Each film coated tablet contains
Lornoxicam …………8 mg
For a full list of excipients, see section 6.1.

Therapeutic indications
Short term treatment of mild to moderate pain associated with extra articular inflammation. Symptomatic treatment of pain and inflammation in osteoarthritis and rheumatoid arthritis.

Posology and method of administration
Larfix film-coated tablets are supplied for oral administration with a sufficient quantity of liquid.
Lornoxicam is not recommended for use in children (under 18 years). No special dosage modification is required for elderly patients, unless renal or hepatic function is impaired, in which case the daily dosage should be considered.

For all patients the appropriate dosing regimen should be based upon individual response to treatment.
Lornoxicam should be given in doses of 4mg or 8 mg, and the daily dose should in general not exceed 16 mg. Renal and liver impairment
Reduction of dose frequency of larfix to once daily in patients suffering from renal and hepatic impairment should be considered.

Undesirable effects
Approximately 16% of patients (in case of long term treatment 20 – 25%) can be expected to experience adverse reaction concerning the gastrointestinal tract, 5% concerning the general disorders and/or central nervous system disorders, and 2% concerning the skin.
In common with other NSAIDs including oxicam the following undesirable effects may occur:
– Gastrointestinal ulcerations with intestinal perforation, which may be severe,
– Duodenal ulcers, haematemesis and melaena,
– Possible onset of severe skin reactions and serious life threatening hypersensitivity reactions,
– In rare cases: intersticial nephritis, glomerulonephritis, renal medullary necrosis or nephrotic syndrome,
– Disturbances of blood count, blood dyscrasia, leucocytopenia.
Gastrointestinal disorders
Frequent (≥1% and <10%): abdominal pain, diarrhoea, dyspepsia, nausea, vomiting. Infrequent (<1%):
constipation, dysphagia, dry mouth, flatulence, gastritis, gastrooesophageal reflux, peptic ulceration and/or gastrointestinal bleeding, stomatitis, haemorrhoidal bleeding.
General disorders
Frequent:
dizziness, headache.
Infrequent:
insomnia, somnolence, malaise, weakness, flushing.
Skin and Subcutaneous Tissue Disorders
Infrequent:
alopecia, dermatitis, pruritus, increased sweating, rash, urticaria, purpura, ecchymoses.

Haemopoietic Disorders
Infrequent:
thrombocytopenia, increased bleeding time, anaemia, decreases in erythrocytes, haemoglobin, leucocytes.

Cardiovascular Disorders
Infrequent:
oedema, hypertension, palpitations, tachycardia, hypotension.

Neurological disorders
Infrequent: drowsiness, dizziness, vertigo, paraesthesia, tremor, taste perversion. Respiratory Disorders
Infrequent:
dyspnoea, bronchospasm, cough, rhinitis.

Renal and Urinary disorders
Frequent:
increase in blood urea nitrogen and creatinine levels.
Infrequent:
micturition disorder.

Psychiatric disorders
Infrequent:
agitation, depression.

Hepato-biliary Disorders
Frequent:
increase in serum transaminase levels, alkaline phosphatase level.
Infrequent:
liver function abnormalities.

Musculoskeletal, Connective Tissue and Bone Disorders
Infrequent:
myalgia, leg cramps.

Disorders of the Eye
Infrequent:
conjunctivitis, vision disorder.

Disorders of the Ear
Infrequent:
tinnitus.

Disorders of the Immune System
Infrequent:
allergic reactions.

Disorders of Metabolism and Nutrition
Infrequent:
alteration in appetite, weight changes.

Interaction with other medicinal products and other forms of interaction Concomitant administration of Lornoxicam and
– Anticoagulants or platelet aggregation inhibitors:
May prolong the bleeding time (increased risk of bleeding)
– sulphonylureas:
May increase the hypoglycaemic effect
– Other non steroidal anti-inflammatory drugs:
Increased risk of adverse reactions
– Diuretics:
Decreased efficacy of loop diuretic drugs
– ACE inhibitors:
The effect of the ACE inhibitor may decrease
– Lithium:
Might lead to an increase for the lithium peak concentration and thus to a possible increase in adverse events.
– Methotrexate and cyclosporine:
Increased serum concentration of methotrexate and cyclosporine
– Cimetidine:
higher plasma concentrations of lornoxicam.
– Digoxin:
Decreased renal clearance of digoxin
Lornoxicam as other NSAIDs depending on the cytochrome P450 2C9 (CYP2C9) isoenzyme) has interactions with known inducers and inhibitors of CYP2C9 isoenzymes (such as tranylcypromine and rifampicin).
NSAIDs increase the risk of spinal or epidural hematoma when given concomitantly to heparin in the context of spinal or peridural anaesthesia.

