Consumer medicine information

Meloxibindo Tablets

Meloxicam

BRAND INFORMATION

Brand name

Meloxibindo Tablets

Active ingredient

Meloxicam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Meloxibindo Tablets.

What is in this leaflet

This leaflet answers some common questions about MELOXIBINDO. It does not contain all available information, nor does it take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking MELOXIBINDO against the benefits they expect it will have for you.

Keep this information.

You may need to read it again later.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

What MELOXIBINDO is used for

MELOXIBINDO is used to treat the symptoms of:

  • osteoarthritis
  • rheumatoid arthritis

Both diseases mainly affect the joints causing pain and swelling.

Although MELOXIBINDO can relieve symptoms such as pain and inflammation, it will not cure your condition.

MELOXIBINDO belongs to a family of medicines called Non-Steroidal Anti-inflammatory Drugs (NSAIDs). These medicines work by relieving pain and inflammation.

Ask your doctor if you have any questions about why MELOXIBINDO has been prescribed for you.

Your doctor may have prescribed MELOXIBINDO for another reason.

Before you take MELOXIBINDO

When you must not take it

Do not take MELOXIBINDO if you have an allergy to:

  • the active ingredient, meloxicam, or any of the other ingredients in MELOXIBINDO (all of these ingredients are listed at the end of this leaflet). This includes rare inherited conditions of galactose intolerance.
  • aspirin or any other NSAID medicine.

Some of the symptoms of an allergic reaction may include:

  • rash, itching or hives on the skin
  • swelling of the face, lips, tongue or other parts of the body
  • shortness of breath, wheezing or troubled breathing.

Ask your doctor if you are unsure if you are allergic to these ingredients.

Do not take MELOXIBINDO if:

  • you are about to undergo coronary artery bypass graft surgery
  • you have a disease of the heart with shortness of breath, and swelling of the feet or lips due to fluid build-up
  • you experience bleeding from the stomach, gut or any other bleeding
  • you have had a stroke resulting from a bleed in the brain or have a bleeding disorder
  • you are breastfeeding, or intend to breastfeed.

The active ingredient in MELOXIBINDO may pass into breast milk and may affect your baby.

  • you currently have a peptic (stomach) ulcer
  • you have Crohn’s Disease or Ulcerative Colitis
  • you have severe liver or kidney problems
  • you are currently taking other medicines known as: sulfinpyrazone (used to treat gout), fluconazole (used to treat fungal infections) or certain sulfur antibiotics (eg. sulfaphenazole or sulfamethoxazole).

Do not give MELOXIBINDO to children and adolescents under 18 years of age.

Do not take MELOXIBINDO if the packaging is torn or shows signs of tampering.

Do not take MELOXIBINDO if the EXPIRY DATE printed on the pack has passed.

Before you start to take it

You must tell your doctor or pharmacist if:

  • you have any allergies to any other medicines, including aspirin or other NSAID medicines
  • you have or have had any medical conditions, especially the following:
    - high blood pressure or fluid retention
    - diabetes
    - high cholesterol
    - heartburn, indigestion, ulcers or other stomach problems
    - kidney or liver disease
    - asthma or any other breathing problems
  • you are using an IUD for birth control
  • you are pregnant or intend to become pregnant
    If it is necessary for you to take MELOXIBINDO, your doctor will discuss the risks and benefits of taking it during pregnancy.
  • you are taking MELOXIBINDO together with any medicines used to treat high blood pressure and some other heart problems such as ACE inhibitors, angiotensin receptor antagonists and diuretics (also called fluid or water tablets).
    When taken together these medicines can cause kidney problems.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking MELOXIBINDO.

Taking other medicines

Before taking MELOXIBINDO, tell your doctor or pharmacist if you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

There may be interference between MELOXIBINDO and some medicines. These include:

  • aspirin, salicylates or other NSAID medicines
  • medicines used to thin your blood (such as warfarin, heparin and ticlopidine)
  • lithium, a medicine used to treat some types of depression
  • antidepressants called selective serotonin reuptake inhibitors (SSRIs)
  • methotrexate, a medicine used to treat rheumatoid arthritis (a painful joint disease) and some types of cancer
  • cyclosporin, a medicine used to treat rheumatoid arthritis and certain problems with the immune system
  • diuretics, also called fluid or water tablets
  • medicines used to treat high blood pressure
  • medicines used to treat heart problems
  • medicines to treat diabetes
  • cholestyramine, a medicine used to treat high cholesterol levels in the blood
  • corticosteroids (drugs usually used to treat inflammatory conditions, such as skin rash and asthma)
  • some medicines used to treat fungal infections
  • some sulfur antibiotics
  • some medicines used to treat irregular heart beats
  • some antihistamines (medicines used to prevent or relieve the symptoms of allergy, such as hay fever or insect stings).

These medicines may be affected by MELOXIBINDO or may affect how well MELOXIBINDO works. Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking MELOXIBINDO.

How to take MELOXIBINDO

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

How much to take

For the treatment of osteoarthritis
The usual dose of MELOXIBINDO is 7.5 mg, taken as a single dose each day.

However, your doctor will prescribe a dose suitable for your condition.

