Consumer medicine information

APO-Diclofenac

Diclofenac sodium

BRAND INFORMATION

Brand name

APO-Diclofenac

Active ingredient

Diclofenac sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Diclofenac.

What is in this leaflet

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

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

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

Keep this leaflet with the medicine. You may need to read it again.

What this medicine is used for

APO-Diclofenac belongs to a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs), which are used to treat pain and reduce inflammation (swelling and redness).

APO-Diclofenac is used to treat:

  • different types of arthritis including rheumatoid arthritis and osteoarthritis
  • other painful conditions where swelling is a problem such as back pain, rheumatism, muscle strains, sprains and tendonitis (e.g. tennis elbow)
  • menstrual cramps (period pain)

It can relieve the symptoms of pain and inflammation but it will not cure your condition.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription. It is not addictive.

There is not enough information to recommend the use of this medicine for children.

Before you use this medicine

When you must not take it

Do not use this medicine if you are allergic (hypersensitive) to:

  • diclofenac
  • or any of the other ingredients listed at the end of this leaflet
  • aspirin
  • ibuprofen
  • any other NSAID
  • lactose, or are lactose intolerant - these tablets contain a small amount of lactose

If you are not sure if you are taking any of the above medicines, ask your doctor or pharmacist.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat, and/or extremities (signs of angiodema)
  • rash, itching or hives on the skin

Many medicines used to treat headache, period pain and other aches and pains contain aspirin or NSAID medicines. If you are allergic to aspirin or NSAID medicines and you use APO-Diclofenac, these symptoms may be severe.

Do not use APO-Diclofenac if you have had any of the following medical conditions:

  • a stomach or intestinal ulcer
  • bleeding from the stomach or bowel (symptoms of which may include blood in your stools or black stools)
  • kidney or liver problems
  • severe heart failure
  • heart bypass surgery

Do not use APO-Diclofenac during the first 6 months of pregnancy, except on doctor's advice. Do not use during the last three months of pregnancy. Use of this medicine during the last 3 months of pregnancy may affect your baby and may delay labour and birth.

Use of non-aspirin NSAIDs can increase the risk of miscarriage, particularly when taken close to the time of conception.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to use it

Tell your doctor if you have any of the following health problems/ medical conditions:

  • established disease of the heart or blood vessels (also called cardiovascular disease, including uncontrolled high blood pressure, congestive heart failure, established ischemic heart disease, peripheral arterial disease or atherosclerotic cardiovascular disease), as treatment with APO-Diclofenac is generally not recommended
  • established cardiovascular disease (see above) or significant risk factors such as high blood pressure, abnormally high levels of fat (cholesterol, triglycerides) in your blood, diabetes, or if you smoke, and your doctor decides to prescribe APO-Diclofenac, you must not increase the dose above 100 mg per day if you are treated for more than 4 weeks.
  • a past history of ulcers (stomach or intestinal)
  • gastrointestinal problems such as stomach ulcer, bleeding or black stools, or have experienced stomach discomfort or heartburn after taking anti-inflammatory medicines in the past
  • diseases of the bowel or inflammation of the intestinal tract (Crohn's disease) or colon (ulcerative or ischemic colitis)
  • past history of haemorrhoids (piles) or irritation of the rectum (back passage)
  • liver or kidney problems
  • a rare liver condition called porphyria
  • bleeding disorders or other blood disorders (e.g. anaemia)
  • asthma or any other chronic lung disease that causes difficulty in breathing
  • hay fever (seasonal allergic rhinitis)
  • repeated chest infections
  • polyps in the nose
  • diabetes
  • dehydration (e.g. by sickness, diarrhoea, before or after recent major surgery
  • swollen feet

Your doctor may want to take special precautions if you have any of the above conditions.

It is generally important to take the lowest dose of APO-Diclofenac that relieves your pain and/or swelling and for the shortest time possible in order to keep your risk for cardiovascular side effects as small as possible.

Tell your doctor if you are pregnant or trying to become pregnant. There is not enough information to recommend the use of APO-Diclofenac during the first 6 months of pregnancy and it must not be used during the last 3 months. APO-Diclofenac may also reduce fertility and affect your chances of becoming pregnant. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you currently have an infection. If you use APO-Diclofenac while you have an infection, some of the signs of the infection such as pain, fever, swelling and redness may be hidden. You may think, mistakenly, that you are better or that the infection is not serious.

Tell your doctor if you are breast-feeding. Breast-feeding is not recommended while you are using this medicine. The active ingredient in APO-Diclofenac passes into breast milk and may affect your baby.

Tell your doctor if you are lactose intolerant. APO-Diclofenac tablets contain lactose.

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives. Your doctor will want to know if you are prone to allergies, especially if you get skin reactions with redness, itching or rash.