Special warnings and precautions for use
For the following disorders, Lornoxicam should only be administered after careful risk benefit assessment.
– Gastrointestinal ulceration and bleeding in medical history:
Clinical monitoring at regular intervals is recommended. Patients developing peptic ulceration and/or gastrointestinal bleeding while taking Lornoxicam should discontinue drug administration and with appropriate therapeutic actions being taken.
– Renal impairment
– Patients with mild renal impairment (Serum creatinine 150 – 300 μmol/L) should be monitored quarterly; patients with moderate renal impairment (Serum creatinine 300 – 700 μmol/L) should be monitored in 1 to 2 months intervals. Should renal function deteriorate during treatment Lornoxicam should be discontinued.
– Patients with blood coagulation disorders
Careful clinical monitoring and laboratory assessment is recommended. (eg. PTT).
– Liver diseases (eg. liver cirrhosis)
Clinical monitoring and laboratory assessment at regular intervals is recommended.
(eg. liver enzymes).
– Long term treatment (longer than 3 months)
Regular laboratory assessments of haematology (haemoglobin), renal functions (creatinine) and liver enzymes are recommended.
– Elderly patients (65 years or above)
Monitoring of renal and hepatic function is recommended
It is important to monitor renal function in patients
– Who are to undergo major surgery?
– With stressed renal function e.g. as a result of significant blood loss or severe dehydration
– With cardiac failure
– receiving concomitant treatment with diuretics
– receiving concomitant treatment with drugs that are suspected to or known to be able to cause kidney damage.
Concomitant treatment with NSAIDs and Heparin in the context of a spinal or peridural anaesthesia increase the risk of spinal/epidural hematom.

Pregnancy and lactation
Lornoxicam should not be used as clinical experience is lacking. The safety of Lornoxicam during pregnancy and lactation has not been established and the drug should therefore not be given in these conditions.
No clinical data is currently available on the possible passage of lornoxicam into mother’s milk. However preclinical data has shown that lornoxicam was found in animal’s milk (in rat lornoxicam levels are approx. 30 % of those in the maternal circulation).
Effects on ability to drive and use machines
Patients who experience dizziness or other central nervous disturbances while taking NSAIDs should refrain from driving or operating machinery.

Overdose
At this time, there is no experience of overdose to permit definition of the consequence of an overdose, or to suggest specific managements. However, it can be expected that after an overdose with Lornoxicam, the following symptoms can be seen, nausea and vomiting, cerebral symptoms (dizziness, ataxia ascending to coma and cramps). Change of liver and kidney function, maybe coagulation disorders.
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 dialysable. No specific antidote is known to date. The usual emergency measures including gastric lavage should be considered. Based on principles only administering activated charcoal immediately after the intake. Lornoxicam can lead to diminished absorption of the preparation. Gastrointestinal disorders can for example be treated with a prostaglandin analogue or ranitidine.

Contraindications
Lornoxicam must not be administered in the following groups of patients:
– Those allergic to lornoxicam, or any of its excipients
– Those who has suffered hypersensitivity reactions (symptoms like asthma, rhinitis, angioedema or urticaria) to other non steroidal anti-inflammatory drugs, including acetylic salicylic acid.
– Patients with gastro-intestinal bleeding, cerebrovascular bleeding or other bleeding disorders
– Patients with active peptic ulceration or with a history of recurrent peptic ulceration
– Patients with severe liver impairment
– Patients with severe renal impairment (Serum creatinine > 700 μmol/L)
– Patients with severe thrombocytopenia
– Patients with severe heart insufficiency
– Elderly patients (>65 years) and weighing less than 50kg and undergoing acute surgery.
– Pregnancy or lactation
– Patients under 18 years of age, due to lack of clinical experience.

PHARMACEUTICAL FORM
Oval shape, white to yellowish oblong film-coated tablet with imprint “L8″on one side and plain on other side.