For the treatment of rheumatoid arthritis
The usual dose of MELOXIBINDO is 15 mg taken as a single dose each day.

Depending on your response, your doctor may reduce this dose to 7.5 mg taken as a single dose each day.

The maximum recommended daily dose of MELOXIBINDO is 15 mg. For patients with kidney problems undergoing dialysis, the maximum recommended daily dose is 7.5 mg.

Ask your doctor for more information if you have been advised to take a different dose.

How to take it

Swallow the tablets with fluid.

It is best to take MELOXIBINDO immediately after food to avoid the chance of an upset stomach.

Try to take MELOXIBINDO at the same time each day, either morning or evening.

How long to take it

Keep taking MELOXIBINDO every day until your doctor tells you to stop.

MELOXIBINDO will not cure your condition but it should help control pain, swelling and stiffness.

If you forget to take it

If it is almost time for your next dose (eg. within 2-3 hours), skip the dose you missed and take the next dose when you are meant to.

Otherwise, take it as soon as you remember, then go back to taking it as you would normally.

Do not try to make up for missed doses by taking more than one dose at a time.

If you are not sure what to do, check with your doctor or pharmacist.

If you have taken too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much MELOXIBINDO. Do this even if there are no signs of discomfort or poisoning.

Signs of an overdose with MELOXIBINDO may include:

  • nausea and/or vomiting
  • headache
  • drowsiness
  • blurred vision
  • dizziness
  • fits or seizures
  • low blood pressure
  • difficulty in breathing
  • impaired consciousness
  • kidney failure.

While you are taking MELOXIBINDO

Things you must do

If you become pregnant while taking MELOXIBINDO, tell your doctor immediately.

If you are about to start any new medicines, tell your doctor and pharmacist that you are taking MELOXIBINDO.

If you are going to have surgery, including dental surgery, tell your doctor or dentist that you are taking MELOXIBINDO.

MELOXIBINDO can slow down blood clotting.

If you get an infection while using MELOXIBINDO, tell your doctor.

MELOXIBINDO may hide some of the signs of an infection (eg. pain, fever, redness and swelling). You may think, mistakenly, that you are better or that the infection is not serious.

Things to be careful of

Be careful driving or operating machinery until you know how MELOXIBINDO affects you.

As with other NSAID medicines, MELOXIBINDO may cause dizziness, drowsiness or blurred vision in some people.

Make sure you know how you react to MELOXIBINDO before you drive a car, operate machinery, or do anything else that could be dangerous if you are not alert.

Side Effects

You should be aware that all medicines carry some risks and that all possible risks may not be known at this stage despite thorough testing.

Check with your doctor as soon as possible if you have any problems while taking MELOXIBINDO, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Tell your doctor if you notice any of the following and they worry you:

  • stomach upset including nausea, vomiting, heartburn, indigestion, belching, cramps or pain
  • headache
  • sore mouth or throat, discomfort when swallowing
  • constipation, diarrhoea or wind
  • dizziness or light-headedness
  • skin rash or itching
  • skin rashes, which may be caused by exposure to sunlight, can blister and may take on the appearance of a severe burn
  • increase in blood pressure
  • tinnitus (ringing in the ear).

These side effects are usually mild.

Tell your doctor immediately if you notice any of the following:

  • blurred vision
  • any change in the amount or colour of your urine (red or brown)
  • any pain or difficulty experienced when urinating
  • collapse or fainting, shortness of breath or tiredness, fast or irregular heartbeat (also called palpitations), chest pain, swollen or sore leg veins
  • severe pain or tenderness in the stomach
  • severe dizziness
  • yellowing of the skin and eyes (known as jaundice)
  • swelling of your ankles, legs or other parts of your body
  • signs of anaemia (such as tiredness, being short of breath and looking pale)
  • irritation of your mucous membranes (eg. lips, mouth, eyes or genitals).

These are rare but serious side effects. You may need urgent medical attention.

If any of the following happen, STOP taking MELOXIBINDO and tell your doctor immediately or go to Emergency at your nearest hospital:

  • vomiting of blood or material that looks like coffee grounds
  • bleeding from your back passage (rectum), black sticky motions (stools) or bloody diarrhoea
  • swelling of the face, lips or tongue which may make swallowing or breathing difficult
  • asthma, wheezing or shortness of breath
  • sudden or severe itching, skin rash or hives
  • weakness in one part or side of your body, slurred speech, blurred vision or visual disturbances.

These are rare but very serious side effects. You may need urgent medical attention or hospitalisation.

Not all of these side effects have been reported with MELOXIBINDO but have been seen with similar medicines.

Other side effects not listed above may occur in some people.

Tell your doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking MELOXIBINDO

Storage

Keep your tablets in their pack until it is time to take them.

If you take them out of their packaging, they will not keep well.

Keep MELOXIBINDO in a cool dry place where the temperature stays below 25 degrees C and protected from light.

MELOXIBINDO should not be stored in direct sunlight or heat.

Keep your tablets where children cannot reach them.

A locked cupboard at least one-and-one-half metres above the ground is a good place to store medicines.