Taking other medicines

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

Some medicines that are important to mention include:

  • other anti-inflammatory medicines, e.g. aspirin, salicylates or ibuprofen
  • warfarin or other "blood thinners" (medicines used to prevent blood clotting)
  • digoxin (a medicine for heart problems)
  • lithium or selective serotonin-reuptake inhibitors (SSRIs), a medicine used to treat some types of depression
  • diuretics (medicines used to increase the amount of urine)
  • ACE inhibitors or beta-blockers (medicines used to treat high blood pressure, heart conditions, glaucoma and migraine)
  • prednisone, cortisone, or other corticosteroids (medicines used to provide relief for inflamed areas of the body)
  • medicines (such as metformin) used to treat diabetes, except insulin
  • methotrexate (a medicine used to treat arthritis and some cancers)
  • ciclosporin, tacrolimus (a medicine used in patients who have received organ transplants)
  • trimethoprim (a medicine used to prevent or treat urinary tract infections)
  • some medicines used to treat infection (quinolone antibacterials)
  • glucocorticoid medicines, used to treat arthritis
  • sulfinpyrazone (a medicine used to treat gout)
  • voriconazole (a medicine used to treat fungal infections)
  • phenytoin (a medicine used to treat seizures)
  • rifampicin (an antibiotic medicine used to treat bacterial infections)

You may need to take different amounts of your medicines or to take different medicines while you are using APO-Diclofenac. Your doctor and pharmacist have more information.

If you have not told your doctor about any of these things, tell him/ her before you start using this medicine.

How to take this medicine

When to take it

It is recommended to take the tablets before meals or on an empty stomach. If they upset your stomach, you can take them with food or immediately after food. They will work more quickly if you take them on an empty stomach but they will still work if you have to take them with food to prevent stomach upset.

How much to take

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the directions, ask your doctor or pharmacist for help. There are different ways to take APO-Diclofenac tablets, depending on your condition. Your doctor will tell you exactly how many tablets to take.

Do not exceed the recommended dose.

To treat arthritis or other painful conditions

The usual starting dose of APO-Diclofenac tablets is 75 mg to 150 mg each day. After the early stages of treatment, it is usually possible to reduce the dose to 75 mg to 100 mg each day.

To treat menstrual cramps (period pain)

The usual starting dose of APO-Diclofenac tablets is 50 mg to 100 mg each day, beginning as soon as cramps begin and continuing until the pain goes away, but for no longer than 3 days.

If necessary, the dose can be raised over several menstrual periods to a maximum of 200 mg each day.

How to take it

The daily dose should be divided into two or three doses taken during the day.

The tablets should be swallowed whole with a full glass of water or other liquid.

Do not break, crush or chew the tablets.

How long to take it

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

If you are using APO-Diclofenac for arthritis, it will not cure your disease but it should help to control pain and inflammation. It usually begins to work within a few hours but several weeks may pass before you feel the full effects of the medicine.

If you forget to take it

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

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

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

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 take too much (overdose)

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

You may need urgent medical attention.

If you take too much APO-Diclofenac, you may experience:

  • vomiting
  • bleeding from the stomach or bowel
  • diarrhoea
  • dizziness
  • ringing in the ears
  • convulsions (fits)

While you are using this medicine

Things you must do

If you take APO-Diclofenac for more than a few weeks, you should make sure to visit your doctor for regular check-ups to ensure that you are not suffering from unnoticed undesirable effects.

If you become pregnant whilst taking or using APO-Diclofenac, tell your doctor immediately. Your doctor can discuss with you the risks of using it while you are pregnant.

Be sure to keep all of your doctor's appointments so that your progress can be checked.

Your doctor will periodically re-evaluate whether you should continue treatment with APO-Diclofenac, if you have established heart disease or significant risks for heart disease, especially in case you are treated for more than 4 weeks.

Your doctor may want to check your kidneys, liver and blood from time to time to help prevent unwanted side effects.

If at any time while taking APO-Diclofenac you experience any signs or symptoms of problems with your heart or blood vessels such as chest pain, shortness of breath, weakness, or slurring of speech, contact your doctor immediately. These may be signs of cardiovascular toxicity.

If you are going to have surgery, make sure the surgeon and anaesthetist know that you are using APO-Diclofenac. NSAID medicines can slow down blood clotting and affect kidney function.

If you get an infection while using APO-Diclofenac, tell your doctor. This medicine may hide some of the signs of an infection (pain, fever, swelling, redness). You may think, mistakenly, that you are better or that the infection is not serious.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using APO-Diclofenac.

Tell any other doctor, dentist or pharmacist who treats you that you are using APO-Diclofenac.

Things you must not do

Do not take any of the following medicines while you are using APO-Diclofenac without first telling your doctor:

  • aspirin (also called ASA or acetylsalicylic acid)
  • other salicylates
  • other medicines containing diclofenac
  • ibuprofen
  • any other NSAID medicine

If you take these medicines together with APO-Diclofenac, they may cause unwanted side effects.

If you need to take something for headache or fever, it is usually okay to take paracetamol. If you are not sure, your doctor or pharmacist can advise you.

Do not stop any other forms of treatment for arthritis that your doctor has told you to follow. This medicine does not replace exercise or rest programs or the use of heat/cold treatments.

Do not give this medicine to anyone else, even if their condition seems similar to yours. Do not use it to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert until you know how APO-Diclofenac affects you. This medicine may cause dizziness, drowsiness, spinning sensation (vertigo) or blurred vision in some people. If you have any of these symptoms, do not drive, use machines, or do anything else that could be dangerous.