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group:
Non-steroidal Anti-inflammatory and antirheumatic agent ATC Code: M 01 AC 05 Lornoxicam is a non steroidal anti-inflammatory drug with analgesic properties and belongs to the class of oxicams. Lornoxicam’s mode of action is partly based on inhibition of the prostaglandin synthesis (inhibition of the cyclooxygenase enzyme). The inhibition of cyclooxygenase does not result in an increase in leukotriene formation.The mechanism of the analgesic action of lornoxicam, as well as that of other NSAIDs, has not yet been fully determined.
Pharmacokinetic properties Lornoxicam is absorbed rapidly and almost completely from the gastrointestinal tract. Maximum plasma concentrations are achieved after approximately 1 to 2 hours. The absolute bioavailability (calculated on AUC) of Larfix film-coated tablets is 90-100%. No first-pass effect was observed. The mean elimination half-life is 3 to 4 hours. Lornoxicam is found in the plasma in unchanged form and as its hydroxylated metabolite. The hydroxylated metabolite exhibits no pharmacological activity.
The plasma protein binding of lornoxicam is 99% and not concentration dependent. Lornoxicam is metabolized completely, and approximately 2/3 is eliminated via the liver and 1/3 via the kidneys as inactive substance. Lornoxicam is metabolized by cytochrome P450 2C9. Due to genetic polymorphism slow and rapid metabolisers exist for this drug, which could result in markedly increased plasma levels of lornoxicam in slow metabolisers. Simultaneous intake of lornoxicam with meals reduced Cmax by approximately 30%. Tmax was increased from 1.5 to 2.3 hours. The absorption of lornoxicam (calculated on AUC) can be reduced up to 20%.

Simultaneous intake with antacids has no effect on the pharmacokinetics of lornoxicam. In elderly subjects the clearance is reduced by 30 to 40%. Apart from this reduced clearance there is no significant change in the kinetic profile of lornoxicam in elderly patients, or in patients with mild hepatic or kidney dysfunction.

Preclinical safety data
Changes in the gastrointestinal tract and kidneys were observed in most toxicity studies, consistent with the anticipated pharmacologic effects of all non steroidal anti- inflammatory drugs (NSAID). Results from chronic dosing in primates demonstrated a tolerated dose of 0.25 mg/kg/day for one year.
The mutagenic potential of Lornoxicam was investigated both in vitro and in vivo. Following a review of the data, and the addition of an in vivo study and an in vitro DNA binding study, it is concluded that there is no clear evidence that Lornoxicam possesses intrinsic genotoxicity activity. Although chromosome aberrations have been induced in bone marrow cells in vivo these only occurred at the maximum tolerated doses and appeared to be associated more with bone marrow toxicity and subsequent regenerative proliferation. Furthermore no evidence of DNA binding of Lornoxicam was found in vitro. These conclusions are supported by negative results in carcinogenicity studies. In these studies mice were dosed for 96 weeks and rats for 104 weeks. Lornoxicam had no effect on the overall incidence of neoplasms, degree of malignancy or multiplicity of neoplasms. In preclinical studies lornoxicam has no adverse effects on male fertility, but in females lornoxicam affected ovulation and nidation and prolonged gestation and parturition. Preclinical studies with lornoxicam on reproduction and development have been performed in both the rat and rabbit. Due to inhibition of cyclooxygenase, preclinical data have shown that lornoxicam caused premature closure of the ductus arteriosus. Although no indication of a teratogenic potential has been found Lornoxicam is contraindicated in pregnancy, due to the lack of clinical experience in humans.

PHARMACEUTICAL PARTICULARS
List of excipients
Lactose
Microcrystalline cellulose
Povidone
Croscarmellose Sodium
Magnesium Stearate
Opadry white 03F58750
Purified Water

Incompatibilities
Not applicable

Shelf life
2 years.

Special precautions for storage Store below 30°C.
Keep all medicines out of reach of children.

Nature and contents of container
10 tablets are packed in Opaque PVC/PVDC blister packs & such 10 blisters are packed in a carton along with pack insert.

MARKETING AUTHORISATION HOLDER
Kusum Healthcare Pvt. Ltd.

D-158 A, Okhla Industrial Area, Phase I New Delhi-110020, INDIA
Telephone: +91-11-41005147/40514919
Telefax: +91-11-40527575
E-Mail: kusumhealth@testing.kusumhealthcare.com
MARKETING AUTHORISATION NUMBER(S)
——- MANUFACTURER NAME
Kusum Healthcare Pvt. Ltd.
SP 289 (A), RIICO Indl. Area Chopanki, Bhiwadi (Rajasthan), INDIA
Telephone: +91-1493-516560/61/63
Telefax: +91-1493-516562
E-Mail: kusumhealth@testing.kusumhealthcare.com
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
——-
DATE OF REVISION OF THE TEXT
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