Disposal

Your pharmacist or doctor should be able to safely dispose of any unused MELOXIBINDO.

Product Description

What MELOXIBINDO looks like

MELOXIBINDO (7.5 & 15 mg meloxicam) is presented in pack sizes of 30’s & 60’s in blister.

  • MELOXIBINDO 7.5
    Light yellow, round, uncoated tablet with score line between ‘F’ and ‘1’ debossed on one side and plain on the other side.
  • MELOXIBINDO 15
    Light yellow, round, uncoated tablet with score line between ‘F’ and ‘2’ debossed on one side and plain on the other side.

Ingredients

Active Ingredient:
Meloxicam.

Each tablet may contain either 7.5 mg or 15 mg of Meloxicam.

Other Ingredients:

  • sodium citrate
  • lactose
  • microcrystalline cellulose
  • povidone
  • crospovidone
  • colloidal anhydrous silica
  • magnesium stearate.

Name and Address of the Sponsor

Aurobindo Pharma Australia Pty Ltd
Unit 3 North Rydelink
277-283 Lane Cove Road
Macquarie Park NSW 2113
Australia

Date of Approval:
31 July 2012

BRAND INFORMATION

Brand name

Meloxibindo Tablets

Active ingredient

Meloxicam

Schedule

S4

 

Name of the medicine

Meloxicam.

Excipients.

Sodium citrate, lactose, microcrystalline cellulose, povidone, crospovidone, anhydrous colloidal silica, magnesium stearate.

Description

Chemical names: 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl)- 2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide and 2H-1,2-benzothiazine-3-carboxamide-4-hydroxy-2-methy-N- (5-methyl-2-thiazolyl)-1,1-dioxide. Molecular Formula: C14H13N3O4S2. Molecular Weight: 351.4. CAS Registry Number: [71125-38-7].
A pale yellow powder with pKa values of 1.09 and 4.18 and a melting point of about 256°C. The substance is practically insoluble in water, soluble in dimethylformamide, slightly soluble in chloroform and acetone, and very slightly soluble in methanol. There are no chiral centres and no polymorphs are formed under normal conditions.
Meloxibindo is available as tablets containing 7.5 mg and 15 mg of meloxicam.

Meloxibindo 7.5.

Light yellow, round, uncoated tablet with score line between ‘F’ and ‘1’ debossed on one side and plain on the other side.

Meloxibindo 15.

Light yellow, round, uncoated tablet with score line between ‘F’ and ‘2’ debossed on one side and plain on the other side.
Inactive: Sodium citrate, lactose, microcrystalline cellulose, povidone, crospovidone, colloidal anhydrous silica, magnesium stearate.

Pharmacology

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class, which has shown anti-inflammatory, analgesic and antipyretic properties in animals. Meloxicam showed anti-inflammatory activity in all standard models of inflammation. A common mechanism for the above effects may exist in the ability of meloxicam to inhibit the biosynthesis of prostaglandins, known mediators of inflammation, by inhibition of cyclooxygenase (COX).
Comparison of the ulcerogenic dose and the anti-inflammatory effective dose in rat adjuvant arthritis model confirmed a greater therapeutic margin in animals over other NSAIDs (piroxicam, diclofenac, naproxen, flurbiprofen). In rats, meloxicam showed greater inhibitory effect on prostaglandin biosynthesis at the site of inflammation than in the gastric mucosa or the kidney.
Selective inhibition of the cyclooxygenase-2 (COX-2) isoenzyme, relative to COX-1, by meloxicam has been demonstrated in vitro on various cell systems: guinea pig macrophages, bovine aortic endothelial cells (for testing of COX-1 activity), mouse macrophages (for testing for COX-2 activity), and human recombinant enzymes expressed in cos-cells and in human whole blood.

Pharmacokinetics.

Absorption.

Meloxicam is well absorbed from the gastrointestinal tract following oral administration (absolute bioavailability 89%). Once daily dosing leads to drug plasma concentrations with a relatively small peak trough fluctuation in the range of 0.4-1.0 microgram/mL for 7.5 mg doses or 0.8-2.0 microgram/mL for 15 mg doses. However, values outside of this range have been encountered (Cmin and Cmax at steady state, respectively). The absorption is not altered by concomitant food intake. Maximum plasma concentrations were regularly achieved between 5-6 hours following tablet administration, irrespective of concomitant food consumption. Drug concentrations are dose proportional for oral 7.5 mg and 15 mg doses, respectively. Steady state conditions are achieved in three to five days. Continuous treatment for periods of up to six months results in similar drug concentrations to those seen at steady state after two weeks of oral treatment with 15 mg meloxicam per day.

Distribution.

Volume of distribution is low (on average, 11 L). In plasma, more than 99% is bound to plasma proteins. Meloxicam penetrates well into synovial fluid to give concentrations approximately half those in plasma.

Metabolism.

