INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
LOXIFLAM 7,5 mg (TABLET)
LOXIFLAM 15 mg (TABLET)

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

LOXIFLAM 7,5 mg (TABLET)
LOXIFLAM 15 mg (TABLET)

COMPOSITION:
Each tablet contains:
7,5 mg Meloxicam
15 mg Meloxicam

PHARMACOLOGICAL CLASSIFICATION:
A 3.1 Antirheumatics (anti-inflammatory agents)

PHARMACOLOGICAL ACTION:
LOXIFLAM is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class which has shown anti-inflammatory, analgesic and antipyretic properties in animals.
The discovery of an inducible form of cyclo-oxygenase 2 (COX-2) whose expression is enhanced by inflammatory mediators has suggested that the COX-2 isoform might be responsible for production of prostaglandins at inflammatory sites.
Selective inhibition of COX-2 is postulated to be related to the anti-inflammatory effect.
PHARMACOKINETIC PROPERTIES:
Meloxicam is 89% absorbed following peroral administration. Absorption is not affected by food intake. Drug concentrations are dose related for peroral 7,5 mg and 15 mg doses respectively. Steady state conditions are achieved in three to five days.
99% is bound to plasma proteins. Meloxicam penetrates into synovial fluid to give concentrations approximately half those in plasma.
Meloxicam is extensively metabolized and less than 5% of the daily dose is excreted unchanged in the faeces, while only traces of the unchanged compound are excreted in the urine. The major metabolic pathway is the oxidation of the methyl group of the thiazolyl-moeity.
Meloxicam is eliminated from the body with a mean half-life of 20 hours. Neither hepatic, nor mild or moderate renal insufficiency substantially affects meloxicam’s pharmacokinetics.
Plasma clearance is on average 8 mL/min. Clearance is halved in the elderly. Volume of distribution is low, on average 10 litres. Inter-individual variation is in the order of 30 –40%.

INDICATIONS:
For the symptomatic treatment of osteoarthritis.
For the symptomatic treatment of rheumatoid arthritis.

CONTRA-INDICATIONS:
Known hypersensitivity to meloxicam or any excipient of the medicine.
LOXIFLAM should be avoided in patients with renal failure unless receiving dialysis, in severe hepatic failure, and in bleeding disorders.
Active peptic ulceration.
Children and adolescents aged less than 15 years.
LOXIFLAM is contra-indicated in patients with a history of hypersensitivity reactions to aspirin or other non-steroidal anti-inflammatory agents, including those in whom attacks of asthma, angio-oedema, urticaria, or rhinitis have been precipitated by aspirin or any other NSAID.
LOXIFLAM should be avoided in pregnant and lactating women.

DOSAGE AND DIRECTIONS FOR USE:
The recommended dose for LOXIFLAM is 7,5 mg once daily for osteoarthritis. In severe cases, this dose can be increased to 15 mg daily. The recommended dose for cases of rheumatoid arthritis is 15 mg once daily.
In patients with an increased risk of adverse reactions, such as the elderly, start treatment with a dose of 7,5 mg/day.
In dialysis patients with severe renal failure the dose should not exceed 7,5 mg per day. As a dosage for use in children has yet to be established, LOXIFLAM should not be used in children and adolescents aged less than 15 years. Swallow LOXIFLAM with water or other fluid in conjunction with food.
The maximum recommended dose of LOXIFLAM is 15 mg daily.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Gastro-intestinal symptoms:

-	More frequent: dyspepsia, nausea, abdominal pain, vomiting, diarrhoea, constipation, and flatulence.
-	Less frequent: abnormalities of liver function parameters (eg. raised transaminases or bilirubin) eructation, oesophagitis, gastroduodenal ulcer, occult or macroscopic gastro-intestinal bleeding.
-	Occasionally: gastro-intestinal perforation, colitis, hepatitis, gastritis, and peptic ulcers.
-	LOXIFLAM should be withdrawn if peptic ulceration or gastro-intestinal bleeding occurs.
-	Damage to the distal small intestine and colon can also occur.

Central nervous system:

-	More frequent: lightheadedness, headache.
-	Less frequent: vertigo, tinnitus, drowsiness.
-	Occasionally: confusion and disorientation, insomnia, nightmares.

Hypersensitivity reactions:

-	May occur frequently and include fever, angio-oedema, bronchospasm, rashes, and anaphylactoid reactions.
-	Hepatotoxicity and aseptic meningitis, which occur less frequently, may also be hypersensitivity reactions.