Elderly patients should take the minimum number of tablets that provides relief of symptoms. Elderly patients, especially those with a low body weight, may be more sensitive to the effects of APO-Diclofenac than other adults.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using APO-Diclofenac.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

If you are over 65 years old, you should be especially careful while taking this medicine. Report any side effects promptly to your doctor. As people grow older, they are more likely to get side effects from medicines.

Do not be alarmed by these lists of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

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

  • stomach upset including nausea (feeling sick), vomiting, indigestion, cramps, loss of appetite, wind
  • heartburn or pain behind or below the breastbone (possible symptoms of an ulcer in the tube that carries food from the throat to the stomach)
  • stomach or abdominal pain
  • constipation, diarrhoea
  • sore mouth or tongue
  • altered taste sensation
  • headache
  • dizziness, spinning sensation
  • drowsiness, disorientation, forgetfulness
  • feeling depressed, anxious or irritable
  • strange or disturbing thoughts or moods
  • shakiness, sleeplessness, nightmares
  • tingling or numbness of the hands or feet
  • feeling of fast or irregular heart beat
  • unusual weight gain or swelling of arms, hands, feet, ankles or legs due to fluid build-up
  • symptoms of sunburn (such as redness, itching, swelling, blistering of the lips, eyes, mouth, and/or skin) that happen more quickly than normal
  • skin inflammation with flaking or peeling
  • vision disorders* (e.g. blurred or double vision)
  • buzzing or ringing in the ears, difficulty hearing
  • hypertension (high blood pressure)
  • hair loss or thinning

NSAIDs, including diclofenac, may be associated with increased risk of gastro-intestinal anastomotic leak. Close medical surveillance and caution are recommended when using this medicine after gastrointestinal surgery.

*If symptoms of vision disorders occur during treatment with APO-Diclofenac, contact your doctor as an eye examination may be considered to exclude other causes.

If any of the following signs appear, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • red or purple skin (possible signs of blood vessel inflammation)
  • severe pain or tenderness in the stomach, vomiting blood or material that looks like coffee grounds, bleeding from the back passage, black sticky bowel motions (stools) or bloody diarrhoea (possible stomach problems)
  • rash, skin rash with blisters, itching or hives on the skin; swelling of the face, lips, mouth, tongue, throat, or other part of the body which may cause difficulty to swallow, low blood pressure (hypotension), fainting, shortness of breath (possible allergic reaction)
  • wheezing, troubled breathing, or feelings of tightness in the chest (signs of asthma)
  • yellowing of the skin and/or eyes (signs of hepatitis/liver failure)
  • persistent nausea, loss of appetite, unusual tiredness, vomiting, pain in the upper right abdomen, dark urine or pale bowel motions (possible liver problems)
  • constant "flu-like" symptoms including chills, fever, sore throat, aching joints, swollen glands, tiredness or lack of energy, bleeding or bruising more easily than normal (possible blood problem)
  • painful red areas, large blisters, peeling of layers of skin, bleeding in the lips, eyes, mouth, nose or genitals, which may be accompanied by fever and chills, aching muscles and feeling generally unwell (possible serious skin reaction)
  • signs of a possible effect on the brain, such as sudden and severe headache, stiff neck (signs of viral meningitis), severe nausea, dizziness, numbness, difficulty in speaking, paralysis (signs of cerebral attack), convulsions (fits)
  • change in the colour or amount of urine passed, frequent need to urinate, burning feeling when passing urine, blood or excess of protein in the urine (possible kidney disorders)
  • sudden and oppressive chest pain (which may be a sign of myocardial infarction or a heart attack)
  • breathlessness, difficulty breathing when lying down, swelling of the feet or legs (signs of cardiac failure)
  • coincidental occurrence of chest pain and allergic reactions (signs of Kounis syndrome)

Tell your doctor if you notice anything else that is making you feel unwell. Some people may have other side effects not yet known or mentioned in this leaflet.

Storage and Disposal

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store this medicine or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What APO-Diclofenac looks like

APO-Diclofenac 25 mg Tablets:
Brown, yellow film coated tablet, biconvex with an intact surface and uniform colour. AUST R 160729.

Blister packs of 50 tablets.

APO-Diclofenac 50 mg Tablets:
Brown, yellow film coated tablet, biconvex with facet on both sides, intact surface and uniform colour. AUST R 160730.

Blister packs of 50 tablets.

*Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 25 or 50 mg of diclofenac as the active ingredient.

In addition, the tablets contain the following inactive ingredients:

  • lactose monohydrate
  • calcium hydrogen phosphate dihydrate
  • microcrystalline cellulose
  • maize starch
  • sodium starch glycollate
  • magnesium stearate
  • colloidal anhydrous silica
  • methacrylic acid copolymer
  • triethyl citrate
  • purified talc
  • titanium dioxide
  • iron oxide yellow.

This medicine contains sugars as lactose.

This medicine is gluten-free, sucrose-free, tartrazine-free and other azo dyes-free.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Tel: (02) 8877 8333
Web: www1.apotex.com/au

APO and APOTEX are registered trademarks of Apotex Inc.

This leaflet was prepared in February 2022.

Published by MIMS April 2022

BRAND INFORMATION

Brand name

APO-Diclofenac

Active ingredient

Diclofenac sodium

Schedule

S4

 

1 Name of Medicine

Diclofenac sodium.