Meloxicam is eliminated almost entirely by hepatic metabolism: two thirds by cytochrome (CYP) P450 enzymes (CYP 2C9 two thirds and CYP 3A4 one third) and one third by other pathways, such as peroxidase oxidation. Meloxicam is almost completely metabolised to four pharmacologically inactive metabolites. The major metabolite, 5'-carboxymeloxicam (60% of dose), from CYP 2C9 mediated metabolism, is formed by oxidation of an intermediate metabolite 5'-hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP 2C9 plays an important role in this metabolic pathway, with a minor contribution from the CYP 3A4 isoenzyme. The patient's peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose respectively.

Excretion.

Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the faeces and urine. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and faeces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6% and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively.
There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. Meloxicam is eliminated from the body with a mean elimination half-life of 20 hours. Plasma clearance ranges from 7-9 mL/min.

Hepatic impairment.

Following a single 15 mg dose of meloxicam, there was no marked difference in plasma concentrations in subjects with mild (Child-Pugh Class I) and moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic insufficiency. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied.

Renal impairment.

Meloxicam pharmacokinetics have been investigated in subjects with different degrees of renal insufficiency. Total drug plasma concentrations decreased with the degree of renal impairment, while free AUC values were similar. Total clearance of meloxicam increased in these patients, probably due to the increase in free fraction, leading to an increased metabolic clearance. There is no need for dose adjustment in patients with mild to moderate renal failure (creatinine clearance greater than 25 mL/min). Patients with severe renal insufficiency have not been adequately studied. The use of meloxicam in patients with severe renal impairment is not recommended.

Hemodialysis.

Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis.
Meloxicam is not dialysable.

Elderly.

Clearance is decreased in the elderly. In clinical studies, steady state pharmacokinetics in the elderly (mean age 67) did not differ significantly from those in a younger population (mean age 50), however elderly females had a higher systemic exposure to meloxicam than did elderly males.

Gender.

Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg meloxicam, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs. 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cmax or tmax across genders.

Clinical Trials

The efficacy of meloxicam in treating the symptoms of osteoarthritis and rheumatoid arthritis has been confirmed in several clinical studies.

Osteoarthritis trials.

Two clinical studies of 6 months duration were performed in patients with osteoarthritis of the hip or knee. In the first study, the efficacy of meloxicam 15 mg (n=306) and piroxicam 20 mg (n=149) were found to be comparable, using as efficacy endpoints improvement in overall pain, pain on movement, global efficacy, change in duration of inactivity and change in quality of life score. In the second study, the efficacy of meloxicam 7.5 mg (n=169) was found to be comparable to that of diclofenac 100 mg SR (n=167) using similar endpoints.
Once daily dosing of meloxicam 7.5 mg (n=153) and 15 mg (n=156) showed a consistently more efficacious response than placebo (n=155) in a 12 week trial in patients with osteoarthritis of the knee or hip. Efficacy was measured by global assessment of disease activity, global assessment of pain and arthritic condition, as measured by the WOMAC (Western Ontario and McMaster University) Osteoarthritis Index. Both doses of meloxicam were also shown to be comparable to diclofenac 50 mg BID (n=152) with regard to efficacy, with a lower incidence of GI adverse events when compared to diclofenac.
Two large scale, randomised, active-controlled clinical studies of 4 weeks duration were conducted in patients with osteoarthritis of the hand, hip, knee or spine. In the first study (MELISSA), the effects of meloxicam 7.5 mg (n=4635) were compared against the effects of diclofenac 100 mg SR (n=4688). In the second study (SELECT), the effects of meloxicam 7.5 mg (n=4320) were compared against the effects of piroxicam 20 mg (n=4336). The results from both studies indicated that meloxicam 7.5 mg was as efficacious as diclofenac 100 mg SR and piroxicam 20 mg, in the treatment of symptomatic osteoarthritis.

Rheumatoid arthritis trials.

The use of meloxicam for the symptomatic treatment of rheumatoid arthritis was evaluated in a double-blind controlled trial involving 894 patients treated for 12 weeks. Meloxicam (7.5 mg, 15 mg and 22.5 mg daily) was compared to placebo, with diclofenac (75 mg twice daily) compared to placebo to establish trial sensitivity. The primary endpoints were number of painful or tender joints; number of swollen joints; investigator's global assessment of disease activity; patient’s global assessment of disease activity and patient's assessment of pain. For all 5 primary endpoints, the meloxicam 7.5 mg group was significantly better than placebo for both mean on trial and last observation. The meloxicam 15 mg group was significantly better for 3 of 5 primary endpoints, excluding painful and swollen joints. In patients who had flared at baseline tender joints, the meloxicam 15 mg group differed almost significantly from the placebo group (p < 0.05 not met due to the lower number of patients).
A second trial also investigated the use of meloxicam for the symptomatic treatment of rheumatoid arthritis. This double-blind placebo controlled trial used three doses of meloxicam (7.5 mg, 15 mg and 22.5 mg daily), in patients with rheumatoid arthritis over a 12 week period. A total of 898 patients were treated with meloxicam. The primary endpoint in this study was the American College of Rheumatology (20%) response criterion (ACR20) response rate, a composite measure of clinical, laboratory and functional measures of rheumatoid arthritis response. For this parameter, all three doses of meloxicam were more effective than placebo for the duration of the study. For the endpoints that comprised the ACR20 criteria, each of the meloxicam groups was superior to placebo at all visits except for C-Reactive Protein. Efficacy reached a plateau at the meloxicam 15 mg dose (Table 1). The overall incidence and severity of adverse events was similar among all three meloxicam groups.
The data from both studies indicate that meloxicam is effective and safe for the treatment of patients with rheumatoid arthritis.

Indications

Meloxibindo is indicated for the symptomatic treatment of osteoarthritis and rheumatoid arthritis.

Contraindications

Peri-operative treatment of pain in patients undergoing coronary artery bypass graft surgery (CABG).
Known hypersensitivity to meloxicam or any excipients of the product. There is a potential for cross sensitivity to aspirin and other NSAIDs.
Signs/symptoms of asthma, nasal polyps, angioedema or urticaria, following the administration of aspirin or other NSAIDs.
Active gastrointestinal ulceration/ perforation.
Active inflammatory bowel disease (Crohn’s disease or ulcerative colitis).
Severe hepatic insufficiency.
Non-dialysed severe renal insufficiency.
Severe uncontrolled heart failure.
Children and adolescents under 18 years of age.
Breastfeeding.
Concomitant administration of drugs known to inhibit CYP 2C9 (e.g. sulfaphenazole, sulfinpyrazone, sulfamethoxazole and fluconazole).
The use of Meloxibindo is contraindicated in patients with rare hereditary galactose intolerance, due to the lactose content of the formulations.
As with all NSAIDs, Meloxibindo is contraindicated in patients with recent cerebrovascular bleeding or established systemic bleeding disorders.

Precautions

Effects on fertility.

Oral treatment with meloxicam at doses up to 5 mg/kg/day in female rats (approximately 2.7 times the human dose based on BSA) and up to 9 mg/kg/day (approximately 5 times the human dose based on BSA) in male rats did not affect mating behaviour or fertility.
Oral treatment of female rats with meloxicam at doses of 1 mg/kg/day (approximately half of the human dose based on BSA) reduced the number of embryonic implantations and increased the number of early resorptions. A no-effect dose for these effects was not established. A reduction in the number of corpora lutea was also observed at 5 mg/kg/day, with the no-effect dose being 2.5 mg/kg/day (approximately 1.5 fold greater than the human dose based on BSA).
The use of meloxicam, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. Meloxicam may delay ovulation. Therefore, in women who have difficulty conceiving, or who are undergoing investigation of infertility, withdrawal of meloxicam should be considered.

Use in pregnancy.

(Category C)
Meloxicam use is not recommended in pregnancy unless it is considered clinically essential.
NSAIDs inhibit prostaglandin synthesis and, when given during the latter part of pregnancy, may cause closure of the fetal ductus arteriosus, fetal renal impairment, inhibition of platelet aggregation and delay of labour and birth. Continuous treatment with NSAIDs during the last trimester of pregnancy should only be given on sound indications. During the last few days before expected birth, agents with inhibitory effects on prostaglandin synthesis should be avoided.
Meloxicam was not teratogenic in rats up to an oral dose of 4 mg/kg/day (approximately 2.2 times the human dose at 15 mg/day for a 50 kg adult based on body-surface-area [BSA]) when given during organogenesis. Meloxicam caused an increased incidence of septal defect of the heart, a rare event, at an oral dose of 60 mg/kg/day (about 60 times the human dose based on BSA) and embryolethality at oral doses > 5 mg/kg/day (5 times the human dose based on BSA) when rabbits were treated throughout organogenesis.
Studies in rats with meloxicam, as with other drugs known to inhibit prostaglandin synthesis, showed an increased incidence of still births, increased length of delivery time and delayed parturition at oral doses > 1 mg/kg/day (approximately 0.6 times the human dose based on BSA), and decreased pup survival at an oral dose of 4 mg/kg/day (approximately 2.1 times the human dose based on BSA) throughout organogenesis. Similar findings were observed in rats receiving oral doses > 0.125 mg/kg/day (less than 0.1 times the human dose based on BSA) during late gestation and the lactation period.
Meloxicam crosses the placental barrier. There are no adequate, well-controlled studies in pregnant women. Meloxicam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in lactation.

Studies of meloxicam excretion in human milk have not been conducted. However, meloxicam was excreted in the milk of lactating rats at concentrations higher than those in plasma. The safety of meloxicam in humans during lactation has not been established and therefore, the drug should not be used during lactation.

Use in children.

Meloxicam is not recommended for use in children and adolescents under 18 years of age (see Contraindications).

Use in the elderly.

Frail or debilitated patients may tolerate side effects less well and such patients should be carefully supervised. As with other NSAIDs, caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic, or cardiac function.

Genotoxicity.

Meloxicam did not demonstrate genotoxic potential in assays for gene mutation in vitro and chromosomal damage in vitro and in vivo.

Carcinogenicity.

Two year dietary studies showed no evidence for carcinogenic activity at meloxicam doses up to 0.8 mg/kg/day (approximately half of the highest human dose at 15 mg/day for a 50 kg person based on body-surface-area [BSA]) in rats and up to 8 mg/kg/day (2.2 times the highest human dose based on BSA) in mice. In rats, the highest dose used was nephrotoxic, while the highest dose used in mice was subtoxic.