Visual disturbances:

-	Some patients may experience blurred vision.

Haematological:

-	More frequent: anaemia.
-	Less frequent: disturbances of blood count, including differential white cell count, leucopaenia, agranulocytosis and thrombocytopaenia. Concomitant administration of a potentially myelotoxic drug, in particular methotrexate, appears to be a predisposing factor to the onset of a cytopaenia.
-	Inhibition of platelet aggregation does occur but it is reversible with other nonsteroidal anti- inflammatory agents.

Dermatological:

-	More frequent: pruritus, skin rash.
-	Less frequent: stomatitis, urticaria, toxic epidermal necrolysis.
-	Occasionally: photosensitisation, bullous reactions, erythema multiforme, Stevens-Johnson Syndrome or toxic epidermal necrolysis may develop.
-	Most patients recovered from skin reactions when Loxiflam was withdrawn.

Renal:

-	Some non-steroidal anti-inflammatory agents have been associated with nephrotoxicity such as interstitial nephritis and nephrotic syndrome. Renal failure may be provoked by NSAIDs especially in patients with pre-existing renal impairment.
-	Haematuria has also occurred.
-	Fluid retention may occur, which may precipitate congestive heart failure in elderly patients. Long-term use or abuse of analgesics, including NSAIDs has been associated with nephropathy.

Cardiovascular:

-	More frequent: oedema.
-	Less frequent: increase in blood pressure, palpitations and flushes.

Pulmonary:

-	Less frequent: alveolitis, pulmonary eosinophilia.

Pancreas:

-	Less frequent: pancreatitis.

SPECIAL PRECAUTIONS:
Special precautions must be taken in the elderly patient, as LOXIFLAM can increase the need for antihypertensive therapy.
Special precautions must also be taken in patients with a history of peptic ulcers or bleeding of the gastro-intestinal tract, and concomitant use of corticosteroids.
To reduce the risk of gastro-intestinal effects, the medicine may be taken with or after food or milk. However, food and milk may reduce the rate and extent of drug absorption.
Gastro-intestinal bleeding, ulceration or perforation can occur at any time during treatment, with or without warning symptoms or a previous history of serious gastro-intestinal events. The consequences of such events are generally more serious in the elderly.
In patients reporting mucocutaneous adverse events, special attention should be paid and consideration given to discontinuing LOXIFLAM.
Meloxicam inhibits the synthesis of renal prostaglandins which play a supportive role in the maintenance of renal perfusion in patients whose renal blood flow and blood volume are decreased. In these patients administration of meloxicam may precipitate overt renal decompensation which is typically followed by recovery to pre-treatment state upon discontinuation of therapy. Patients at greatest risk of such reactions are dehydrated patients, those with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease, those receiving a diuretic or those having undergone major surgical procedures which led to hypovolaemia. In such patients the volume of diuresis and the renal function should be carefully monitored at the beginning of therapy.
The dose of LOXIFLAM in patients with end-stage renal failure on haemodialysis should not be higher than 7.5 mg. No dose reduction is required in patients with mild or moderate renal impairment (i.e. in patients with a creatinine clearance of greater than 25 mL/min).
Occasional elevations of serum transaminases or other indicators of liver function has been reported. In most cases these have been small and transient increases above the normal range. If the abnormality is significant or persistent, LOXIFLAM should be stopped and follow up tests carried out.
No dose reduction is required in patients with clinically stable liver cirrhosis.
Frail or debilitated patients may tolerate side-effects less well and such patients should be carefully supervised. Caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function.
Induction of sodium, potassium and water retention and interference with natriuretic effects of diuretics may occur with LOXIFLAM. Cardiac failure or hypertension may be precipitated or exacerbated in susceptible patients as a result.
NSAIDs should be used with caution in patients with infections, since symptoms such as fever and inflammation may be masked, and also used with caution in patients with asthma or allergic disorders.
Other general precautions to be observed include administration to patients with haemorrhagic disorders, hypertension, and impaired renal, hepatic, or cardiac function.
Patients undergoing therapy with some NSAIDs may need to be monitored for the development of blood, kidney, liver, or eye disorders. NSAIDs should be used with caution in the elderly and may need to be given in reduced doses. Regular use of NSAIDs during the 3rd trimester of pregnancy may result in closure of fetal ductus arteriosus in utero, and possibly in persistent pulmonary hypertension of the newborn.
The onset of labour may be delayed and its duration increased. Some NSAIDs can interfere with thyroid function tests by lowering serum-thyroid hormone concentrations.

INTERACTIONS:
Notable interactions involving NSAIDs include enhancement of the effects of oral anticoagulants and increased plasma concentrations of lithium, methotrexate, and cardiac glycoside.
It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing LOXIFLAM treatment. LOXIFLAM may increase the haematological toxicity of methotrexate. In this situation strict monitoring of blood cell count is recommended.
An increased risk of bleeding through inhibition of platelet functions and irritation of the gastroduodenal mucosa may occur when LOXIFLAM is co-administered with oral anticoagulants, parenterally administered heparin, thrombolytics and ticlopidine.
Interactions with coumarin type anticoagulants have been reported with NSAIDs. If such a co-prescription cannot be avoided, close monitoring of the effects of the anticoagulants is required.
The risk of nephrotoxicity may be increased if given with ACE inhibitors, cyclosporin, tacrolimus, or diuretics. Effects on renal function may lead to reduced excretion of some drugs. There may also be an increased risk of hyperkalaemia with ACE inhibitors and potassium-sparing diuretics. The antihypertensive effects of some antihypertensives including ACE inhibitors, beta-blockers, and diuretics may be reduced.
Angiotensin converting enzyme inhibitors can also produce impairment and combined use with NSAIDs should be undertaken with great care. Prostaglandin inhibition may also lead to salt and water retention particularly when there is pre-existing hypertension or sodium depletion.
NSAIDs, therefore, tend to counteract the action of diuretics and antihypertensives.
There have been reports of severe hyponatraemia and other symptoms resembling the syndrome of inappropriate antidiuretic hormone secretion in patients taking NSAIDs. Hyperkalaemia is more likely to occur in patients with specific risk factors such as those receiving potassium supplements or potassium-sparing diuretics.
There may be an increased risk of bleeding during concomitant use of LOXIFLAM and oxpentifylline.
NSAIDs have been reported to decrease the efficacy of the intrauterine devices.
Treatment with LOXIFLAM is associated with the potential for acute renal insufficiency in patients who are dehydrated. Patients receiving LOXIFLAM and diuretics should be adequately hydrated and be monitored for renal function prior to initiating treatment.
Cholestyramine binds meloxicam in the gastro-intestinal tract leading to a faster elimination of meloxicam. Nephrotoxicity of cyclosporin may be enhanced by LOXIFLAM via renal prostaglandin mediated effects. During combined treatment renal function should be assessed regularly.
Convulsions may occur due to an interaction with quinolones. NSAIDs may enhance the effects of phenytoin and sulphonylurea antidiabetics. The effects of NSAIDs might be enhanced by use with moclobemide. The concomitant use of more than one NSAID (including aspirin) should be avoided because of the increased risk of adverse effects. The risk of gastro-intestinal bleeding and ulceration associated with NSAIDs is increased when used with corticosteroids or, possibly, alcohol, bisphosphonates, or oxpentifylline.
The manufacturer of mifepristone advises that NSAIDs or aspirin should be avoided for 8 to 12 days after mifepristone use because of a theoretical risk that these prostaglandin synthetase inhibitors may alter the efficacy of mifepristone.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
In case of an overdose, the standard measures of gastric evacuation and general symptomatic and supportive treatment should be used as there is no known antidote.

IDENTIFICATION:
LOXIFLAM 7,5 mg tablet is a round, pale yellow, flat bevelled tablet, bisected on one side.
LOXIFLAM 15 mg tablet is a round, pale yellow, biconvex tablet.

PRESENTATION:
LOXIFLAM 7,5 mg TABLETS: Blister pack of 30 tablets
LOXIFLAM 15 mg TABLETS: Blister pack of 10 and 30 tablets

STORAGE INSTRUCTIONS:
Store below 25°C in well-closed containers.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:
LOXIFLAM 7,5 mg TABLETS: 36/3.1/0101
LOXIFLAM 15 mg TABLETS: 36/3.1/0102

NAME AND BUSINESS ADDRESS OF APPLICANT:
PHARMACARE LIMITED
Building 12
Healthcare Park
Woodlands Drive
Woodmead
Sandton
2148

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
22 August 2002

575046/051215
UNIPRINT - POS

New addition to this site: May 2006
Source: Pharmaceutical Industry
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