Consumer medicine information

Melobic Tablets

Meloxicam

BRAND INFORMATION

Brand name

Melobic Tablets

Active ingredient

Meloxicam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

Melobic tablets

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Melobic

Melobic contains the active ingredient Meloxicam. Melobic is used to treat the symptoms of osteoarthritis and rheumatoid arthritis.

For more information, see Section 1. Why am I using Melobic? in the full CMI.

2. What should I know before I use Melobic

Do not use Melobic if you have ever had an allergic reaction to meloxicam or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Melobic? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Melobic and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Melobic?

Follow the instructions provided by your doctor and pharmacist.

  • For osteoarthritis, the usual dose of Melobic is 7.5 mg once daily.
  • For rheumatoid arthritis, the usual dose of Melobic is 15 mg once daily.

Swallow Melobic whole with a full glass of water with or immediately after food.

More instructions can be found in Section 4. How do I use Melobic? in the full CMI.

5. What should I know while using Melobic?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Melobic.
  • If you are going to have surgery, tell the nurse, surgeon, or anaesthetist that you are taking Melobic as it can slow down blood clotting.
Things you should not do
  • Do not stop taking Melobic or lower the dosage without checking with your doctor
Driving or using machines
  • Be careful driving or operating machinery until you know how Melobic affects you
  • This medicine may cause dizziness, drowsiness or blurred vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.
Looking after your medicine
  • Keep Melobic in a cool dry place where the temperature stays below 25°C.
  • Keep it where children cannot reach it.

For more information, see Section 5. What should I know while using Melobic? in the full CMI.

6. Are there any side effects?

Common side effects: aching muscles, allergic reactions, back pain, being sick, blood in the urine, burping, chest tightness, constipation, cough, cramps, dehydration, dizziness, drowsiness, excessive sweating, fatigue, feeling sick, fluid retention, flu-like symptoms, headache, heartburn, increased appetite, increased blood pressure, itching or flaking skin, joint pain, loose stools, muscle spasms/ tenderness/ weakness, pain, passing wind, reflux, runny or blocked nose, shortness of breath, sore mouth/throat, stomach upset, trouble sleeping, upper respiratory tract infections.

Serious side effects: asthma, blurred vision, heartbeat irregularities, infection, photosensitivity, rash, severe skin reactions, sharp chest pain, swelling of skin/mucous membranes/stomach/intestines/liver, ulcers, urine changes

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Melobic tablets

Active ingredient(s): Meloxicam

Consumer Medicine Information (CMI)

This leaflet provides important information about using Melobic. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Melobic.

Where to find information in this leaflet:

1. Why am I using Melobic?
2. What should I know before I use Melobic?
3. What if I am taking other medicines?
4. How do I use Melobic?
5. What should I know while using Melobic?
6. Are there any side effects?
7. Product details

1. Why am I using Melobic?

Melobic contains the active ingredient meloxicam. Melobic belongs to a group of medicines called nonsteroidal anti-inflammatory drugs (NSAIDs). These medicines work by relieving pain, swelling, and redness.

Melobic is used to treat the symptoms of:

  • Osteoarthritis (OA) is a chronic disorder that causes damage to the cartilage and surrounding tissues and is characterized by pain, stiffness, and loss of function.
  • Rheumatoid arthritis (RA) is an inflammatory arthritis in which joints, usually including those of the hands and feet, are inflamed, resulting in swelling, pain, and often destruction of joints.

Both diseases mainly affect the joints causing pain and swelling.

Although Melobic can relieve the symptoms of pain and inflammation, it will not cure your condition.

2. What should I know before I use Melobic?

Warnings

Do not use Melobic if:

  • you are allergic to:
    - meloxicam, Aspirin or any other non steroidal anti inflammatory drugs (NSAIDs).
    - or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • Are under 18 years of age
  • Are pregnant or think you may be pregnant (see Pregnancy and Breastfeeding)
  • Are breastfeeding (see Pregnancy and Breastfeeding)
  • Are going to have or have just had heart bypass surgery
  • Have galactose intolerance (a rare genetic condition)
  • Have a hole in or experience bleeding from the stomach, gut or any other bleeding
  • Have uncontrolled heart failure
  • Have severe liver problems
  • Have severe, non-dialysis kidney disease
  • Have had a stroke due to a bleed in the brain
  • Have a stomach ulcer
  • Have or have had inflammation of the stomach lining
  • Have an inflammatory bowel disease such as Crohn's disease or ulcerative colitis now or in the past
  • Are taking any of these medicines:
    - fluconazole (a medicine used to treat fungal infections) or
    - certain sulfur antibiotics (e.g. sulfamethoxazole)
    - methotrexate (a medicine used to treat diseases of the immune system and some cancers).
  • Had any of the following reactions after taking aspirin or an NSAID:
    - asthma
    - nasal polyps (painless growths inside the nose or sinuses)
    - swelling of the face, lips, mouth, tongue or throat (which may cause difficulty in swallowing or breathing)
    - hives or an itchy rash