Gastrointestinal effects.

Serious gastrointestinal (GI) toxicity such as bleeding, ulceration and perforation of the stomach, small intestine or large intestine, which may be potentially fatal, can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Minor upper GI problems, such as dyspepsia, are common and may occur at any time during NSAID therapy. Therefore physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue, increasing the likelihood of developing a serious adverse GI event at some time during the course of therapy. However, even short term therapy is not without risk.
Studies have shown that patients with a prior history of ulcer disease and/or gastrointestinal bleeding and who use NSAIDs have a greater than 10 fold higher risk of developing a gastrointestinal bleed than patients with neither of these factors.
Caution is advised in patients most at risk of developing a gastrointestinal complication with NSAIDs: the elderly, patients using any other NSAID or aspirin concomitantly or patients with a prior history of or recent gastrointestinal disease such as ulceration and gastrointestinal bleeding.
NSAIDs should be prescribed with caution in patients with a prior history of or recent ulcer disease or gastrointestinal bleeding.
For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
In clinical trials, meloxicam has been shown to cause fewer GI adverse events (including dyspepsia, abdominal pain, nausea, vomiting etc.) than other NSAIDs with which it has been compared (see Table 2).
As with other NSAIDs, caution should be exercised when treating patients with a history of upper gastrointestinal disease and in patients receiving treatment with anticoagulants. Patients with GI symptoms should be monitored. Meloxicam therapy should cease if peptic ulceration or GI bleeding occurs. The consequences of such events are generally more serious in the elderly.
Co-administration of meloxicam with drugs known to inhibit CYP 3A4 should be undertaken with caution. A combination of meloxicam and substances known to inhibit both CYP 3A4 and CYP 2C9 should be avoided because of the increased risk of toxicity.

Cardiovascular effects.

Long term therapy with some COX-2 selective NSAIDs of the coxib class has been shown to increase the risk of serious cardiovascular thrombotic events. Meloxicam is a COX-2 selective NSAID. Meloxicam has not been demonstrated to increase the risk of cardiovascular adverse events compared to nonselective NSAIDs in clinical trials. However, long term placebo controlled data to adequately assess any cardiovascular risk are not available for meloxicam.
All NSAIDs, both COX-2 selective and nonselective, may cause an increased risk of serious cardiovascular thrombotic events. This may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
Meloxicam should be used at the lowest dose and for the shortest duration consistent with effective treatment.

Skin reactions.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Meloxicam should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Renal effects.

NSAIDs inhibit 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, administration of an NSAID may precipitate overt renal decompensation which is typically followed by recovery to pretreatment state upon discontinuation of nonsteroidal anti-inflammatory therapy.
Patients at greatest risk of such a reaction are elderly individuals, dehydrated patients, those with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease, those receiving concomitant treatment with a diuretic, ACE inhibitor or angiotensin II receptor antagonist or those having undergone major surgical procedures which led to hypovolaemia. In such patients, the volume of diuresis and renal function should be carefully monitored at the beginning of therapy.
In rare cases, NSAIDs may cause interstitial nephritis, glomerulonephritis, renal medullary necrosis or nephrotic syndrome.
The dose of meloxicam 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).
The extent to which metabolites of meloxicam may accumulate in patients with renal failure has not been studied. As some metabolites are excreted by the kidney, patients with significantly impaired renal function should be more closely monitored.

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics.

The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment.
This includes use in fixed-combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution, particularly in elderly patients or those with pre-existing renal impairment.

Hepatic effects.

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including meloxicam. These laboratory values may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes, have been reported with NSAIDs.
Patients with signs and/or symptoms suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with meloxicam. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc), meloxicam should be discontinued.

Fluid retention and oedema.

Induction of sodium, potassium and water retention and interference with the natriuretic effects of diuretics may occur with NSAIDs. Cardiac failure or hypertension may be precipitated or exacerbated in susceptible patients as a result. For patients at risk, clinical monitoring is recommended.

Driving and operating machinery.

There are no specific studies about effects on the ability to drive vehicles and to use machinery. Patients who experience visual disturbances, drowsiness or other central nervous system disturbances should refrain from these activities.

Pre-existing asthma.

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, meloxicam should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.

Use in patients being treated with corticosteroids.

Meloxicam cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

Use in patients with fever and infection.

The pharmacological activity of meloxicam in reducing inflammation and possibly fever may diminish the utility of these diagnostic signs in detecting complications of presumed non-infectious, painful conditions.

Anaphylactoid reactions.

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to meloxicam. Meloxicam should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Lactose.

Meloxibindo 7.5 mg contains 23.5 mg lactose and Meloxibindo tablets 15 mg contains 20 mg lactose per maximum recommended daily dose. Patients with rare hereditary conditions of galactose intolerance, e.g. galactosaemia should not take this medicine.

Interactions

General.

In vitro drug interaction studies revealed that the metabolism of meloxicam is predominantly mediated via the CYP 2C9 isoenzyme, with a minor contribution of the CYP 3A4 isoenzyme in the liver. Co-administration of meloxicam with drugs known to inhibit CYP 2C9 is contraindicated. Co-administration of meloxicam with drugs known to inhibit CYP 3A4 (ketoconazole, itraconazole, erythromycin) or drugs known to be metabolised by CYP 3A4 (terfenadine, astemizole, cyclosporin, class III antiarrhythmic drugs such as amiodarone and quinidine) should be undertaken with caution (see Precautions, Gastrointestinal effects).

Antacids.

No pharmacokinetic interaction was detected with concomitant administration of antacids.

Cimetidine.

Concomitant administration of 200 mg cimetidine QID did not alter the single dose pharmacokinetics of 30 mg meloxicam.

Digoxin.

Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after beta-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam.

Frusemide.

Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of frusemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with frusemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Frusemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with frusemide and meloxicam, patients should be observed closely for signs of declining renal function (see Associations requiring precaution, Diuretics), as well as to assure diuretic efficacy.

Cytochrome P450 inhibitors.

Co-administration of meloxicam with drugs known to inhibit CYP 2C9 is contraindicated. Co-administration of meloxicam with drugs known to inhibit CYP 3A4 should be undertaken with caution (see Precautions, Gastrointestinal effects).

Other prostaglandin synthetase inhibitors (PSIs) including glucocorticoids and salicylates (acetylsalicylic acid).

Co-administration of PSIs may increase the risk of gastrointestinal ulcers and bleeding, via a synergistic effect, and is not recommended. The concomitant use of meloxicam with other NSAIDs is not recommended.

Oral anticoagulants, antiplatelet drugs, systemically administered heparin, thrombolytics and selective serotonin reuptake inhibitors (SSRIs).

There is an increased risk of bleeding via inhibition of platelet function, when NSAIDs are co-administered. If such co-prescribing cannot be avoided, close monitoring of their effects on coagulation is required.

Lithium.

NSAIDs have been reported to increase lithium plasma levels (via decreased renal excretion of lithium), which may reach toxic values. The concomitant use of lithium and NSAIDs is not recommended. If this combination appears necessary, lithium plasma concentrations should be monitored carefully during the initiation, adjustment and withdrawal of meloxicam treatment.

Methotrexate.

Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from human serum binding sites. However, as with other NSAIDs, meloxicam may increase the haematologic toxicity of methotrexate. In this situation, strict monitoring of blood cell count is recommended.
NSAIDs can reduce the tubular secretion of methotrexate thereby increasing the plasma concentrations of methotrexate. For this reason, for patients on high dosages of methotrexate (more than 15 mg/week) the concomitant use of NSAIDs is not recommended. The risk of an interaction between NSAIDs and methotrexate should be considered also in patients on low dosage of methotrexate, especially in patients with impaired renal function. In case combination treatment is necessary, blood cell count and renal function should be monitored. Caution should be taken in case both NSAID and methotrexate are given within 3 days, in which case the plasma level of methotrexate may increase and cause increased toxicity. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant meloxicam treatment, it should be considered that the haematological toxicity of methotrexate can be amplified by treatment with NSAIDs.

Contraception.

NSAIDs have been reported to decrease the efficacy of intrauterine devices.

Diuretics.

Treatment with NSAIDs is associated with the potential for acute renal insufficiency in patients who are dehydrated. Patients receiving meloxicam and diuretics should be adequately hydrated and be monitored for renal function prior to initiating treatment.

Cyclosporin.

Nephrotoxicity of cyclosporin may be enhanced by NSAIDs via renal prostaglandin mediated effects. During combined treatment, renal function is to be measured.

Antihypertensives (beta-blockers, ACE-inhibitors, vasodilators, diuretics).

A reduced effect of the antihypertensive drug by inhibition of vasodilating prostaglandins has been reported during treatment with NSAIDs.

Angiotensin-II receptor antagonists.

NSAIDs and angiotensin-II receptor antagonists as well as ACE inhibitors exert a synergistic effect on the decrease of glomerular filtration. In patients with pre-existing renal impairment this may lead to acute renal failure.

Cholestyramine.

Cholestyramine binds to meloxicam in the gastrointestinal tract leading to a faster elimination of meloxicam.

Oral hypoglycaemics.

Interactions with oral hypoglycaemics cannot be excluded.

Adverse Effects

The meloxicam phase II/III safety database includes 10,122 osteoarthritis patients and 1012 rheumatoid arthritis patients treated with meloxicam 7.5 mg/day and 3,505 osteoarthritis patients and 1351 rheumatoid arthritis patients treated with meloxicam 15 mg/day. Meloxicam at these doses was administered to 661 patients for at least six months and to 312 patients for at least one year. Approximately 10,500 of these patients were treated in ten placebo and/or active-controlled osteoarthritis trials, and 2362 of these patients were treated in ten placebo and/or active-controlled rheumatoid arthritis trials. Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across meloxicam trials.
A 12-week, multicentre, double-blind, randomised trial was conducted in patients with osteoarthritis of the knee or hip to compare the efficacy and safety of meloxicam with placebo and with an active control. Table 3 presents the adverse events that occurred in ≥ 1% of the meloxicam treatment groups.
Adverse events that occurred in ≥ 1% of the MOBIC treatment groups in two 12-week placebo controlled rheumatoid arthritis trials are presented in Table 4.
Higher doses of meloxicam (22.5 mg and greater) have been associated with an increased risk of serious GI events, therefore the daily dose of meloxicam should not exceed 15 mg.
The following is a list of adverse events occurring in < 1% of patients, which may be causally related to the administration of meloxicam. The information is based on clinical trials involving patients who have been treated with daily oral doses of 7.5 or 15 mg meloxicam over a period of up to 18 months (mean duration of treatment 127 days).

Blood and lymphatic system disorders.

Blood count abnormal (including differential white cell count), leukopenia, thrombocytopenia, anaemia.
Concomitant administration of a potentially myelotoxic drug, in particular methotrexate, appears to be a predisposing factor to the onset of a cytopenia.

Cardiac disorders.

Palpitations.

Ear and labyrinth disorders.

Tinnitus.

Gastrointestinal disorders.

Gastrointestinal perforation, occult or macroscopic gastrointestinal haemorrhage, gastroduodenal ulcer, colitis, oesophagitis, stomatitis.
Gastro-intestinal haemorrhage, ulceration or perforation may potentially be fatal.

Hepatobiliary disorders.

Transitory abnormalities of liver function parameters (e.g. raised transaminases or bilirubin).

Nervous system disorders.

Somnolence.

Renal and urinary disorders.

Renal function test abnormal (increased serum creatinine and/or serum urea).

Respiratory, thoracic and mediastinal disorders.

Onset of asthma attacks in individuals allergic to aspirin or other NSAIDs.
Skin and subcutaneous tissue disorders. Urticaria, photosensitivity reaction.

Vascular disorders.

Flushing.

Post-market adverse drug reactions.

Additional reports of adverse events which may be causally associated to the administration of meloxicam during worldwide post-marketing experience are included below.

General disorders and administration site conditions.

In rare cases, other drugs of this class are reported to cause meningitis.

Eye disorders.

Visual disturbance including blurred vision, conjunctivitis.

Gastrointestinal disorders.

Gastritis.

Hepatobiliary disorders.

Hepatitis.

Immune system disorders.

Anaphylactic reaction, anaphylactoid reaction and other immediate hypersensitivity.

Psychiatric disorders.

Confusional state, disorientation, mood altered.

Renal and urinary disorders.

Acute renal failure. The use of NSAIDs may be related to micturition disorders, including acute urinary retention.

Skin and subcutaneous tissue disorders.

Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, dermatitis bullous, erythema multiforme.

Other adverse events.

Additional adverse events, reported from clinical trials or from spontaneous reports, where evidence for a causal association with meloxicam use is unclear, are the following: cardiac failure, angina, myocardial infarction, arrhythmia, vasculitis, agranulocytosis, interstitial nephritis, convulsion, liver failure.

Dosage and Administration

Osteoarthritis.

The recommended dose of meloxicam is 7.5 mg once daily, to be swallowed with fluid, in conjunction with food. Depending on the adequacy of response, the severity of the arthritic condition and the patient's concomitant diseases, the dose may be increased to 15 mg/day. Patients should generally be maintained on the lowest dose consistent with achieving a satisfactory therapeutic response.

Rheumatoid arthritis.

The recommended dose of meloxicam is 15 mg once daily, to be swallowed with fluid, in conjunction with food. Depending on the adequacy of response and the severity of the condition, the dose may be reduced to 7.5 mg/day. Patients should generally be maintained on the lowest dose consistent with achieving a satisfactory therapeutic response.
The maximum recommended daily dose of meloxicam is 15 mg. A dose of 15 mg/day should not be exceeded. As a dose for children has not been established, use should be restricted to adults (see Use in children under Precautions).

Renal insufficiency.

The dose of meloxicam in patients with end-stage renal failure on haemodialysis should not be higher than 7.5 mg/day. 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).

Hepatic insufficiency.

Patients with severe hepatic impairment have not been adequately studied. No dose reduction is required in patients with mild to moderate hepatic impairment.
In patients with increased risks of adverse reactions, treatment should be started at 7.5 mg/day and increased to 15 mg/day only if clinically justified.
Meloxicam should be used at the lowest dose and for the shortest duration consistent with effective treatment.

Overdosage

Patients should be managed with symptomatic and supportive care following an NSAID overdose. In cases of acute overdose, activated charcoal is recommended. Administration of activated charcoal is recommended for patients who present 1-2 hours after overdose. For substantial overdose or severely symptomatic patients, activated charcoal may be administered repeatedly.
Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
It has been shown in a clinical trial that cholestyramine accelerates the elimination of meloxicam. The typical signs and symptoms of NSAID overdose include nausea, vomiting, headache, drowsiness, blurred vision and dizziness. Rare cases of seizures, hypotension, apnoea, coma and renal failure have been reported with severe NSAID overdose.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Meloxibindo 7.5 and 15 mg tablets (7.5 and 15 mg meloxicam) are presented in pack sizes of 30’s and 60’s in PVC/Aluminium blisters.

Storage

Store below 25°C. Protect from light.

Poison Schedule

S4.