoxicam.
Lornoxicam should be prescribed in patients with uncontrolled arterial hypertension, chronic heart failure, ischemic heart disease, peripheral artery diseases and/or cerebrovascular disorders only after a thorough evaluation of indications. Evaluation is also required before prescribing a long-term treatment in patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking).
Concomitant treatment with NSAIDs and heparin increases the risk of spinal/epidural hematoma spinal or epidural anesthesia (see “Interaction with other medicinal products and other forms of interaction”).
Adverse skin reactions.
On the background of using NSAIDs very rarely skin reactions occur, they include exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrosis, sometimes some of them are fatal (see section “Adverse reactions”). The risk of such reactions is highest at the beginning of treatment: in most cases such reactions occur during the first month of drug therapy. Lornoxicam should be discontinued at the first sign of skin rash, mucosal lesions and other manifestations of hypersensitivity.
Caution should be exercised when using the drug in patients with bronchial asthma or with the history of this disease, since NSAIDs provoke bronchial spasm in patients.
Connective tissue diseases.
In patients with systemic lupus erythematosus and mixed connective tissue disease, the risk of aseptic meningitis may be increased.
Concomitant use of tacrolimus.
Influence on the results of laboratory tests
As well as other NSAIDs, lornoxicam may cause episodic increase in transaminases, bilirubin in the blood serum, and increase in blood concentrations of urea and creatinine, as well as other deviations in the laboratory parameters. If the deviations are significant and last for a long time, the treatment should be stopped and the necessary research should be conducted.
Lornoxicam, as well as other drugs that inhibit cyclooxygenase/prostaglandin synthesis may decrease fertility, it is not recommended in women trying to get pregnant. Lornoxicam should be discontinued in women having difficulty with getting pregnant or undergoing examination to determine the cause of infertility.
In the presence of chicken pox in exceptional cases severe infections of skin and soft tissues may develop. Until now the effect of NSAIDs on aggravation of these infections cannot be excluded. It is recommended to avoid using lornoxicam in the case of chicken pox.
The drug contains lactose. If you have known intolerance to some sugars, contact your physician before taking this medicinal product.
Use during pregnancy and lactation.
Lornoxicam is contraindicated during the III trimester of pregnancy. There is no clinical data regarding the use of lornoxicam in the I-II trimesters and during labor, therefore, the drug is not recommended in this period.
There is not enough clinical data on the use of lornoxicam in pregnant women. Animal studies have revealed reproductive toxicity.
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or development of the embryo/fetus. Epidemiological data suggest an increased risk of miscarriage, as well as development of cardiac defects when using prostaglandin synthesis inhibitors during early pregnancy. The risk increases with the increased dose and duration of therapy. In animals, the use of prostaglandin synthesis inhibitors results in increased pre- and postimplantation fetal death and embryo-fetal lethality. Prostaglandin synthesis inhibitors should not be used in the I and II trimesters of pregnancy. Application is possible only when absolutely necessary.
During the III trimester of pregnancy when using any prostaglandin synthesis inhibitors such effects on fetus are possible:
- cardiopulmonary toxicity (premature closure of the arterial duct and pulmonary hypertension);
- renal dysfunction, which may progress to renal failure, and thus to a reduction in amniotic fluid.
The pregnant women and the fetus in late pregnancy may be subject to some effects of the inhibitors of prostaglandin synthesis:
-possible prolongation of bleeding;
- inhibition of the contractile function of the uterus, which can lead to a delay or prolongation of labor.
Thus, the use of lornoxicam is contraindicated during the III trimester of pregnancy (see section “Contraindications”).
Breastfeeding period. There are no data on excretion of lornoxicam in human breast milk. Relatively high concentrations of lornoxicam are excreted in the milk of lactating rats. Therefore, lornoxicam should not be used during the breastfeeding period.
Effects on ability to drive and use machines
In case of dizziness and/or drowsiness due to drug administration, one shouldn’t drive or work with other machines.
Dosage and administration.
Larfix Tablets should be taken orally with enough water.
For all patients the appropriate dosage regime should be based on an individual response to the treatment.
8-16 mg lornoxicam daily, divided into 2-3 doses. The maximum recommended daily dose is 16 mg.
Osteoarthritis and rheumatoid arthritis
The recommended initial dose of lornoxicam is 12 mg daily, divided into 2-3 doses.
The maintenance dose should not exceed 16 mg daily.
Elderly (age 65 years and over), except for patients with impaired liver or kidney function, do not need dosage adjustment. But lornoxicam should be administered with precaution as there is a high probability of origin of gastrointestinal adverse effects.
Renal impairment. For patients with mild to moderate renal impairment the maximum recommended daily dose is 12 mg, divided in 2 or 3 doses.
Hepatic impairment. For patients with moderate hepatic impairment the maximum recommended daily dose is 12 mg, divided in 2 or 3 doses (see section “Peculiarities of use”).
Undesirable effects may be minimized by using the lowest effective drug dose for the shortest duration necessary to control symptoms (see section “Peculiarities of use”).
Lornoxicam should not be used in children below 18 years of age due to a lack of data on drug safety and efficacy.
At present, there is no experience of overdose to permit definition of the consequence of an overdose, or to suggest specific managements.
Symptoms: such symptoms as nausea, vomiting, cerebral symptoms (dizziness, visual disorders) can be observed. Severe symptoms are ataxia ascending to coma and cramps, liver and kidney damages; impaired coagulation is also possible.
Treatment: in the case of a real or suspected overdose, the medication should be withdrawn. Due to its short half-life, lornoxicam is rapidly excreted. Lornoxicam is not dialyzable. No specific antidote is known at present. The usual emergency measures including gastric lavage should be taken. Based on common principles, intake of activated charcoal shortly after Lornoxicam overdose can lead to diminished absorption of the preparation. Gastrointestinal disorders can for example be treated with a prostaglandin analogue or ranitidine.
Most commonly adverse reactions ofNSAIDsaffect gastrointestinal tract. When administered NSAIDs may occur peptic ulcer, perforation or gastrointestinal bleeding that sometimes are fatal, particularly in the elderly patients (see sect. «Peculiaritiesofuse»). Nausea, vomiting, diarrhea, flatulence,constipation, dyspepsia, stomachpain, melena, vomitingwithblood, aphthousstomatitis, exacerbation of colitis and Crohn's disease were registeredduring the NSAIDs treatment. Gastritiswasobservedlessfrequently.
Itisbelievedthataboutin 20 % of patients, treated with lornoxicam, adverse reactions may occur.Themostcommon adversereactionsoflornoxicamarenausea, dyspepsia,indigestion, stomach pain, vomiting, diarrhea. Thesesymptomsweregenerallyobservedless than in 10 % of patients which took part in the study. Edema, hypertensionandheart failure wereregisteredduringtheNSAIDstreatment.
ClinicalandepidemiologicaldatashowthatadministrationofsomeNSAIDs, especiallyathighdosesand on long-term use, canbeassociatedwithincreasedriskof arterial thromboembolic events, e.g., myocardial infarction and stroke (see section «Peculiarities of use»).
Exceptionallyseriousinfectiouscomplicationsof skinandsubcutaneoustissueduring chicken pox were reported.
Infections and invasions: pharyngitis.
Blood and lymphatic system adverse reactions: anemia, thrombocytopenia, leukopenia,prolonged bleeding time, ecchymosis. NSAIDs can cause class-specific potentially severe hematologic disorders such as neutropenia, agranulocytosis, aplastic and hemolytic anemia.
Immune system adverse reactions:hypersensitivity reactions, anaphylactoid reactions and anaphylaxis.
Metabolic adverse reactions: loss of appetite, changes of body weight.
Psychic adverse reactions: insomnia, depression, anxiety, nervosity, excitability.
Nervous system adverse reactions: mild and transient headache, dizziness, somnolence, paresthesia, dysgeusia, tremor, migraine, aseptic meningitis in patients with systemic lupus erythematous (SLE) and mixed connective tissue diseases (see sect. ” Peculiarities of use”).
Visual organs adverse reactions: conjunctivitis, visual disorder.
Acoustic organ and balance adverse reactions: vertigo, tinnitus.
Cardiovascular system adverse reactions: heartbeat, tachycardia, edemas, heart failure, flush, hypertension, congestions, hemorrhages, hematomas.
Respiratory system adverse reactions:rhinitis, dyspnoea, cough, bronchospasm.
GIT adverse reactions: nausea, stomach pain, dyspepsia, diarrhea, vomiting, constipation, flatulence, eructation, dry mouth, gastritis, peptic ulcers, midriff abdominal pain, duodenal ulcer, oral ulcers, melena, vomiting with blood, stomatitis, esophagitis, gastroesophageal reflux, dysphagia, aphthous stomatitis, glossitis, peptic ulcers perforations, gastrointestinal bleedings.
Liver and gallbladder adverse reactions: increase of liver enzymes level (ALT, AST), liver failure, hepatitis, jaundice, cholestasis.
Skin and subcutaneous tissue adverse reactions: rash, itching, hyperhidrosis, erythematous rashes, urticaria, angioneurotic edema, alopecia, dermatitis, eczema, purpura, edema and such bullous reactions as erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal system and connective tissue adverse reactions:arthralgia, bone pain, muscle spasms, myalgia.
Kidneys and urinary system adverse reactions:nocturia, urinary disorders, increase of urea nitrogen and creatinine blood levels, lornoxicam can cause acute renal failure in patients having kidney diseases, which depend on renal prostaglandins and play an important role in maintenance of renal blood flows (see sect. ”Peculiarities of use”). Nephrotoxicity in various forms including nephritis, nephrotic syndrome is a class-specific effect of NSAIDs.
General disorders: uneasiness, facial edema, asthenia.
Shelf life. 2 years.
Store at a temperature NMT 25°C.Keep it out of reach of children.
There are 10 tablets in a blister. There are 3 or 10 blisters in a carton box.
Conditions of supply.
SP 289 (A), RIICO Indl. Area, Chopanki, Bhiwadi (Raj.), India.
1 tablet contains 4 mg or 8 mg of lornoxicam. Non-steroidal anti-inflammatory and antirheumatic drugs.
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