2 Qualitative and Quantitative Composition

Each tablet contains 25 mg or 50 mg of diclofenac sodium as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

25 mg tablets (AUST R 160729).

Brown yellow film-coated tablet, biconvex with an intact surface and uniform colour.

50 mg tablets (AUST R 160730).

Brown yellow film-coated tablet, biconvex with facet on both sides, intact surface and uniform colour.

4 Clinical Particulars

4.1 Therapeutic Indications

Inflammatory and degenerative forms of rheumatism: rheumatoid arthritis and osteoarthritis.
Relief of acute or chronic pain states in which there is an inflammatory component.
Symptomatic treatment of primary dysmenorrhoea.

4.2 Dose and Method of Administration

APO-Diclofenac enteric coated tablets are intended for oral administration.

Pregnancy.

See Section 4.3 Contraindications; Section 4.6 Fertility, Pregnancy and Lactation.
After assessing the risk/benefit ratio in each individual patient, the lowest effective dose for the shortest possible duration should be used. Adverse effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see Section 4.4 Special Warnings and Precautions for Use). Patients on long term treatment should be reviewed regularly with regards to efficacy, risk factors and ongoing need for treatment.
The tablets should be swallowed whole with liquid, preferably before meals, and must not be divided or chewed.
Initial dosage is 75 to 150 mg daily. For long-term therapy, 75 to 100 mg daily is usually sufficient.
The daily dose should generally be prescribed in two or three divided doses.
In primary dysmenorrhoea the daily dosage, which should be individually adapted, is generally 50 to 150 mg. Initially, a dose of 50 to 100 mg should be given and, if necessary, raised in the course of several menstrual cycles up to a maximum of 200 mg/day. Treatment should be started upon appearance of the first symptoms and depending on the symptomatology, continued for a few days.

4.3 Contraindications

Gastric or duodenal ulcer, gastrointestinal bleeding or perforation.
Patients who are hypersensitive to the active ingredient, diclofenac, or any of the excipients contained in the tablets.
Third trimester of pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).
Patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).
Renal failure (see Section 4.4 Special Warnings and Precautions for Use).
Severe cardiac failure (see Section 4.4 Special Warnings and Precautions for Use).
Treatment of perioperative pain in setting of coronary artery bypass surgery (CABG).
Patients in whom diclofenac, aspirin or other NSAIDs induce asthma, angioedema, urticaria, or other allergic-type reactions because severe, rarely fatal, anaphylactic type reactions to diclofenac have been reported in such patients.

4.4 Special Warnings and Precautions for Use

Cardiovascular thrombotic events.

Observational studies have indicated that non-selective NSAIDs may be associated with an increased risk of serious cardiovascular events, including myocardial infarction and stroke, which may increase with dose or duration of use. Patients with cardiovascular disease, history of atherosclerotic cardiovascular disease or cardiovascular risk factors may also be at greater risk (see Section 4.2 Dose and Method of Administration).
Treatment with diclofenac is generally not recommended in patients with established cardiovascular disease (congestive heart failure, established ischemic heart disease, peripheral arterial disease) or uncontrolled hypertension. If needed, patients with established cardiovascular disease, uncontrolled hypertension, or significant risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia, diabetes mellitus and smoking) should be treated with diclofenac only after careful consideration and only at doses ≤ 100 mg daily when treatment continues for more than 4 weeks.
As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the lowest effective daily dose should be used for the shortest duration possible. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially when treatment continues for more than 4 weeks.
Physicians and patients should remain alert for the signs and symptoms of serious arteriothrombotic events (e.g. chest pain, shortness of breath, weakness, slurring of speech), which can occur without warnings. Patients should be informed about signs and/or symptoms of serious cardiovascular toxicity and be instructed to see a physician immediately in case of such an event.
There is no consistent evidence that the concurrent use of aspirin mitigates the possible increased risk of serious cardiovascular thrombotic events associated with NSAID use.

Peri-operative bleeding.

Pre-operative administration of diclofenac may increase the risk of post-operative bleeding.
Since diclofenac may temporarily inhibit platelet aggregation, children undergoing minor procedures such as tonsillectomy, myringotomy, circumcision, orchidopexy and strabismus surgery should be carefully monitored.

Hypertension.

NSAIDs may lead to the onset of new hypertension or worsening of pre-existing hypertension and patients taking anti-hypertensives with NSAIDs may have an impaired antihypertensive response. Caution is advised when prescribing NSAIDs, including diclofenac to patients with hypertension. Blood pressure should be monitored closely during initiation of NSAID treatment and at regular intervals thereafter.

Heart failure.

Fluid retention and oedema have been observed in some patients taking NSAIDs, including diclofenac therefore caution is advised in patients with fluid retention or heart failure.

Gastrointestinal effects.

Close medical surveillance is imperative and particular caution should be exercised when prescribing NSAIDs, including diclofenac in patients with symptoms indicative of gastrointestinal disorders (GI) or with a history suggestive of gastro-intestinal ulceration, bleeding or perforation (see Section 4.8 Adverse Effects (Undesirable Effects)).
Upper GI ulcers, gross bleeding or perforation caused by NSAIDs, including diclofenac occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated in one year. The risk of GI bleeding is higher with increasing NSAID doses, with increasing duration of use and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation and in the elderly. Gastric or duodenal ulceration, perforation or gastrointestinal bleeding, which can be fatal, have been reported in patients receiving diclofenac. Studies to date have not identified any subset of patients who are not at risk of developing these problems.
Caution is advised in patients with risk factors for gastrointestinal events who may be at greater risk of developing serious gastrointestinal events, e.g. the elderly, those with a history of serious gastrointestinal events, smoking and alcoholism.
The concurrent use of aspirin and NSAIDs, including diclofenac also increases the risk of serious gastrointestinal adverse events.
To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly, the treatment should be initiated and maintained at the lowest effective dose. Gastrointestinal bleeding, ulceration and perforation in general have more serious consequences in the elderly. They can occur at any time during treatment with or without warning symptoms or a previous history. In instances where gastrointestinal bleeding or ulcerations occur in patients receiving diclofenac, the drug should be withdrawn immediately. Physicians should warn patients about what the signs and symptoms of serious gastrointestinal toxicity and what steps to take if they occur.
Combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low-dose acetylsalicylic acid (ASA)/ aspirin or other medicinal products likely to increase gastrointestinal risk.
Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding). Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants, anti-platelet agents or selective serotonin-reuptake inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Close medical surveillance and caution should also be exercised in patients with ulcerative colitis or with Crohn's disease, as well as in patients suffering from pre-existing dyshaemopoiesis or disorders of blood coagulation, as their condition may be exacerbated (see Section 4.8 Adverse Effects (Undesirable Effects)).
NSAIDs, including diclofenac, may be associated with increased risk of gastro-intestinal anastomotic leak. Close medical surveillance and caution are recommended when using diclofenac after gastro-intestinal surgery.

Serious skin reactions.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS) 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 NSAIDs, including diclofenac (see Section 4.8 Adverse Effects (Undesirable Effects)). These serious adverse events are idiosyncratic and are independent of dose or duration of use. 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. Patients should be advised of the signs and symptoms of serious skin reactions and to consult their doctor at the first appearance of skin rash, mucosal lesion or any other sign of hypersensitivity, and diclofenac should be discontinued.

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.

Pre-existing asthma.

In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions to NSAIDs such as asthma exacerbations (so-called intolerance to analgesics/ analgesics-asthma), Quincke's oedema or urticaria are more frequent than in other patients. Therefore, special precaution is recommended in such patients. This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.

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

The use of an ACE inhibiting drug (ACE-inhibitors 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.

Infection.

Like other NSAIDs, diclofenac may mask the usual signs and symptoms of infection due to its pharmacodynamic properties.

Haematological effects.

Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients with haemostatic disorders should be carefully monitored.
During prolonged treatment, a slight reduction in haemoglobin has been noted in some patients. On rare occasions, blood dyscrasias have been reported. Periodic blood counts are therefore recommended.

Hypersensitivity.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, have been reported with diclofenac. These reactions can occur without earlier exposure to the drug. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction. Presenting symptoms of such reactions can include chest pain occurring in association with an allergic reaction to diclofenac.

Lactose intolerance.

Diclofenac tablets contain lactose and therefore are not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

Use in hepatic impairment.

Close medical surveillance is required when prescribing diclofenac to patients with impaired liver function, as their condition may be exacerbated (see Section 4.3 Contraindications).
As with other NSAIDs, including diclofenac elevations of one or more liver enzymes may occur during diclofenac therapy. These laboratory abnormalities may progress, remain unchanged, or revert to normal despite continued therapy. Borderline elevations [i.e. 1.2 to 3 times the upper limit of normal (ULN)], or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. In clinical trials, meaningful elevations (i.e. more than 3 times the ULN) of AST and/or ALT occurred in about 4% of patients treated for several months, including marked elevations (i.e. more than 8 times the ULN) in about 1% of patients. Transaminase elevations were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis (see Section 4.8 Adverse Effects (Undesirable Effects)).
Transaminase elevations were reversible on cessation of therapy, and even among patients with marked elevations, signs and symptoms of liver disease occurred only in isolated cases. Most patients with borderline elevations did not have therapy interrupted, and transaminase elevations in most of these cases disappeared or did not progress. There were no identifying features to distinguish those patients who developed marked elevations from those who did not.
In addition to the enzyme elevations seen in clinical trials, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, have been reported.
Severe hepatotoxicity may develop without prodromal symptoms, so transaminases should be measured periodically in patients receiving long-term therapy with diclofenac. The optimum times for making the measurements are not known. In most patients who have developed marked transaminase elevations, abnormal tests occurred during the first 2 months of therapy with diclofenac. Based on this experience the first transaminase measurement should be made no later than 8 weeks after the start of diclofenac treatment. As with other NSAIDs, including diclofenac if abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc), diclofenac should be discontinued.
To minimise the possibility of hepatic injury becoming severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g. nausea, fatigue, lethargy, pruritus, jaundice, abdominal tenderness in the right upper quadrant and "flu-like" symptoms) and the appropriate action to take should these signs and symptoms appear.
Caution should be exercised when using diclofenac in patients with hepatic porphyria, since diclofenac may trigger an attack.

Use in renal impairment.

As a class, NSAIDs have been associated with renal papillary necrosis and other pathology during long-term administration in animals.
Fluid retention and oedema have been reported in association with NSAID therapy, including diclofenac. Owing to the importance of prostaglandins for maintaining renal blood flow, particular caution is called for in patients with impaired cardiac or renal function, history of hypertension, in the elderly, in patients being treated with diuretics or medicinal products that can significantly impact renal function, and in those with extracellular volume depletion from any cause, e.g. in the peri- or post-operative phase of major surgical operations (see Section 4.3 Contraindications). Monitoring of renal function as a precautionary measure is therefore recommended when using diclofenac in such cases. Discontinuation of therapy is typically followed by recovery to the pre-treatment state.

Use in the elderly.

In elderly patients, who are generally more prone to side effects, particular caution should be exercised. It is recommended that the lowest effective dosage be used in elderly patients or those with a low body weight.

Paediatric use.

Diclofenac is not recommended for use in children as safety and efficacy in this age group have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The following interactions include those observed with diclofenac and/or other pharmaceutical forms of diclofenac:

Lithium/ digoxin.

When given together with preparations containing lithium or digoxin, diclofenac may raise their plasma concentrations and these concentrations should be monitored during treatment with diclofenac.

Diuretics and anti-hypertensive agents.

Like other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may cause a decrease in their antihypertensive effect. Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. When NSAIDs, including diclofenac are combined with diuretics, ACE inhibitors or angiotensin II receptor antagonists, the risk of worsening of renal function, including possible acute renal failure (which is usually reversible) may be increased in some patients, especially when renal function is compromised (e.g. dehydrated or elderly patients). Patients should be adequately hydrated and monitoring of renal function is recommended after initiation of concomitant therapy and periodically thereafter. Concomitant treatment with potassium-sparing drugs may be associated with increased serum potassium levels, thus making it necessary to monitor the latter (see Section 4.4 Special Warnings and Precautions for Use).

Other NSAIDs and corticosteroids.

The concomitant use of diclofenac with systemic NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects. Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal undesirable effects. Concurrent treatment with aspirin lowers the plasma concentration, peak plasma levels and AUC values of diclofenac. The use of both drugs concurrently is not recommended.

Anticoagulants and anti-platelet agents.

Caution is recommended since concomitant administration could increase the risk of bleeding (see Section 4.4 Special Warnings and Precautions for Use). The concurrent use of NSAIDs and warfarin has been associated with severe, sometimes fatal, haemorrhage. The exact mechanism of the interaction between NSAIDs and warfarin is unknown, but may involve enhanced bleeding from NSAID-induced gastrointestinal ulceration or an additive effect of anticoagulation by warfarin and inhibition of platelet function by NSAIDs. Diclofenac should be used with caution in combination with warfarin and such patients should be closely monitored.

Selective serotonin reuptake inhibitors (SSRIs).

Concomitant administration of systemic NSAIDs, including diclofenac and SSRIs may increase the risk of gastrointestinal bleeding (see Section 4.4 Special Warnings and Precautions for Use).

Antidiabetic agents.

Diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there are isolated reports of both hypoglycaemic and hyperglycaemic effects in the presence of diclofenac, which necessitated changes in the dosage of antidiabetic agents. For this reason, monitoring of blood glucose levels is recommended as a precautionary measure during concomitant therapy. There have also been isolated reports of metabolic acidosis when diclofenac was co-administered with metformin, especially in patients with pre-existing renal impairment.

Methotrexate.

Caution should be exercised when NSAIDs, including diclofenac are administered less than 24 hours before or after treatment with methotrexate, since the blood concentration of methotrexate may rise and the toxicity of this substance be increased.

Cyclosporin and tacrolimus.

Nephrotoxicity of cyclosporin may be enhanced through effects of NSAIDs, including diclofenac, on renal prostaglandins. Therefore, diclofenac should be given at doses lower than those that would be used in patients not receiving cyclosporin or tacrolimus.

Drugs known to cause hyperkalemia.

Concomitant treatment with potassium sparing drugs (e.g. diuretics, ciclosporin, tacrolimus or trimethoprim) may be associated with increased serum potassium levels, which should therefore be monitored frequently (see Section 4.4 Special Warnings and Precautions for Use).

Glucocorticoids.

The addition of glucocorticoids to NSAIDs, though sometimes necessary for therapeutic reasons, may aggravate gastrointestinal side effects.

Quinolone antibacterials.

There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.

CYP2C9 inhibitors.

Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as sulfinpyrazone and voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism. Concomitant administration of voriconazole with diclofenac may increase plasma diclofenac levels.

CYP2C9 inducers.

Caution is recommended when co-prescribing diclofenac with CYP2C9 inducers (such as rifampicin), which could result in a significant decrease in plasma concentration and exposure to diclofenac.

Phenytoin.