Check with your doctor if you:

  • any allergies to other medicines, foods, preservatives, or colours
  • a current infection
  • advanced or chronic kidney disease
  • any problems with your
    - heart or blood vessels
    - liver
    - blood pressure
  • fluid retention
  • diabetes
  • high cholesterol
  • any clotting or bleeding disorder
  • asthma.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Tell your doctor immediately if you become pregnant while taking Melobic.

Birth control

Tell your doctor if you are using an intrauterine device (IUD) to prevent pregnancy. NSAID medicines, like Melobic, may decrease the effectiveness of the birth control device.

Children and adolescents

The safety and effectiveness in adolescents or children younger than 18 years have not been established.

3. What if I am taking other medicines?

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

Some medicines may interfere with Melobic and affect how it works. These include:

  • other non-steroidal anti-inflammatory drugs (NSAIDs): aspirin, celecoxib, diclofenac, etoricoxib, ibuprofen, indometacin, ketoprofen, mefenamic acid, naproxen, piroxicam, rofecoxib, salicylates, or sulindac.
  • warfarin or heparin, medicines used to thin the blood
  • furosemide, other diuretics or medicines used to treat high blood pressure
  • Amiodarone or quinidine, two medicines used to treat fast, slow or irregular heart beats
  • Ciclosporin, a medicine used to treat inflammatory conditions suppress the immune system
  • Ketoconazole and itraconazole, medicines used to treat fungal infections
  • Erythromycin, a commonly used broad-spectrum antibiotic
  • Lithium, a tablet used to treat mood disorders
  • Cortisone, dexamethasone, prednisolone, prednisone, or any other steroid medicine used to treat inflammatory conditions (e.g. skin rashes or asthma)
  • Pemetrexed, a medicine injected into a vein that is used to treat some lung cancers
  • Sulfonylureas, oral medicines used to treat diabetes
  • citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline, medicines used to treat depression and anxiety (called SSRIs).

Medicines that may reduce the effect of Melobic include:

  • Cholestyramine, a medicine used for lowering blood fats (cholesterol).

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Melobic.

4. How do I use Melobic?

How much to take

The dose depends on your condition and any medicines that you are taking.

Osteoarthritis (OA)

The usual starting dose for osteoarthritis is 7.5 mg, taken as a single dose each day. Depending on your response, your doctor may increase the single daily dose to 15 mg.

Rheumatoid arthritis (RA)

The usual dose for rheumatoid arthritis is 15 mg taken as a single dose each day. If needed, your doctor may reduce the single daily dose to 7.5 mg.
Ask your doctor for more information if you have been advised to take a different dose.
Patients with kidney problems undergoing dialysis should not take more than 7.5 mg each day.

Follow the instructions provided and use Melobic until your doctor tells you to stop

Do not exceed the maximum recommended daily dose of 15 mg.

When to take Melobic

  • Melobic should be swallowed whole with a full glass of water with or immediately after food. This may help reduce the risk of getting an upset stomach.
  • Take Melobic once a day, at about the same time each day. Taking it at the same time ech day will help you remember when to take it.

If you forget to use Melobic

Melobic should be used regularly at the same time each day. If you miss taking your dose at the usual time, and it is 2-3 hours before your next dose, skip the dose you missed and take your 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 take a double dose to make up for the dose you missed.

If you are not sure what to do, ask your doctor or pharmacist.
If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you use too much Melobic

If you think that you have used too much Melobic, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

The symptoms of an overdose may include:

  • nausea and/or vomiting
  • headache
  • drowsiness and/or dizziness
  • blurred vision
  • fits or seizures
  • fainting, feeling weak, light-headed, tired, confused and having blurred vision (signs of low blood pressure)
  • difficulty in breathing
  • being unaware of what happens to you or around you
  • changes in amount of urine, fluid retention, confusion, and/or nausea.

5. What should I know while using Melobic?

Things you should do

If you are going to have surgery, tell the nurse, surgeon, or anaesthetist that you are taking Melobic. Melobic can slow down blood clotting and put you at risk of bleeding.

Keep your medical appointments so that your progress can be monitored.

Your doctor may want to perform tests now and then to detect any side effects, such as anaemia.

Continue taking Melobic for as long as your doctor tells you.

Talk to your doctor or pharmacist if you do not feel any better after several days of taking Melobic.

Remind any doctor, dentist or pharmacist you visit that you are using Melobic.

Things you should not do

  • Do not stop using this medicine your medicine or lower the dosage without speaking to your doctor first.

Things to be careful of

Tell your doctor if you get an infection while using Melobic. Melobic may hide some of the signs of an infection, such as pain, fever, redness and swelling. You may think, mistakenly, that you have improved or that the infection is not serious.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Melobic affects you.

Melobic may cause dizziness or blurred vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous in some people

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Store Melobic in a cool dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
General problems:
  • Flu-like symptoms: runny or blocked nose, cough, sore mouth or throat, discomfort when swallowing
  • fatigue
  • fluid retention in lower body
  • swelling of hands, ankles or feet
  • allergic reaction.
Gut and digestion:
  • indigestion (stomach upset) including heartburn/reflux, feeling sick (nausea), vomiting, burping or passing more wind than usual, cramps, pain, constipation, loose stools (diarrhoea).
Nervous system:
  • headache
  • dizziness
  • spinning sensation
  • trouble sleeping
  • drowsiness.
Skin:
  • itching or flaking
  • excessive sweating that's not related to heat or exercise
  • irritation of the moist internal linings of the body such as the mucous membranes (e.g. lips, mouth, throat, nasal passages, eyelids, intestines or genitals).
Breathing:
  • cough
  • shortness of breath, chest tightness.
Nutrition:
  • dehydration
  • increased appetite.
Muscle and bone:
  • back pain
  • pain or swelling in or near a joint
  • muscle spasms
  • aching muscles, muscle tenderness or weakness, not caused by exercise
  • pain in extremity.
Infections:
  • runny or stuffy nose, sneezing, or swelling of the lining of the nose
  • swelling of the air-filled spaces in your forehead, cheeks or nasal passages.
Urine:
  • blood in the urine.
Blood:
  • increased blood pressure (BP) over several days (if self-checked at home with a suitable BP machine).
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Gut and bowel:
  • bleeding from the back passage, black sticky stools or bloody diarrhoea
  • severe pain or tenderness in the stomach
  • vomiting of blood or material that looks like coffee grounds.
Liver:
  • yellowing of the skin or the
  • whites of the eyes
  • pain in the abdomen
  • loss of appetite.
Kidney and bladder:
  • any pain or difficulty when urinating
  • any change in the amount or colour of urine.
Eyes:
  • blurred vision or difficulty seeing.
Lungs:
  • sharp chest pain, usually worse when you inhale or cough.
Heart:
  • fast or irregular heartbeat
  • chest pain
  • swollen ankles or legs (oedema of the lower limbs).
Severe allergic reaction:
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.
Severe skin and soft tissue reactions:
  • sudden unexplained bruising or blood spots under the skin that were not caused by an injury
  • itching, blistering or peeling of the skin, which can be potentially life-threatening
  • rashes which may be caused by sunlight, can blister, and may take on the appearance of a severe burn
  • swelling of skin or mucosa, such as swelling around the eyes, face and lips, mouth or throat, possibly making breathing difficult.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Very Serious Side effects

Very serious side effectsWhat to do
Signs of a stroke
  • weakness or numbness or paralysis of the face, arm or leg on either or both sides of the body
  • slurred speech
  • difficulty speaking or understanding
  • loss of vision, sudden blurring or decreased vision in one or both eyes
  • Headache, usually severe and fast onset or unexplained change in the pattern of headaches.
Call an ambulance (dial 000) at once if you experience these side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Melobic contains

Active ingredient
(main ingredient)		meloxicam
Other ingredients
(inactive ingredients)
  • sodium citrate
  • lactose monohydrate
  • microcrystalline cellulose
  • povidone
  • crospovidone
  • colloidal anhydrous silica
  • magnesium stearate
Potential allergenslactose

Do not take this medicine if you are allergic to any of these ingredients.

What Melobic looks like

Melobic is the brand name of your medicine. It is available as tablets in two strengths.

Melobic 7.5 mg tablets Light yellow, round, uncoated tablet with score line between ‘F’ and ‘1’ debossed on one side and plain on the other side.

Available in blister packs of 30 and 60's* tablets.

Melobic 15 mg tablets - Light yellow, round, uncoated tablet with score line between ‘F’ and ‘2’ debossed on one side and plain on the other side.

Available in blister packs of 30 and 60* tablets.

*Not distributed in Australia.

Melobic 7.5mg tablets: AUST R 188882

Melobic 15mg tablets AUST R 188883

Who distributes Melobic

Melobic is supplied in Australia by:

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St
Cremorne VIC 3121
Ph: 1800 195 055

This leaflet was prepared in October 2024

Published by MIMS December 2024

BRAND INFORMATION

Brand name

Melobic Tablets

Active ingredient

Meloxicam

Schedule

S4

 

1 Name of Medicine

Meloxicam.

2 Qualitative and Quantitative Composition

Melobic is available as tablets containing 7.5 mg and 15 mg of meloxicam.
Excipients with known effect: lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Melobic 7.5.

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

Melobic 15.

Light yellow, round, uncoated tablet with score line between 'F' and '2' debossed on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Meloxicam should be used at the lowest dose and for the shortest duration consistent with effective treatment.
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 Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
The dose of meloxicam in patients with end-stage renal failure on haemodialysis should not be higher than 7.5 mg/day (see Section 5.2 Pharmacokinetic Properties, Renal impairment, Haemodialysis). 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) nor in patients with mild to moderate hepatic impairment. In non-dialysed patients with severe renal impairment meloxicam is contraindicated (see Section 4.3 Contraindications).
In patients with increased risks of adverse reactions, e.g. a history of gastrointestinal disease or risk factors for cardiovascular disease, the treatment should be started at a dose of 7.5 mg/day and increased to 15 mg/day only if clinically justified.

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.

Pregnancy.

See Section 4.3 Contraindications; Section 4.6 Fertility, Pregnancy and Lactation.

4.3 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;
Pregnancy;
Breastfeeding;
Concomitant administration of drugs known to inhibit CYP 2C9 (e.g. sulfaphenazole, sulfinpyrazone, sulfamethoxazole and fluconazole); and
The use of meloxicam is contraindicated in patients with rare hereditary galactose intolerance, due to the lactose content of the formulations.
As with all NSAIDs, Meloxicam is contraindicated in patients with recent cerebrovascular bleeding or established systemic bleeding disorders.

4.4 Special Warnings and Precautions for Use

Gastrointestinal effects.

As with other NSAIDs gastrointestinal (GI) bleeding, ulceration or perforation, which may be potentially fatal, can occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The consequences of such events are generally more serious in the elderly. 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 1).
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 ulceration or 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 including myocardial infarction and stroke. This may increase with dose and duration of use.
Patients with cardiovascular disease, history of atherosclerotic cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. To minimise the potential risk of an adverse cardiovascular event in patients taking meloxicam especially in those with cardiovascular risk factors the lowest effective dose should be used for the shortest possible duration.
Physicians and patients should remain alert for such cardiovascular events even in the absence of previous cardiovascular symptoms. Patients should be informed about signs and/or symptoms of serious cardiovascular toxicity and the steps to take if they occur.

Skin reactions.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia with systemic symptoms (DRESS) (see Drug reaction with eosinophilia with systemic symptoms (DRESS)), have been reported very rarely in association with the use of meloxicam. 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.

Drug reaction with eosinophilia with systemic symptoms (DRESS).

DRESS has been reported in patients taking NSAIDs. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue the NSAID and evaluate the patient immediately.

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.

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.

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.

Melobic 7.5 contains 23.5 mg lactose and Melobic 15 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.

Use in hepatic impairment.

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.
Physicians and patients should remain alert for hepatotoxicity. Patients should be informed about the signs and/or symptoms of hepatotoxicity. Patients with signs and/or symptoms suggesting liver dysfunction (e.g. nausea, fatigue, lethargy, pruritus, jaundice, abdominal tenderness in the right upper quadrant and "flu-like" symptoms), 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.

Use in renal impairment.

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 pre-treatment 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 renal function, including volume of diuresis, 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.

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.

Paediatric use.

Meloxicam is not recommended for use in children and adolescents under 18 years of age (see Section 4.3 Contraindications).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of 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. Coadministration of meloxicam with drugs known to inhibit CYP 3A4 (ketoconazole, itraconazole, erythromycin) or drugs known to be metabolised by CYP 3A4 (terfenadine, astemizole, ciclosporin, class III antiarrhythmic drugs such as amiodarone and quinidine) should be undertaken with caution (see Section 4.4 Special Warnings and Precautions for Use, 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.

Furosemide (frusemide).

Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide (frusemide) and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide (frusemide) agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide (frusemide) single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide (frusemide) and meloxicam, patients should be observed closely for signs of declining renal function (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Diuretics), as well as to assure diuretic efficacy.

Cytochrome P450 inhibitors.

Co-administration of meloxicam with drugs known to inhibit CYP 2C9 is contraindicated. Coadministration of meloxicam with drugs known to inhibit CYP 3A4 should be undertaken with caution (see Section 4.4 Special Warnings and Precautions for Use, 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 coadministered. 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.

Pemetrexed.

For the concomitant use of meloxicam with pemetrexed in patients with creatinine clearance from 45 to 79 mL/min, the administration of meloxicam should be paused for 5 days before, on the day of, and 2 days following pemetrexed administration. If a combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, especially for myelosuppression and gastro-intestinal adverse reactions. In patients with creatinine clearance below 45 mL/min the concomitant administration of meloxicam with pemetrexed is not recommended.

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.

Ciclosporin.

Nephrotoxicity of ciclosporin 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.

Colestyramine.

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

Oral hypoglycaemics.

Interactions via CYP 2C9 can be expected in combination with medicinal products such as oral antidiabetics (sulfonylureas), which may lead to increased plasma levels of these drugs and meloxicam. Patients concomitantly using meloxicam with sulfonylureas should be carefully monitored for hypoglycaemia.

4.6 Fertility, Pregnancy and Lactation

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.
(Category C)
Meloxicam use is contraindicated in pregnancy (see Section 4.3 Contraindications).
Inhibition of prostaglandin-synthesis may adversely affect pregnancy and/or the embryofetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in early pregnancy.
The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In preclinical studies, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryofetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenesis period.
From about 20 weeks of pregnancy all prostaglandin-synthesis inhibitors may expose the fetus to: renal dysfunction, which may progress to renal failure with oligohydramnios (see Oligohydramnios and neonatal renal impairment).
During the third trimester of pregnancy all prostaglandin-synthesis inhibitors may expose the fetus to: cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension).
The mother and the neonate, at the end of pregnancy, to: possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; inhibition of uterine contractions resulting in delayed or prolonged labour.
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.

Oligohydramnios and neonatal renal impairment.

Use of NSAIDs from about 20 weeks gestation may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.
These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation.
Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.
 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.

4.7 Effects on Ability to Drive and Use Machines

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.

4.8 Adverse Effects (Undesirable 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 2 presents the adverse events that occurred in ≥ 1% of the meloxicam treatment groups.
Adverse events that occurred in ≥ 1% of the meloxicam treatment groups in two 12-week placebo controlled rheumatoid arthritis trials are presented in Table 3.
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.

Reproductive system and breast disorders.

Infertility female, ovulation delayed.

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.
The following serious undesirable effects have been reported in association with the use of NSAIDs and cannot be ruled out for meloxicam. These include oligohydramnios and neonatal renal impairment.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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 colestyramine 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 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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.

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 4). 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.

5.2 Pharmacokinetic Properties

Absorption.

Meloxicam is well absorbed from the gastrointestinal tract following oral administration (absolute bioavailability 89%). Once daily dosing leads to mean drug plasma concentrations with a relatively narrow Cmaxss - Cminss window in the range of 0.3-1.0 microgram/mL for 7.5 mg doses or 0.7-1.9 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, 16 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 unlabelled 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 colestyramine 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. Total plasma clearance ranged from 7-9 mL/min following multiple oral doses of meloxicam.

Special populations.

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 has 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 (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). A reduced protein binding was observed in patients with end stage renal disease in haemodialysis (see Section 4.2 Dose and Method of Administration).

Haemodialysis.

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

5.3 Preclinical Safety Data

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients in meloxicam tablets include: sodium citrate dihydrate, lactose monohydrate, microcrystalline cellulose, povidone, crospovidone, colloidal anhydrous silica and magnesium stearate.
See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Melobic 7.5 and 15 mg tablets (7.5 and 15 mg meloxicam) are presented in PVC/PVDC/Al blister packs of 30's and 60's*.
*Some of these pack sizes are not marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Chemical name: 4-hydroxy-2-methyl-N-(5-methyl-thiazol-2-yl)-2H-1,2-benzothiazine-3- carboxamide-1,1-dioxide.
Molecular weight: 351.4.
Molecular formula: C14H13N3O4S2.
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, and very slightly soluble in ethanol (96 per cent). There are no chiral centres and shows polymorphism.

CAS number.

71125-38-7.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes