Voltarol Pain-eze Extra Strength 25mg Tablets

1. Name Of The Medicinal Product

Voltarol Pain-eze^® Extra Strength 25mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains diclofenac potassium 25mg.

Chemical name: potassium-[o-[(2,6-dichlorophenyl)-amino]-phenyl]-acetate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Pale red, round biconvex sugar-coated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Short term relief of headache, dental pain, period pain, rheumatic pain, muscular pain and backache and the symptoms of colds and flu, including fever.

4.2 Posology And Method Of Administration

Adults and children aged 14 years and over:

Take one tablet every 4 to 6 hours as needed. No more than 3 tablets (75 mg) should be taken in any 24 hour period.

Voltarol Extra Strength 25mg Tablets should not be used for longer than 3 days. If symptoms persist or worsen consult your doctor.

The tablets should be swallowed whole with a drink of water.

Children and Adolescents:

Voltarol Extra Strength 25mg Tablets are not to be used in children and adolescents under 14 years of age.

4.3 Contraindications

• Known hypersensitivity to diclofenac or to any of the excipients. Patients in whom attacks of asthma, urticaria, angioedema, or acute rhinitis are precipitated by aspirin or other non-steroidal anti-inflammatory drugs such as ibuprofen.

• Gastric or intestinal ulcer, bleeding or perforation.

• Pregnancy or breastfeeding (see section 4.6 Pregnancy and lactation).

• Severe hepatic, renal or cardiac failure (see section 4.4 Special warnings and special precautions for use).

• Concomitant use of anticoagulants and antiplatelets (see section 4.5 Interactions)

• Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (see section 4.5 Interactions)

4.4 Special Warnings And Precautions For Use

Warnings

Gastrointestinal bleeding, ulceration or perforation, which can be fatal, have been reported with all NSAIDs and may occur at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occur in patients receiving diclofenac, the medicinal product should be withdrawn.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs, including diclofenac (see section 4.8 Undesirable effects). 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. Diclofenac should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can occur in rare cases without earlier exposure to diclofenac.

In common with other NSAIDs, diclofenac may mask the signs and symptoms of infection due to its pharmacodynamic properties.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Precautions

General

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and Cardiovascular risks below).

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.

Caution is indicated in the elderly. In particular, it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight.

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAIDs therapy (see Renal effects below).

Pre-existing asthma

In patients with asthma, seasonal allergic rhinitis, swelling of nasal mucosa (i.e. nasal polypus), chronic obstructive pulmonary disease or chronic infection 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), angioedema or urticaria are more frequent than in other patients.

Gastrointestinal effects

As with all NSAIDs, close medical surveillance is imperative and caution should be exercised when prescribing diclofenac in patients with symptoms indicative of gastrointestinal (GI) disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see section 4.8 Undesirable effects). The risk of GI bleeding is higher with increasing NSAID doses and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation and in the elderly.

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 Interaction with other medicinal products and other forms of interaction).

Close medical surveillance should also be exercised in patients with ulcerative colitis or Crohn's disease, as their condition may be exacerbated (see section 4.8 Undesirable effects).

Cardiovascular and cerebrovascular effects

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (150 mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Available data do not suggest an increased risk with use of low dose diclofenac (up to 75 mg/day) up to 3 days for relief of pain or fever.

Hepatic effects

Close medical surveillance is required when prescribing diclofenac to patients with impaired hepatic function, as their condition may be exacerbated.

As with other NSAIDs, values of one or more liver enzymes may increase. In the case of diclofenac being prescribed for a prolonged period, regular monitoring of hepatic function is indicated as a precautionary measure. If abnormal liver function tests persist or worsen, if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash), diclofenac should be discontinued. Hepatitis may occur without prodromal symptoms.

Caution is called for when using diclofenac in patients with hepatic porphyria, since it may trigger an attack.

Renal effects

Caution is called for in patients with impaired renal function, particularly the elderly and patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function and in those patients with substantial extracellular volume depletion.

As fluid retention and oedema have been reported in association with NSAID therapy, particular caution is called for in elderly patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and in those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see section 4.3 Contraindications). Monitoring of renal function is recommended as a precautionary measure when using diclofenac in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.

Haematological effects

Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients with defects of haemostasis should be carefully monitored.

Dermatological effects

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for 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. Voltarol Pain-eze Extra Strength 25mg Tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The label will state:

Read the enclosed leaflet before taking this medicine.

Do not take if you:

• have or have ever had a stomach ulcer, perforation or bleeding

• are allergic to diclofenac or any other ingredient of the product, acetylsalicylic acid, ibuprofen or other related painkillers

• are taking other NSAID painkillers, or aspirin

• are pregnant or breastfeeding

Speak to a pharmacist or your doctor before taking this product if you:

• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, liver, heart, kidney or bowel problems

• are intolerant to some sugars

• are on a controlled potassium diet

• are a smoker

• If symptoms persist or worsen, consult your doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Lithium and digoxin: Diclofenac may increase plasma concentrations of lithium and digoxin.

Diuretics and antihypertensive 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. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, which should therefore be monitored frequently (see section 4.4 Special warnings and special precautions for use).

Other NSAIDs including cyclooxygenase-2 selective inhibitors and corticosteroids:

Co-administration of diclofenac with aspirin or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs (see section 4.4 Special warnings and special precautions for use).

Selective serotonin reuptake inhibitors (SSRIs) and anti-platelet agents: Increased risk of gastrointestinal bleeding (see section 4.4 Special warnings and special precautions for use).

Antidiabetics: Clinical studies have shown that diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However, there have been isolated reports of both hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. Monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

Methotrexate: Caution is recommended when NSAIDs are administered less than 24 hours before or after treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increased.

Ciclosporin and tacrolimus: Diclofenac, like other NSAIDs, may increase the nephrotoxicity of ciclosporin due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin or tacrolimus.

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

4.6 Pregnancy And Lactation

Pregnancy

The use of diclofenac in pregnant women has not been studied. Therefore, Voltarol Pain-eze Extra Strength 25mg Tablets should not be used during pregnancy except on the advice of a doctor.

Lactation

Like other NSAIDs, diclofenac passes into the breast milk in small amounts. Therefore, Voltarol Pain-eze Extra Strength 25mg Tablets should not be administered during breast feeding in order to avoid undesirable effects in the infant.

Fertility

As with other NSAIDs, 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.

4.7 Effects On Ability To Drive And Use Machines

Usually there is no effect at the recommended low-dose and short duration of treatment. However patients experiencing visual disturbances, dizziness, vertigo, somnolence or other central nervous system disturbances while taking diclofenac should refrain from driving or using machines.

4.8 Undesirable Effects

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: common (

Available data do not suggest an increased risk with use of low dose diclofenac (up to 75 mg/day) for up to 3 days treatment for the relief of pain or fever

Table 1

Blood and lymphatic system disorders
	Very rare:	Thrombocytopenia, leukopenia, anaemia (including haemolytic anaemia and aplastic anaemia), agranulocytosis.
Immune system disorders
	Rare:	Hypersensitivity, anaphylactic and anaphylactoid reaction (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.
Eye disorders
	Very rare:	Visual disturbance, vision blurred, diplopia.
Ear and labyrinth disorders
	Common:	Vertigo.
	Very rare:	Tinnitus, hearing impaired.
Cardiac disorders
	Very rare:	Palpitations, chest pain, cardiac failure, myocardial infarction.
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, diarrhoea, hemorrhagic melaena, gastrointestinal ulcer (with or without bleeding or perforation).
	Very rare:	Colitis, (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis, glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis.
Hepatobiliary disorders
	Common:	Transaminases increased.
	Rare:	Hepatitis, jaundice, liver disorder.
	Very rare:	Fulminant hepatitis
Skin and subcutaneous tissue disorders
	Common:	Rash.
	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.
Renal and urinary disorders
	Very rare:	Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.
General disorders and administration site conditions
	Rare:	Oedema.

Clinical trial and epidemiological data suggest that use of diclofenac (particularly at high doses 150 mg daily and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

4.9 Overdose

Symptoms

There is no typical clinical picture resulting from diclofenac overdosage. Overdose 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.

Therapeutic measures

Management of acute poisoning with NSAIDs essentially consists of supportive measures and symptomatic treatment. These should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorder, and respiratory depression.

Special measures such as forced diuresis, dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to the high protein binding and extensive metabolism.

Activated charcoal may be considered in case of a potentially toxic overdose, and gastric decontamination (e.g. vomiting, gastric lavage) in case of a potentially life-threatening overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: NSAID, ATC code: {M01 AB 05}

Voltarol Pain-eze Extra Strength 25mg Tablets contain the potassium salt of diclofenac, a non-steroidal anti-inflammatory drug with pronounced analgesic and anti-pyretic properties.

Voltarol Pain-eze Extra Strength 25mg Tablets have a rapid onset of action and are therefore suitable for the treatment of acute episodes of pain and inflammation.

In migraine attacks Diclofenac potassium has been shown to be effective in relieving the headache and in improving the accompanying symptom of nausea.

Diclofenac is a potent inhibitor of prostaglandin bio-synthesis and modulator of arachidonic acid release and uptake.

Diclofenac possesses clinically demonstrable analgesic, antipyretic and anti-inflammatory effects.

Diclofenac in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.

5.2 Pharmacokinetic Properties

Absorption

Diclofenac is rapidly and completely absorbed from sugar-coated tablets. Food intake does not affect absorption.

Peak plasma concentration after one 50mg sugar-coated tablet was 3.9 mmol/l after 20-60 minutes. The plasma concentrations show a linear relationship to the size of the dose.

Diclofenac undergoes first-pass metabolism and is extensively metabolised.

Distribution

Diclofenac is highly bound to plasma proteins (99.7%), chiefly albumin (99.4%).

Elimination

The total systemic clearance of diclofenac in plasma is 263 + 56 ml/min (mean + SD).

The terminal half life in plasma is 1-2 hours.

Repeated oral administration of Voltarol Pain-eze Extra Strength 25mg Tablets for 8 days in daily doses of 50mg three times a day does not lead to accumulation of diclofenac in the plasma.

Approximately 60% of the dose administered is excreted in the urine in the form of metabolites, and less than 1% as unchanged substance. The remainder of the dose is eliminated as metabolites through the bile in the faeces.

Biotransformation

The biotransformation of diclofenac involves partly glucuronidation of the intact molecule but mainly single and multiple hydroxylation followed by glucuronidation.

In patients suffering from renal impairment, no accumulation of the unchanged active substance can 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 about four times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.

Characteristics in patients:

The age of the patient has no influence on the absorption, metabolism, or excretion of diclofenac.

In the presence of impaired hepatic function (chronic hepatitis, non-decompensated cirrhosis) the kinetics and metabolism are the same as for patients without liver disease.

5.3 Preclinical Safety Data

Relevant information on the safety of Voltarol Pain-eze Extra Strength 25mg Tablets is included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core

Aerosil 200 (silica aerogel)

Calcium phosphate, tribasic

Magnesium stearate

Maize starch

Polyvinylpyrrolidone K30, PH

Sodium carboxymethyl starch

Coating

Avicel PH 101 (cellulose)

Iron oxide, red 17266

Polyethylene glycol 8000

Polyvinylpyrrolidone K30, PH

Sucrose, cryst

Talc PH

Titanium dioxide, PH

6.2 Incompatibilities

None

6.3 Shelf Life

30 months.

6.4 Special Precautions For Storage

Store below 30°C and protect from moisture.

6.5 Nature And Contents Of Container

PVC/PE/PVdC blister strips containing 9 tablets.

6.6 Special Precautions For Disposal And Other Handling

Medicines should be kept out of the reach of children.

7. Marketing Authorisation Holder

Novartis Consumer Health UK Ltd

Wimblehurst Road

Horsham

West Sussex

RH12 5AB

Trading as: Novartis Consumer Health or Zyma Healthcare.

8. Marketing Authorisation Number(S)

PL 00030/0054.

9. Date Of First Authorisation/Renewal Of The Authorisation

03/12/2010

10. Date Of Revision Of The Text

24/05/2011

LEGAL CATEGORY

P

Velosef for Injection

The wording of leaflets is regularly updated. This electronic text is the most up-to-date version and may differ from the leaflet in your pack. If you have any questions about the information provided, please ask your doctor or pharmacist.

VELOSEF FOR INJECTION

Cefradine

Your doctor has prescribed Velosef for Injection for you. This leaflet gives a summary of information about your medicine. If you want to know more, or are not sure about anything, ask your doctor or pharmacist.

What Is In Velosef Injection?

The active ingredient in Velosef is cefradine. Velosef is available in two strengths and each vial contains either 500mg or 1g cefradine. Cefradine is an antibiotic and a member of the family of medicines called cephalosporins. The other ingredient is L-arginine. The powder in the vial is dissolved in water for injections or another infusion fluid before administration.

Who Supplies Velosef Injection?

U.K. PRODUCT LICENCE held by:

E.R. Squibb & Sons Limited

Uxbridge Business Park

Sanderson Road

Uxbridge

Middlesex

UB8 1DH

IRISH PRODUCT AUTHORISATION held by:

Bristol-Myers Squibb Pharmaceuticals Limited

Co Dublin

Ireland

Manufacturer

Bristol-Myers Squibb Srl

Via Del Murillo

Sermoneta

Latina

Italy

What Is This Medicine For?

Velosef is used to treat bacterial infections in the chest, urinary tract or skin. The injection is given when patients are unable to take an oral antibiotic medicine or when the infection needs to be treated quickly. Velosef is also used to treat infections after surgery.

Before Your Medicine Is Administered

What Should My Doctor Know Before I Receive Velosef Injection?

Tell your doctor if you are allergic to any of the ingredients in Velosef or similar medicines such as other cephalosporins and penicillins.

What If I Am Pregnant Or Think I Might Be Pregnant?What If Am Breast-Feeding?

If you are pregnant, planning to become pregnant or breast feeding, speak to your doctor.

What If I Have Problems With My Liver Or Kidneys?

Tell your doctor about any previous problems with your liver or kidneys, as the dose of Velosef may need to be adjusted. Your doctor may want to monitor your liver or kidney function whilst you are taking Velosef.

What If I Am A Diabetic?

If you use chemical tests to check for sugar in the urine, Velosef may cause a false positive reaction. This does not occur with dipstick type tests. Ask your doctor which type of test kit you should use.

Can I Take Other Medicines?

If you are taking any other medicines it is important to discuss this with your doctor or pharmacist. These include furosemide (‘water tablets’) or probenecid and medicines bought at a pharmacy or elsewhere e.g. supermarket.

Is It All Right To Drink Alcohol?

There is no interaction between Velosef and moderate amounts of alcohol. However, you should check with your doctor whether drinking is advisable for you.

Administration Of Your Medicine

What Is The Dose Of Velosef Injection And How Will It Be Given?

Velosef will be given by injection into a large muscle, or slow injection into a vein, or as an intravenous drip. Your doctor will decide what dose is required and how long the treatment should continue, based on your symptoms and the results of blood tests. The usual dose for treatment of infections is 2-4g daily, given in four equally divided doses. The dose given for prevention of infections after surgery is 1-2g. The usual dose for children is 50-100mg/kg bodyweight/day.

Undesirable Effects

What Are The Unwanted Effects Of Velosef Injection?

In a few patients, especially those with a history of allergy, asthma, hay fever or nettle rash, Velosef may cause diarrhoea or a rash. Skin and hypersensitivity reactions may include unexpected itchy red swelling on skin, fever, joint pain or fluid retention. More rarely, there have been reports of inflammation of the tongue, heartburn, headache, dizziness, shortness of breath, pins and needles, nausea, vomiting, abdominal pain, fungal infections, vaginal inflammation. Occasionally, patients complain of pain, bruising and inflammation at the injection site. Very rarely, blood/liver disorders occur and any diarrhoea with blood and mucus should be reported to your doctor, nurse or pharmacist. There have also been very rare reports of more serious allergic reactions including anaphylaxis and Stevens Johnson syndrome. If you notice any other unusual or unexpected symptoms tell your doctor or pharmacist.

Looking After Your Medicine

This medicine will be stored in the pharmacy until it is given to you by your doctor or nurse. It should not be stored above 25°C. It should not be used after the expiry date shown on the outer packaging.

DATE OF PREPARATION October 2005

PLEASE DETACH BEFORE HANDING ABOVE SECTION TO THE PATIENT

VELOSEF
FOR INJECTION

Voltarol Ampoules

1. Name Of The Medicinal Product

Voltarol^® Ampoules

2. Qualitative And Quantitative Composition

The active ingredient is sodium-[o-[(2,6-dichlorophenyl)-amino]-phenyl]-acetate) (diclofenac sodium).

Each 3ml ampoule contains 75mg diclofenac sodium Ph.Eur.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Solution for injection in ampoules.

4. Clinical Particulars

4.1 Therapeutic Indications

Ampoules for im use:

The ampoules are effective in acute forms of pain, including renal colic, exacerbations of osteo- and rheumatoid arthritis, acute back pain, acute gout, acute trauma and fractures, and post-operative pain.

Ampoules used in intravenous infusion:

For treatment or prevention of post-operative pain in the hospital setting.

4.2 Posology And Method Of Administration

Undesirable 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).

Adults:

Voltarol ampoules (given im or iv) should not be given for more than two days; if necessary, treatment can be continued with Voltarol tablets or suppositories.

Intramuscular injection: The following directions for intramuscular injection must be adhered to in order to avoid damage to a nerve or other tissue at the injection site.

One ampoule once (or in severe cases twice) daily intramuscularly by deep intragluteal injection into the upper outer quadrant. If two injections daily are required it is advised that the alternative buttock be used for the second injection. Alternatively, one ampoule of 75mg can be combined with other dosage forms of Voltarol (tablets or suppositories) up to the maximum daily dosage of 150mg.

Renal colic: One 75mg ampoule intramuscularly. A further ampoule may be administered after 30 minutes if necessary. The recommended maximum daily dose of Voltarol is 150mg.

Intravenous Infusion: Immediately before initiating an intravenous infusion, Voltarol must be diluted with 100-500ml of either sodium chloride solution (0.9%) or glucose solution (5%). Both solutions should be buffered with sodium bicarbonate solution (0.5ml 8.4% or 1ml 4.2%). Only clear solutions should be used.

Voltarol must not be given as an intravenous bolus injection.

Two alternative regimens are recommended:

For the treatment of moderate to severe post-operative pain, 75mg should be infused continuously over a period of 30 minutes to 2 hours. If necessary, treatment may be repeated after 4-6 hours, not exceeding 150mg within any period of 24 hours.

For the prevention of post-operative pain, a loading dose of 25mg-50mg should be infused after surgery over 15 minutes to 1 hour, followed by a continuous infusion of approx. 5mg per hour up to a maximum daily dosage of 150mg.

Children:

Voltarol ampoules are not recommended for use in children.

Elderly: Although the pharmacokinetics of Voltarol are not impaired to any clinically relevant extent in elderly patients, nonsteroidal anti-inflammatory drugs should be used with particular caution in such patients who generally are more prone to adverse reactions. In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight (see also Precautions) and the patient should be monitored for GI bleeding during NSAID therapy.

The recommended maximum daily dose of Voltarol is 150mg.

4.3 Contraindications

• Hypersensitivity to the active substance, sodium metabisulphite or any of the excipients.

• Active, gastric or intestinal ulcer, bleeding or perforation

• History of gastrointestinal bleeding or perforation, relating to previous NSAID therapy

• Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding)

• Last trimester of pregnancy (see section 4.6 Pregnancy and lactation)

• Severe hepatic, renal or cardiac failure (see section 4.4 Special warnings and precautions for use).

• Like other non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac is also contraindicated in patients in whom attacks of asthma, angioedema, urticaria or acute rhinitis are precipitated by ibuprofen, acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

Specifically for iv use.

• Concomitant NSAID or anticoagulant use (including low dose heparin).

• History of haemorrhagic diathesis, a history of confirmed or suspected cerebrovascular bleeding.

• Operations associated with a high risk of haemorrhage.

• A history of asthma.

• Moderate or severe renal impairment (serum creatinine >160µmol/l).

• Hypovolaemia or dehydration from any cause.

4.4 Special Warnings And Precautions For Use

General

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 Posology and method of administration and GI and cardiovascular risks below.)

The concomitant use of Voltarol 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 (see section 4.5 Interactions with other medicaments and other forms of interaction).

Caution is indicated in the elderly on basic medical grounds. In particular, it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight (see section 4.2 Posology and Method of administration).

As with other nonsteroidal anti-inflammatory drugs including diclofenac, allergic reactions, including anaphylactic/anaphylactoid reactions can also occur without earlier exposure to the drug (see section 4.8 Undesirable effects).

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

The sodium metabisulphite present in solution for injection can also lead to isolated severe hypersensitivity reactions and bronchospasm.

Gastrointestinal effects:

Gastrointestinal bleeding (haematemesis, melaena), ulceration or perforation which can be fatal has been reported with all NSAIDs including diclofenac and may occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be withdrawn.

As with all NSAIDs, including diclofenac, close medical surveillance is imperative and particular caution should be exercised when prescribing diclofenac in patients with symptoms indicative of gastrointestinal disorders, or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see section 4.8 Undesirable effects). The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses including diclofenac, and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation.

The elderly have increased frequency of adverse reactions to NSAIDs especially gastro intestinal bleeding and perforation which may be fatal (see section 4.2 Posology and method of administration).

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.

Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low dose acetylsalicylic acid (ASA/aspirin or medicinal products likely to increase gastrointestinal risk. (See section 4.5 Interactions with other medicaments and other forms of interaction).

Patients with a history of GI toxicity, particularly when 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 such as warfarin, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents such as acetylsalicylic acid (see section 4.5 Interaction with other medicaments and other forms of interaction).

Close medical surveillance and caution should be exercised in patients with ulcerative colitis, or with Crohn's disease as these conditions may be exacerbated (see section 4.8 Undesirable effects).

Hepatic effects:

Close medical surveillance is required when prescribing Voltarol to patients with impairment of hepatic function as their condition may be exacerbated.

As with other NSAIDs, including diclofenac, values of one or more liver enzymes may increase. During prolonged treatment with Diclofenac, regular monitoring of hepatic function is indicated as a precautionary measure.

If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Voltarol should be discontinued.

Hepatitis may occur with diclofenac without prodromal symptoms.

Caution is called for when using diclofenac in patients with hepatic porphyria, since it may trigger an attack.

Renal effects:

As fluid retention and oedema have been reported in association with NSAIDs therapy, including diclofenac, particular caution is called for in patients with impaired cardiac or renal function, history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see section 4.3 Contraindications). Monitoring of renal function is recommended as a precautionary measure when using diclofenac in such cases. Discontinuation therapy is usually followed by recovery to the pre-treatment state.

Skin effects:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs, including Voltarol (see section 4.8 Undesirable effects). Patients appear to be at the 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. Voltarol should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8 Undesirable effects).

Cardiovascular and cerebrovascular effects:

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy including diclofenac.

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diclofenac after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking).

Haematological effects:

During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended.

Voltarol may reversibly inhibit platelet aggregation (see anticoagulants in section 4.5 Interaction with other medicaments and other forms of interactions). Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

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 on NSAIDs like 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 (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.

Like other drugs that inhibit prostaglandin synthetase activity, diclofenac sodium and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of bronchial asthma.

Female fertility:

The use of Voltarol may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Voltarol should be considered (see section 4.6 Pregnancy and Lactation).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The following interactions include those observed with diclofenac gastro-resistant tablets and/or other pharmaceutical forms of diclofenac.

Lithium: If used concomitantly, Voltarol may increase plasma concentrations of lithium. Monitoring of the serum lithium level is recommended.

Digoxin: If used concomitantly, Voltarol may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.

Diuretics and antihypertensive agents: Like other NSAIDs, concomitant use of Voltarol with diuretics and antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.

Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, which should therefore be monitored frequently (see section 4.4 Special warnings and precautions for use).

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). Although clinical investigations do not appear to indicate that Voltarol has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulant concomitantly (see section 4.4 Special warnings and precautions for use). Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other nonsteroidal anti-inflammatory agents, diclofenac in a high dose can reversibly inhibit platelet aggregation.

Other NSAIDs including cyclooxygenase-2 selective inhibitors and corticosteroids: Co-administration of diclofenac with other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs (see section 4.4 Special warnings and precautions for use).

Antidiabetics: Clinical studies have shown that Voltarol can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

Methotrexate: Diclofenac can inhibit the tubular renal clearance of methotrexate hereby increasing methotrexate levels. Caution is recommended when NSAIDs, including diclofenac, are administered less than 24 hours before treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increase. Cases of serious toxicity have been reported when methotrexate and NSAIDs including diclofenac are given within 24 hours of each other. This interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSAID.

Ciclosporin: Diclofenac, like other NSAIDs, may increase the nephrotoxicity of ciclosporin due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. This might be mediated through renal antiprostagladin effects of both NSAID and calcineurin inhibitor.

Quinolone antibacterials: Convulsions may occur due to an interaction between quinolones and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID.

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

Colestipol and cholestyramine: These agents can induce a delay or decrease in absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least one hour before or 4 to 6 hours after administration of colestipol/ cholestyramine.

Cardiac glycosides: Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Potent 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.

4.6 Pregnancy And Lactation

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and or cardiac malformation and gastroschisis after 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 in believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has shown to result in increased pre-and post-implantation loss and embryo-foetal lethality.

In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during organogenetic period. If Voltarol is used by a woman attempting to conceive, or during the 1st trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)

- renal dysfunction, which may progress to renal failure with oligo-hydroamniosis

The mother and the neonate, at the end of the 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

Consequently, Voltarol is contra-indicated during the third trimester of pregnancy.

Lactation

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, diclofenac should not be administered during breast feeding in order to avoid undesirable effects in the infant.

Female fertility

As with other NSAIDs, the use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac should be considered. See also section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disturbances, drowsiness or fatigue while taking NSAIDs should refrain from driving or operating machinery.

4.8 Undesirable Effects

Adverse reactions are ranked under the heading of frequency, the most frequent first, using the following convention: very common: (>1/10); common (

The following undesirable effects include those reported with other short-term or long-term use.

Table 1

Blood and lymphatic system disorders
Very rare	Thrombocytopenia, leucopoenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.
Immune system disorders
Rare Very rare	Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock). Angioneurotic oedema (including face oedema).
Psychiatric disorders
Very rare	Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.
Nervous system disorders
Common Rare Very rare Unknown	Headache, dizziness. Somnolence, tiredness. Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident. Confusion, hallucinations, disturbances of sensation, malaise.
Eye disorders
Very rare Unknown	Visual disturbance, vision blurred, diplopia. Optic neuritis.
Ear and labyrinth disorders
Common Very rare	Vertigo. Tinnitus, hearing impaired.
Cardiac disorders
Very rare	Palpitations, chest pain, cardiac failure, myocardial infarction.
Vascular disorders
Very rare	Hypertension, hypotension, vasculitis.
Respiratory, thoracic and mediastinal disorders
Rare Very rare	Asthma (including dyspnoea). Pneumonitis.
Gastrointestinal disorders
Common Rare Very rare	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia. Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer with or without bleeding or perforation (sometimes fatal particularly in the elderly). Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis.
Hepatobiliary disorders
Common Rare Very rare	Transaminases increased. Hepatitis, jaundice, liver disorder. Fulminant hepatitis, hepatic necrosis, hepatic failure.
Skin and subcutaneous tissue disorders
Common Rare Very rare	Rash. Urticaria. 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.
Renal and urinary disorders
Very rare	Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.
General disorders and administration site conditions
Common Rare	Injection site reaction, injection site pain, injection site induration Oedema
Reproductive system and breast disorders
Very rare	Impotence

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4 Special warnings and special precautions for use).

4.9 Overdose

Symptoms

There is no typical clinical picture resulting from diclofenac over dosage. Over dosage can cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhoea, dizziness, disorientation, excitation, coma, drowsiness, tinnitus, fainting or convulsions. In the case of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measures

Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults gastric lavage should be considered within one hour of ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patients clinical condition.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group

Nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

Voltarol is a nonsteroidal agent with marked analgesic/anti- inflammatory properties. It is an inhibitor of prostaglandin synthetase, (cyclo-oxygenase). Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings. When used concomitantly with opioids for the management of post-operative pain, Voltarol often reduces the need for opioids.

5.2 Pharmacokinetic Properties

Absorption

After administration of 75mg diclofenac by intramuscular injection, absorption sets in immediately, and mean peak plasma concentrations of about 2.558 ± 0.968µg/ml (2.5µg/mL

Intravenous infusion: When 75mg diclofenac is administered as an intravenous infusion over 2 hours, mean peak plasma concentrations are about 1.875 ± 0.436µg/ml (1.9µg/mL

Bioavailability:

The area under the concentration curve (AUC) after intramuscular or intravenous administration is about twice as large as it is following oral or rectal administration as this route avoids "first-pass" metabolism.

Distribution

The active substance is 99.7% protein bound, mainly to albumin (99.4%).

Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hours after the peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 hours. Two hours after reaching the peak plasma values, concentrations of the active substance are already higher in the synovial fluid than they are in the plasma and remain higher for up to 12 hours.

Metabolism

Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

Elimination

Total systemic clearance of diclofenac in plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours.

About 60% of the administered dose is excreted in the urine in the form of the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.

Characteristics in patients

Elderly: No relevant age-dependent differences in the drug's absorption, metabolism or excretion have been observed, other than the finding that in five elderly patients, a 15 minute iv infusion resulted in 50% higher plasma concentrations than expected with young healthy subjects.

Patients with renal impairment: In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of <10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.

Patients with hepatic disease: In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Voltarol ampoules also contain mannitol, sodium metabisulphite (E.223), benzyl alcohol, propylene glycol, sodium hydroxide and water.

6.2 Incompatibilities

The ampoules used im or iv as an infusion should not be mixed with other injection solutions.

6.3 Shelf Life

Two years.

6.4 Special Precautions For Storage

Protect from light and heat (store below 30°C).

Medicines should be kept out of the reach of children.

The infusion solution should not be used if crystals or precipitates are observed.

6.5 Nature And Contents Of Container

The glass ampoules (Ph.Eur. Type I) contain colourless to faintly yellow liquid and come in packs of 10.

6.6 Special Precautions For Disposal And Other Handling

Intravenous infusions should be freshly made up and used immediately. Once prepared, the infusion should not be stored.

7. Marketing Authorisation Holder

Novartis Pharmaceuticals UK Ltd.,

Trading as Geigy Pharmaceuticals,

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR.

8. Marketing Authorisation Number(S)

PL 00101/0466

9. Date Of First Authorisation/Renewal Of The Authorisation

11 July 1997

10. Date Of Revision Of The Text

1 July 2011

LEGAL CATEGORY

POM

Scholl Advance Athlete's Foot Cream

1. Name Of The Medicinal Product

Scholl Advance Athlete's Foot Cream

2. Qualitative And Quantitative Composition

Terbinafine hydrochloride 1% w/w

For excipients, see 6.1

3. Pharmaceutical Form

Cream

4. Clinical Particulars

4.1 Therapeutic Indications

The treatment of tinea pedis (athlete's foot) caused by Trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum) and Epidermophyton floccosum.

4.2 Posology And Method Of Administration

Adults and the Elderly

Scholl Advance Athlete's Foot Cream is applied once or twice daily to the affected skin and surrounding area in a thin layer and rubbed in gently. Before application the affected skin areas should be cleansed and dried thoroughly. In the case of intertriginous infections (interdigital, intergluteal, inguinal) the application may be covered with a gauze strip, especially at night.

Duration of treatment is one week for tinea pedis. Relief of symptoms usually occurs within a few days. Irregular use or premature discontinuation of treatment carries the risk of recurrence. If there are no signs of improvement after two weeks, the diagnosis should be verified by a physician.

Children

The experience with terbinafine cream in children is limited. Therefore, its use in children under 16 years cannot be recommended.

Method of administration

Topical administration

4.3 Contraindications

Hypersensitivity to terbinafine or any of the excipients in the cream

4.4 Special Warnings And Precautions For Use

This product is for external use only. Contact with the eyes should be avoided.

This product contains cetyl alcohol and stearyl alcohol, which may cause local skin reactions (e.g. contact dermatitis)

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There are no known drug interactions with terbinafine cream.

4.6 Pregnancy And Lactation

Foetal toxicity and fertility studies suggest no adverse effects.

There is no clinical experience with terbinafine cream in pregnant women. Therefore, unless the potential benefits outweigh any potential risks, Scholl Advance Athlete's Foot Cream should not be administered during pregnancy.

Terbinafine is excreted in breast milk and therefore breast-feeding mothers should not use Scholl Advance Athlete's Foot Cream.

4.7 Effects On Ability To Drive And Use Machines

None known

4.8 Undesirable Effects

Occasionally, redness, itching or stinging occur at the site of application: However, treatment rarely has to be discontinued for this reason. This must be distinguished from allergic reactions, which occur rarely but require discontinuation.

4.9 Overdose

No adverse events in relation to ingestion of terbinafine cream have been reported to date. However, if accidental ingestion occurs, gastric emptying may be used if considered appropriate. Adverse reactions similar to those possible after oral administration of terbinafine tablets (e.g. headache, nausea, dizziness and upper gastrointestinal complaints) may occur following accidental ingestion of the cream.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Terbinafine, ATC code: D01A E15

Terbinafine is an allylamine which has a broad spectrum of antifungal activity. At low concentrations, terbinafine is fungicidal against dermatophytes, moulds and certain dimorphic fungi.

The treatment effect of terbinafine is long-lasting: Less than 10% of patients suffering from tinea pedis and treated with terbinafine 1% cream for one week experienced a relapse or reinfection within three months after start of treatment.

Terbinafine interferes specifically with fungal sterol biosynthesis at an early step. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death. Terbinafine acts by inhibition of squalene epoxidase in the fungal cell membrane.

The enzyme squalene epoxidase is not linked to the cytochrome P450 system. Terbinafine does not influence the metabolism of hormones or other drug substances.

5.2 Pharmacokinetic Properties

Less than 5% of the dose is absorbed after topical application to humans; systemic exposure is therefore very slight

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium hydroxide

Benzyl alcohol

Sorbitan stearate

Cetyl palmitate

Cetyl alcohol

Stearyl alcohol

Polysorbate 60

Isopropyl myristrate

Purified water

6.2 Incompatibilities

None known

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Aluminium tube with tamper-evident membrane seal, internal lacquer coating and HDPE screw cap containing 7.5g or 15g of cream

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Scholl Consumer Products Ltd.

Venus

1 Old Park Lane

Trafford Park

Manchester

M41 7HA

8. Marketing Authorisation Number(S)

PL 00587/0242

9. Date Of First Authorisation/Renewal Of The Authorisation

15/02/07

10. Date Of Revision Of The Text

17/08/07

testosterone buccal system

Generic Name: testosterone buccal system (tes TOSS ter one)

Brand Names: Striant

What is testosterone buccal system?

Testosterone is a naturally occurring "male" sex hormone necessary for many processes in the body.

Testosterone buccal system is used to treat men with low testosterone levels.

Testosterone buccal system may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about testosterone buccal system?

Notify your doctor if you experience nausea; vomiting; swelling of the ankles; changes in skin color; too frequent or prolonged erections; breathing disturbances, including those associated with sleep; yellowing of the skin or eyes; dark colored urine; or problems with urination. Notify your doctor if a female partner experiences male-pattern baldness, excessive body hair growth, an increase in acne, menstrual irregularities, or signs of masculinity.

Regularly inspect the gum where the testosterone buccal system is applied. Promptly report any changes to your doctor or dentist.

What should I discuss with my healthcare provider before using testosterone buccal system?

Do not use testosterone buccal system if you have cancer of the breast or prostate. Testosterone may worsen some cancers of these types.

Before using testosterone buccal system, tell your doctor if you have

• 
  

  had a previous allergic reaction to testosterone;

  
  


• 
  

  diabetes;

  
  


• 
  

  sleep apnea (brief periods of not breathing during sleep) or if you have risk factors for sleep apnea (e.g., obesity, chronic lung disease);

  
  


• 
  

  difficulty with urination due to enlargement of the prostate;

  
  


• 
  

  heart disease; or

  
  


• liver disease or kidney disease.

You may not be able to use testosterone buccal system, or you may need a dosage adjustment or special monitoring if you have any of the conditions listed above.

Testosterone buccal system is not approved for use by women and must not be used by women. Testosterone buccal system is in the FDA pregnancy category X. This means that testosterone is known to cause birth defects in an unborn baby. Do not use testosterone buccal system if you are pregnant or could become pregnant during treatment. Testosterone buccal system is not approved for use by women and must not be used by women. It is not known whether testosterone from the buccal system will pass into breast milk.Do not use testosterone buccal system if you are breast-feeding a baby. Men over 65 years of age that use testosterone buccal system may be at increased risk for the development of prostatic enlargement or cancer. You may not be able to use buccal system testosterone, or you may require a lower dose or special monitoring.

How should I use testosterone buccal system?

Use testosterone buccal system exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

To use the testosterone buccal system (Striant):

• 
  

  Hold one buccal system with the flat side on your fingertip. Place the curved side onto your gum, as high as possible above the left or right incisor tooth. Hold your finger on the outside of your lip over the system for 30 seconds to ensure the system is attached to the gum. If the system sticks to the cheek and not the gum, this is acceptable.

  
  


• 
  

  The buccal system should remain in place for 12 hours. To remove the system, move it slightly toward the back or front of the mouth then slide it toward the teeth from removal. With each new application, rotate to alternate sides of the mouth. This avoids scratching the gum. Check to see that the system is in place after eating, drinking, brushing the teeth, or using mouthwash.

  
  


• 
  

  As the buccal system absorbs moisture from the mouth, it will begin to soften and will mold to the shape of the gum. The system does not dissolve completely, but will remain in place. It will not move until you remove it.

  
  


• 
  

  If a buccal system falls off before 8 hours of use, remove it and replace it with a new system in the same place.

  
  


• 
  

  Change the buccal system and alternate sides of the mouth 12 hours after application of the original system. If a buccal system falls off after 8 hours but before 12 hours of use, remove the system and replace it with a new system above the opposite incisor. This will serve as the second dose for the day.

  
  


• 
  

  Do not chew or swallow the testosterone buccal system.

  
  


• 
  

  Regularly inspect the gum where the testosterone buccal system is applied. Promptly report any changes to your doctor or dentist.

  
  

Your doctor may want to perform tests to monitor the amount of testosterone in the body, liver function, prostate function, cholesterol levels, or other factors during treatment with testosterone buccal system.

It is important to use testosterone buccal system regularly to get the most benefit.

Dispose of all used systems properly, out of the reach of children and pets.

Store testosterone buccal system at room temperature away from moisture and heat.

What happens if I miss a dose?

Apply the next system as soon as you remember. Do not use two doses simultaneously, unless otherwise directed by your doctor.

What happens if I overdose?

An overdose of testosterone buccal system is not likely to threaten life. If you do suspect an overdose, or if a system has been ingested, call an emergency room or poison control center for advice.

What should I avoid while using testosterone buccal system?

Regularly inspect the gum where the testosterone buccal system is applied. Promptly report any changes to your doctor or dentist.

Testosterone buccal system side effects

If you experience any of the following serious side effects, stop using testosterone buccal system and seek emergency medical attention or contact your doctor immediately:

• 
  

  an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives);

  
  


• 
  

  nausea or vomiting;

  
  


• 
  

  changes in skin color;

  
  


• 
  

  swelling of the ankles or legs;

  
  


• 
  

  breathing disturbances, including those associated with sleep;

  
  


• 
  

  too frequent or prolonged erections;

  
  


• 
  

  liver damage (yellowing of the skin or eyes, nausea, abdominal pain or discomfort, unusual bleeding or bruising, or severe fatigue); or

  
  


• 
  

  dark colored urine or problems with urination.

  
  

Other, less serious side effects may be more likely to occur. Continue to use testosterone buccal system and talk to your doctor if you experience

• 
  

  irritation or changes in the gum at the system application site;

  
  


• 
  

  bitter or unusual taste in the mouth;

  
  


• 
  

  headache;

  
  


• 
  

  emotional changes;

  
  


• 
  

  increased blood pressure;

  
  


• 
  

  decreased interest in sex;

  
  


• 
  

  changes in blood cholesterol or number of red blood cells (detected by blood tests);

  
  


• 
  

  prostate changes or difficulty urinating;

  
  


• 
  

  enlarged, swollen or tender breasts; or

  
  


• 
  

  acne.

  
  

Notify your doctor if a female partner experiences male-pattern baldness, excessive body hair growth, an increase in acne, menstrual irregularities, or signs of masculinity.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

Testosterone buccal system Dosing Information

Usual Adult Dose for Hypogonadism -- Male:

Parenteral: Short-acting (testosterone solution and propionate): 25 mg to 50 mg IM 2 to 3 times a week.
Long-acting (enanthate and cypionate): 50 to 400 mg IM every 2 to 4 weeks.
Subcutaneous implant: 2 to 6 pellets (75 mg each) implanted subcutaneously every 3 to 6 months.

Topical:
Transdermal Film: 2.5 to 5 mg applied to the back, abdomen, upper arm, or upper thigh once a day, preferably at night.
Gel (in tubes, packets or spray): 5 grams applied once daily, preferably in the morning. May increase as needed to a maximum of 10 grams once a day.

Buccal: 30 mg patch to the gum region twice daily; morning and evening (about 12 hours apart). Patch should be placed just above the incisor tooth. With each application, the patch should be rotated to alternate sided of the mouth.

Testosterone 30 mg/1.5 mL transdermal solution:
Starting dose is 60 mg of testosterone (1 pump actuation of 30 mg of testosterone to each axilla), applied once daily, at the same time each morning. The dose of testosterone may be decreased from 60 mg (2 pump actuations) to 30 mg (1 pump actuation) or increased from 60 mg to 90 mg (3 pump actuations) or from 90 mg to 120 mg (4 pump actuations) based on the serum testosterone concentration from a single blood draw 2 to 8 hours after applying the solution and at least 14 days after starting treatment or following dose adjustment.

Testosterone 10 mg/0.5 g transdermal gel:
Starting dose is 40 mg of testosterone (4 pump actuations of 30 mg to clean, dry intact skin of the front and inner thighs), applied once daily, at the same time each morning. Let application site dry before putting on pants or shorts. The dose can be adjusted between a minimum of 10 mg of testosterone (1 pump actuation) and a maximum of 70 mg of testosterone (7 pump actuations) on the basis of total serum testosterone concentrations 2 hours post application. The dose should be titrated based on the serum testosterone concentration from a single blood draw 2 hours after applying and at approximately 14 days and 35 days after starting treatment or following dose adjustment. In addition, serum testosterone concentration should be assessed periodically thereafter.

Testosterone 20.25 mg/1.25 g transdermal gel:
Starting dose 40.5 mg of testosterone (2 pump actuations), applied topically to the shoulders and upper arms once daily in the morning. The dose can be adjusted between a minimum of 20.25 mg of testosterone (1 pump actuation) and a maximum of 81 mg of testosterone (4 pump actuations). The dose should be titrated based on the pre dose morning serum testosterone concentration at approximately 14 days and 28 days after starting treatment or following dose adjustment. Additionally, serum testosterone concentration should be assessed periodically thereafter.

Usual Adult Dose for Breast Cancer--Palliative:

Parenteral: Short-acting (testosterone solution and propionate): 50 mg to 100 mg IM 2 to 3 times a week.
Long-acting (enanthate and cypionate): 200 to 400 mg IM every 2 to 4 weeks.
Subcutaneous implant: 2 to 6 pellets (75 mg each) implanted subcutaneously every 3 to 6 months

Testosterone is approved by the FDA for the palliation of androgen responsive metastatic breast cancer in women who are 1 to 5 years postmenopausal or who are proven to have a hormone-dependent tumor noted by previous beneficial response to castration.

Female patients should be observed for signs of virilization. Women should be instructed to report any hoarseness, acne, changes in menstrual periods, or increases in facial hair. Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. A decision may be made by the patient and the physician that some virilization will be tolerated during the treatment for malignant disease.

Usual Adult Dose for Postpartum Breast Pain:

Parenteral: Short-acting (testosterone solution and propionate): 25 mg to 50 mg IM for 3 to 4 days, starting at the time of delivery.

Usual Pediatric Dose for Delayed Puberty -- Male:

Parenteral:
Initiation of pubertal growth: Long-acting (enanthate and cypionate): 40 to 50 mg/square meter IM monthly until the growth rate falls to prepubertal levels.
Terminal growth phase: Long-acting (enanthate and cypionate): 100 mg/square meter IM monthly until the growth ceases.
Maintenance virilizing dose: Long-acting (enanthate and cypionate): 100 mg/square meter intramuscular twice monthly.

Subcutaneous implant: 2 to 6 pellets (75 mg each) implanted subcutaneously every 3 to 6 months.

Dosages used to treat delayed puberty are generally started at the lower end of the dosing range and titrated according to patient response and tolerance. The duration of therapy should be limited to 4 to 6 months. Serum concentrations of testosterone should be determined following 3 to 4 weeks of daily use. If desired results have not been achieved at 6 to 8 weeks an alternative testosterone regimen should be considered.

Wrist and hand bone age should be assessed prior to initiation of testosterone therapy and every 6 months to monitor bone maturation. Exogenous androgen therapy can accelerate bone maturation without producing a compensatory gain in linear growth. Use over long periods can result in fusion of the epiphyseal growth centers and termination of the growth process.

What other drugs will affect testosterone buccal system?

Before using testosterone buccal system, tell your doctor if you are taking any of the following medicines:

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  warfarin (Coumadin);

  
  


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  insulin or an oral diabetes medication such as glipizide (Glucotrol), glyburide (Diabeta, Micronase, Glynase), repaglinide (Prandin), rosiglitazone (Avandia), pioglitazone (Actos), and others;

  
  


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  propranolol (Inderal, Inderal LA, others); or

  
  


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  a corticosteroid such as hydrocortisone (Cortef, Hydrocortone, Solu-Cortef), dexamethasone (Decadron, Hexadrol others), methylprednisolone (Depo-Medrol, Medrol, Solu-Medrol), prednisolone (Prelone, Pediapred), prednisone (Deltasone, Orasone, others), and others.

  
  

You may not be able to use testosterone buccal system, or you may require a dosage adjustment or special monitoring during treatment if you are taking any of the medicines listed above.

Drugs other than those listed here may also interact with testosterone buccal system. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including vitamins, minerals, and herbal products.

More testosterone buccal system resources

• Testosterone buccal system Side Effects (in more detail)
• Testosterone buccal system Dosage
• Testosterone buccal system Use in Pregnancy & Breastfeeding
• Testosterone buccal system Drug Interactions
• Testosterone buccal system Support Group
• 146 Reviews for Testosterone system - Add your own review/rating

Compare testosterone buccal system with other medications

• Breast Cancer, Palliative
• Delayed Puberty, Male
• Hypogonadism, Male
• Postpartum Breast Pain

Where can I get more information?

• Your pharmacist has additional information about testosterone buccal system written for health professionals that you may read.

See also: testosterone system side effects (in more detail)