When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac should be considered.
(Category C)
NSAIDs inhibit prostaglandin synthesis and, when given during the latter part of pregnancy, may cause closure of the foetal ductus arteriosus, foetal renal impairment, inhibition of platelet aggregation and delay labour and birth.
The use of diclofenac in pregnant women has not been studied and safety in pregnancy has not been established. Therefore, diclofenac should not be used in pregnant women during the first two trimesters or in women who are likely to become pregnant unless the potential benefit to the mother outweighs the risk to the foetus.
Use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of uterine inertia, premature closure of the ductus arteriosus and oligohydramnios and neonatal renal impairment (see Oligohydramnios and neonatal renal impairment; see Section 4.3 Contraindications).
Data from epidemiological studies suggest an increased risk of miscarriage after the use of a prostaglandin synthesis inhibitor in early pregnancy.

Oligohydramnios and neonatal renal impairment.

Use of NSAIDs from about 20 weeks gestation may cause foetal 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.
If, after careful consideration of alternative treatment options for pain management, NSAID treatment is necessary from about 20 weeks to the end of the second trimester, limit use to the lowest effective dose and shortest duration possible. Use of diclofenac during the third trimester of pregnancy is contraindicated (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Consider ultrasound monitoring of amniotic fluid if treatment extends beyond 48 hours. Discontinue treatment with NSAIDs if oligohydramnios occurs.
 Following oral doses of 50 mg administered every 8 hours, the active substance, diclofenac, passes into the breast milk. As with other drugs which are excreted in milk, diclofenac is not recommended for use in nursing women.

4.7 Effects on Ability to Drive and Use Machines

Patients experiencing visual disturbances, dizziness, vertigo, somnolence or other central nervous disturbances while taking diclofenac should refrain from driving a vehicle or operating machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.
The following undesirable effects include those reported with diclofenac tablets and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use:

Blood and lymphatic system disorders.

Very rare: thrombocytopenia, leucopoenia, anaemia (including haemolytic anaemia and aplastic anaemia), agranulocytosis, positive Coombs' test.

Immune system disorders.

Rare: hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).
Very rare: angioneurotic oedema (including face oedema).

Psychiatric disorders.

Very rare: disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.

Nervous system disorders.

Common: headache, dizziness.
Rare: somnolence.
Very rare: paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident, myoclonic encephalopathy (described in two patients).

Eye disorders.

Very rare: visual disturbance, blurred vision, diplopia.

Ear and labyrinth disorders.

Common: vertigo.
Very rare: tinnitus, impaired hearing.

Cardiac disorders.

Uncommon*: myocardial infarction, cardiac failure, palpitations, chest pain.
* The frequency reflects data from long-term treatment with a high dose (150 mg/day).
Frequency unknown: Kounis syndrome.

Vascular disorders.

Very rare: hypertension, vasculitis.

Respiratory, thoracic and mediastinal disorders.

Rare: asthma (including dyspnoea).
Very rare: pneumonitis.

Gastrointestinal disorders.

Common: nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia.
Rare: gastritis, gastrointestinal haemorrhage, haematemesis, haemorrhagic diarrhoea, melaena, gastrointestinal ulcer (with or without bleeding or perforation), gastrointestinal stenosis, or perforation, which may lead to peritonitis, proctitis (suppositories).
Very rare: colitis (including haemorrhagic colitis, ischemic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis, glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis, haemorrhoids aggravated (suppositories).

Hepatobiliary disorders.

Common: transaminases increased.
Rare: hepatitis, jaundice, liver disorder.
Very rare: fulminant hepatitis, hepatic necrosis, hepatic failure.

Pregnancy, puerperium and perinatal conditions.

Unknown: Oligohydramnios, neonatal renal impairment.

Skin and subcutaneous tissue disorders.

Common: rashes or skin eruptions.
Rare: urticaria.
Very rare: bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), dermatitis exfoliative, loss of hair, photosensitivity reaction, purpura, allergic purpura, pruritus.
Unknown: drug reaction with eosinophilia with systemic symptoms (DRESS).

Renal and urinary disorders.

Very rare: acute kidney injury (acute renal failure), haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.

General disorders and administration site conditions.

Common: application site irritation.
Rare: oedema.
Very rare: impotence (association with diclofenac intake is doubtful). Worsening of haemorrhoids has been reported with use of diclofenac suppositories. Toxic shock syndrome has been reported in patients administered NSAIDs post-operatively.

Description of selected adverse drug reactions.

Arteriothrombotic events.

Meta-analysis and pharmacoepidemiological data point towards an increased risk of arteriothrombotic events (for example myocardial infarction) associated with the use of diclofenac, particularly at a high dose (150 mg daily) and during long-term treatment (see Section 4.4 Special Warnings and Precautions for Use). A recent meta-analysis (CNT) estimates that, in comparison with placebo, allocation to diclofenac caused around 3 additional major vascular events per 1000 participants per year. This estimate reflects data from long term treatment with high dose diclofenac (150 mg/day).

Visual effects.

Visual disturbances such as visual impairment, blurred vision or diplopia appear to be NSAID class effects and are usually reversible on discontinuation. A likely mechanism for the visual disturbances is the inhibition of prostaglandin synthesis and other related compounds that alter the regulation of retinal blood flow resulting in potential changes in vision. If such symptoms occur during diclofenac treatment, an ophthalmological examination may be considered to exclude other causes.

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 http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

There is no typical clinical picture resulting from an overdosage of diclofenac. Overdosage can cause symptoms such as vomiting, gastrointestinal haemorrhage, diarrhoea, dizziness, tinnitus or convulsions. In the event of significant poisoning, acute renal failure and liver damage are possible.

Treatment.

Management of acute poisoning with NSAIDs consists essentially of supportive and symptomatic treatment.
The therapeutic measures to be taken in cases of overdosage are as follows:
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 nasogastric tube, once the airway is protected.
Supportive and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression. Haematological and biochemical parameters, and the presence or absence of blood in the stools, should be monitored.
Specific therapies such as forced diuresis, dialysis, or haemoperfusion are probably of no help in eliminating NSAIDs, because of their high protein-binding rate and extensive metabolism.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Diclofenac sodium, a non-steroidal compound, exhibits pronounced antirheumatic, anti-inflammatory, analgesic and antipyretic properties.
As with other NSAIDs, its mode of action is not known; however, its ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect.
In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac elicit a clinical response characterised by relief from signs and symptoms such as pain at rest, pain on movement, morning stiffness, and swelling of the joints, as well as by an improvement in function.
In addition, clinical studies have revealed that in primary dysmenorrhoea, diclofenac is capable of relieving the pain and reducing the extent of bleeding. Low concentrations of diclofenac sodium inhibit the aggregation of platelets induced in vitro by collagen and by adenosine diphosphate. Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in canine cartilage at concentrations equivalent to the concentrations reached in humans. It is unknown whether or not diclofenac sodium affects the integrity of human osteoarthritic cartilage.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Diclofenac is completely absorbed from the enteric-coated tablets after their passage through the stomach. Following ingestion of one tablet with or after a meal, its passage through the stomach is slower than when it is taken before a meal, but the amount of active substance absorbed remains the same. In fasting subjects, the mean peak plasma concentration of 1.5 microgram/mL (5 micromol/L) is attained on average 2 hours after ingestion of one tablet of 50 mg. The plasma concentrations, as measured by the area under the time-concentration curve, are in linear relation to the size of the dose.
After administration of diclofenac for 15 days in an oral dose of 25 mg three times daily, there was no evidence of the drugs accumulation in plasma.

Distribution.

In a study in 16 patients with rheumatoid arthritis and knee joint effusions it was found that diclofenac enters the synovial fluid where maximum concentrations were measured 2 to 4 hours after oral administration. The apparent half-life for elimination from the synovial fluid was 3 to 6 hours. Only 4 to 6 hours after administration, therefore, concentrations of the active substance were already higher in the synovial fluid than they were in the plasma and remained higher for up to 12 hours. These results could possibly explain why the duration of clinical effect is longer than might be inferred from the short plasma half-life of diclofenac.
Diclofenac becomes bound to serum proteins to the extent of 99.7%, chiefly to albumin (99.4%).

Metabolism.

Following oral administration, about half the active substance is metabolised during its first passage through the liver ("first-pass" effect).
The total systemic clearance of diclofenac in plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1 to 2 hours.
The biotransformation of diclofenac partly involves glucuronidation of the intact molecule, but mainly single and multiple hydroxylation followed by glucuronidation.

Excretion.

About 60% of the administered dose is excreted in the urine in the form of metabolites from one of the two previously mentioned processes. Less than 1% is excreted as unchanged substance. The remainder of the dose is eliminated as metabolites through the bile in the faeces.
No relevant age-dependent differences in the drugs absorption, metabolism or excretion have been observed.
In patients suffering from renal impairment, no accumulation of the unchanged active substance could be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of < 10 mL/min, the theoretical steady-state plasma levels of metabolites are four times higher than in normal subjects. However, the metabolites appear to be satisfactorily cleared through the bile.
In the presence of impaired hepatic function (chronic hepatitis, non-decompensated cirrhosis), the kinetics and metabolism of diclofenac were the same as in patients without liver disease.

5.3 Preclinical Safety Data

Genotoxicity.

Diclofenac showed no mutagenic effects in the studies conducted.

Carcinogenicity.

Dietary administration of diclofenac to mice and rats at doses up to 0.5 mg/kg/day revealed no carcinogenic activity. However, the plasma concentration of diclofenac at this dose level was 20 to 100 times lower than that in humans. Administration of higher doses to rats and mice resulted in increased mortality due to gastrointestinal ulceration. Diclofenac showed no carcinogenic effects in the studies conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, calcium hydrogen phosphate, microcrystalline cellulose, maize starch, sodium starch glycollate, magnesium stearate, colloidal anhydrous silica, methacrylic acid copolymer, triethyl citrate, purified talc, titanium dioxide and iron oxide yellow.

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.

6.5 Nature and Contents of Container

Blister Pack (PP/Al or PVC/PVDC/Al) of 50 tablets.

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

Diclofenac sodium is an odourless, yellowish-white, crystalline powder sparingly soluble in water. It is a phenylacetic acid derivative, structurally similar to both the phenylalkanoic acid and the anthranilic acid series of compounds.

Chemical structure.

Chemical Name: Sodium 2-[(2,6-dichlorophenyl)-amino] phenyl]-acetate.
Structural Formula:
Molecular Formula: C14H10Cl2NNaO2.
Molecular Weight: 318.13.

CAS number.

15307-79-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes