Dyloject^® 75 mg/2 ml Solution for Injection

The active ingredient is diclofenac sodium [sodium-(o-[(2,6-dichlorophenyl)-amino]-phenyl]-acetate)]. Each 2 ml vial contains 75 mg of diclofenac sodium. For a full list of excipients, see Section 6.1.

Solution for Injection

Intramuscular use

Dyloject 75 mg/2 ml Solution for Injection is 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.

Intravenous use

For treatment or prevention of post-operative pain in supervised healthcare settings.

Instructions on using the vial

1. Remove the green flip cap

2. Aseptically withdraw the appropriate amount (not more than 2 ml) for either IV use or deep IM injection. As with all parenteral products, Dyloject should be inspected visually for particulate matter or discoloration prior to administration.

Adults

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see Section 4.4).

Dyloject 75 mg/2 ml Solution for Injection should not be given for more than two days.

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 vial once (or in severe cases twice) daily, intramuscularly by deep intragluteal injection into the upper outer quadrant of the buttock. If two injections daily are required, it is advised that the alternative buttock be used for the second injection.

Recommended IM injection procedure

1. The patient may lie down or stand, whichever is more comfortable.

2. The exposed buttocks should be inspected to find the most suitable injection site. Avoid scars and lumps and choose the buttock which is free from any problems. If more than one injection needs to be given, the other buttock should be used.

3. The injection site should be thoroughly disinfected, e.g. with alcohol, and allowed to dry.

4. To ensure deep intramuscular injection, give high into upper outer quadrant of the buttock, taking particular care to avoid the sciatic nerve and blood vessels. Avoid injecting into an area where resistance is felt. N.B. In obese patients, avoid deposition of the drug into the subcutaneous fatty tissue. In small thin patients with little muscle bulk, be especially aware of the sciatic nerve, which may be quite superficial.

5. Prior to injection of solution, draw back to ensure that no blood vessel has been penetrated. If blood is drawn, withdraw the needle to another site and check again.

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

Intravenous use: Dyloject 75 mg/2 ml Solution for Injection may be given as an intravenous bolus injection. Two alternative regimens are recommended for bolus injection.

• For the treatment of moderate to severe post-operative pain, 75 mg should be injected intravenously. If necessary, treatment may be repeated after 4 to 6 hours, not exceeding 150 mg within any period of 24 hours.

• For the prevention of post-operative pain, a loading dose of 25 mg to 50 mg administered as a 5 to 60 second intravenous bolus after surgery, followed by additional injections up to a maximum daily dosage of 150 mg. If necessary, treatment may be repeated after 4 to 6 hours, not exceeding 150 mg within any period of 24 hours.

Phlebitis: Intravenous drug administration has been associated with the occurrence of Thrombophlebitis. Clinical studies comparing Dyloject 75 mg/2 ml Solution for Injection to Voltarol^® Ampoules have demonstrated reduced severity and one fourth the incidence of phlebitis (p=0.0032).

Children: Dyloject 75 mg/2 ml Solution for Injection is not recommended for use in children.

Elderly: The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy. The recommended maximum daily dose of Dyloject 75 mg/2 ml Solution for Injection is 150 mg.

Patients with renal impairment: Hydroxypropylbetadex (HPβCD), when administered intravenously, is predominantly eliminated through glomerular filtration. Therefore, patients with severe renal impairment defined as creatinine clearance below 30 ml/min should not be treated with Dyloject 75 mg/2 ml Solution for Injection. See Section 4.4, Special warnings and precautions for use.

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

Severe heart failure, renal failure, and hepatic failure (see Section 4.4)

During the last trimester of pregnancy (see Section 4.6).

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, angioedema, urticaria or rhinitis) in response to ibuprofen, aspirin or other NSAIDS.

Hypersensitivity to diclofenac sodium, or to any of the excipients.

The excipient HPβCD is predominantly eliminated through the kidney by glomerular filtration. Therefore, Dyloject 75 mg/2 ml Solution for Injection is contraindicated in patients with severe renal impairment (defined as creatinine clearance below 30 ml/min). See Section 4.4, Special warnings and precautions for use.

Specifically for IV use

Concomitant NSAID including cyclooxygenase-2 selective inhibitors or anticoagulant use (including low dose heparin).

A 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 > 160 µmol/l). Hypovolaemia or dehydration from any cause.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see Section 4.2, and gastrointestinal and cardiovascular risks below).

The use of Dyloject 75 mg/2 ml Solution for Injection with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see Section 4.5). Concomitant use during IV use is contraindicated (see Section 4.3).

Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see Section 4.2).

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs. They can occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see Section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and Section 4.5).

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see Section 4.5). Concomitant use with anticoagulants during IV treatment is contraindicated (see Section 4.3).

When gastrointestinal bleeding or ulceration occurs in patients receiving Dyloject 75 mg/2 ml Solution for Injection, the drug should be withdrawn.

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see Section 4.8).

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).

Dermatological: 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. Dyloject 75 mg/2 ml Solution for Injection should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Hepatic: Close medical surveillance is also imperative in patients suffering from severe impairment of hepatic function.

Hypersensitivity reactions: As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug.

Like other NSAIDs, Dyloject 75 mg/2 ml Solution for Injection may mask the signs and symptoms of infection due to its pharmacodynamic properties.

Renal impairment: HPβCD, when administered intravenously, is predominantly eliminated through the kidney by glomerular filtration. Therefore, patients with renal impairment (defined as creatinine clearance below 30 ml/min) should not be treated with Dyloject 75 mg/2 ml Solution for Injection. See Section 5.2, Pharmacokinetic properties.

Precautions

Cardiovascular, Renal and Hepatic Impairment: The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics or those recovering from major surgery and the elderly. Renal function should be monitored in these patients (see also section 4.3).

Renal impairment: HPβCD, when administered intravenously, is predominantly eliminated through the kidney by glomerular filtration. Therefore, patients with renal impairment (defined as creatinine clearance below 30 ml/min) should not be treated with Dyloject 75 mg/2 ml Solution for Injection. See Section 5.2, Pharmacokinetic properties.

Hepatic: If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (eosinophilia, rash, etc.), Dyloject 75 mg/2 ml Solution for Injection should be discontinued. Hepatitis may occur without prodromal symptoms.

Use of Dyloject 75 mg/2 ml Solution for Injection in patients with hepatic porphyria may trigger an attack.

Haematological: Dyloject 75 mg/2 ml Solution for Injection may reversibly inhibit platelet aggregation (see Anticoagulants in Section 4.5). Patients with defect of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

Long-term treatment: Dyloject 75 mg/2 ml Solution for Injection is not recommended for long term use. Prescribers should select follow-on treatment based on prescribing information for the specific product selected. All patients who are receiving non-steroidal anti-inflammatory agents long term, should be monitored as a precautionary measure, e.g. renal function, hepatic function (elevation of liver enzymes may occur) and blood counts. This is particularly important in the elderly.

Respiratory disorders: Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients. IV use in patients with history of asthma is contraindicated (see Section 4.3).

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.

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, smoking).

Impaired female fertility: The use of Dyloject 75 mg/2 ml Solution for Injection 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 Dyloject 75 mg/2 ml Solution for Injection should be considered.

Lithium and digoxin: Decreased elimination of lithium and digoxin.

Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see Section 4.4).

Antidiabetic agents: 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 hypoglycaemic and hyperglycaemic effects which have required adjustment to the dosage of hypoglycaemic agents.

Ciclosporin: Increased risk of nephrotoxicity.

Methotrexate: Decreased the elimination of methotrexate.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Other analgesics including cyclooxygenase-2 selective inhibitors and corticosteroids: Avoid concomitant use of two or more NSAIDs (including aspirin) or corticosteroids as this may increase the risk of adverse effects (see Section 4.4).

Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate and increase plasma glycoside and HPβCD levels.

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

Anti-hypertensives: Reduced anti-hypertensive effect.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see Section 4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see Section 4.4).

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Pregnancy

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see Section 4.3). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

Lactation

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

See Section 4.4 Special warnings and precautions for use, regarding female fertility.

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

Side effects observed following parenteral diclofenac administration

If serious side effects occur, Dyloject 75 mg/2 ml Solution for Injection should be withdrawn. Frequency estimate: frequent: >10%; occasional: > 1 to 10%; rare: > 0.001 to 1%; isolated cases: < 0.001%.

Gastrointestinal tract

Occasional: epigastric pain, other gastrointestinal disorders (e.g. nausea, vomiting, diarrhoea, dyspepsia, flatulence, anorexia).

Rare: gastrointestinal bleeding (haematemesis, melaena, bloody diarrhoea), abdominal pain/tenderness, gastrointestinal ulcers with or without bleeding or perforation, mouth ulcerations, tooth and tongue disorders or dysphagia.

In isolated cases: aphthous stomatitis, glossitis, esophageal lesions, lower gut disorders (e.g. non-specific haemorrhagic colitis and exacerbations or ulcerative colitis or Crohn's proctocolitis, colonic damage and stricture formation), pancreatitis, or constipation.

Central nervous system

Occasional: headache, dizziness or vertigo.

Rare: drowsiness, tiredness, dysgeusia, paraesthesia, balance impairment, aponia, hypoaesthesia, migraine, speech disorder, or trismus.

In isolated cases: disturbances of sensation, memory disturbance, disorientation, insomnia, irritability, convulsions, depression, anxiety, nightmares, tremor, psychotic reactions, or aseptic meningitis.

General disorders

Rare: pain, chest pain, chest tightness, malaise, rigors, bloody discharge, feeling abnormal, feeling hot, or pyrexia.

Musculoskeletal and connective tissue disorders

Occasional: pain in jaw.

Rare: facial pain, joint stiffness, myalgia, back pain, chest wall pain, neck pain, muscle cramp, or muscle tightness.

Special senses

Rare: eyelid oedema, eyelid pruritus, increased lacrimation, or eye pain.

In isolated cases: disturbances of vision (blurred vision, diplopia), impaired hearing, tinnitus, or taste disturbances.

Skin

Occasional: rashes or skin eruptions.

Rare: urticaria, pruritus, or sweating increased.

In isolated cases: bullous eruptions, eczema, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome (acute toxic epidermolysis), erythroderma (exfoliative dermatitis), loss of hair, photosensitivity reactions, or purpura including allergic purpura.

Kidney

Rare: oedema, renal pain.

In isolated cases: acute renal insufficiency, urinary abnormalities (e.g. haematuria, proteinuria), interstitial nephritis, nephrotic syndrome, or papillary necrosis.

Liver

Occasional: elevation of serum aminotransferase enzymes (ALT, AST).

Rare: liver function disorders including hepatitis (in isolated cases fulminant) with or without jaundice, or increased lipase.

Blood

Rare: neutrophilia.

In isolated cases: thrombocytopenia, leucopenia, agranulocytosis, hemolytic anaemia, or aplastic anaemia.

Hypersensitivity

Rare: hypersensitivity reactions (e.g. bronchospasm, anaphylactic/anaphylactoid systemic reactions including hypotension), respiratory disorder NOS, or rhinorrhoea.

In isolated cases: vasculitis, or pneumonitis.

Cardiovascular and cerebrovascular

Occasional: haemorrhage

Rare: phlebitis, hypotension, bradycardia, or flushing.

In isolated cases: palpitations, chest pain, hypertension, or congestive heart failure.

Laboratory abnormalities

Rare: elevated creatine phosphokinase, ketonuria, haematuria, or bilirubin in urine.

Other organ systems

In isolated cases: impotence.

Reactions to the intramuscular injection

Occasional: reactions such as local pain and induration.

In isolated cases: abscesses and local necrosis at the injection site.

Reactions to the intravenous injection

Occasional: thrombophlebitis.

Rare: cannula site reaction, infusion site discomfort or burning, injection site stinging, or pyrexia.

Additional adverse events have been documented following diclofenac administration

Cardiovascular and cerebrovascular: 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).

Additional adverse reactions have been documented following non-selective NSAIDs therapy

Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Other adverse reactions reported less commonly include:

Renal: Renal failure.

Neurological and special senses: Optic neuritis, reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see Section 4.4).

Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measure

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 a potentially life-threatening overdose.

Good urine output should be ensured.

Renal and liver function should be closely monitored.

Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

Frequent or prolonged convulsions should be treated with intravenous diazepam.

Other measures may be indicated by the patient's clinical condition.

Pharmacotherapeutic group

Non-steroidal anti-inflammatory drugs (NSAIDs). ATC code M01AB.

Mechanism of action

Dyloject 75 mg/2 ml Solution for Injection is a non-steroidal 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, diclofenac sodium often reduces the need for opioids.

Absorption

Intramuscular injection: After administration of Dyloject 75 mg/2 ml Solution for Injection intramuscularly, absorption sets in immediately, and mean peak plasma concentrations of about 2.569 ± 1.092 µg/ml (2.5 µg/ml equals approximately 8 µmol/l) are reached in 39 minutes. In comparative clinical studies, the rate of absorption for Dyloject 75 mg/2 ml Solution for Injection was more rapid than Voltarol^® Ampoules - peak plasma concentration for Voltarol^® was 1.541 ± 0.419 µg/ml at 48 minutes. The extent of absorption of Dyloject 75 mg/2 ml Solution for Injection was bioequivalent to Voltarol^® Ampoules. The amount of diclofenac absorbed after IM administration is in linear proportion to the size of the dose.

Intravenous injection: After administration of Dyloject 75 mg/2 ml Solution for Injection intravenously, absorption sets in immediately, and mean peak plasma concentrations of about 15.147 ± 2.829 µg/ml (2.5 µg/ml equals approximately 8 µmol/l) are reached in 3 minutes. In comparative clinical studies, the rate of absorption for Dyloject 75 mg/2 ml Solution for Injection was more rapid than Voltarol^® Ampoules - peak plasma concentration for Voltarol^® was 5.668 ± 0.974 µg/ml at 30 minutes. The extent of absorption of Dyloject 75 mg/2 ml Solution for Injection was bioequivalent to Voltarol^® Ampoules.

In clinical studies comparing the analgesic efficacy of Dyloject to Voltarol^®, Dyloject was found to have a more rapid onset of analgesic action. At the 15- and 30-minute post-dose times, Dyloject 75 mg/2 ml Solution for Injection was statistically superior to Voltarol^® as measured on the VAS and categorical pain intensity and pain relief scales (p < 0.05). At 15 minutes after dosing, the proportion of patients reporting a 30% reduction in pain intensity differed significantly for those given Dyloject and Voltarol^® (52% versus 21%, respectively; p = 0.0022). Dyloject was statistically superior to Voltarol^® over the initial 0-2 hour TOTPAR interval both on the VAS scale (p = 0.009) and the categorical scale (p = 0.019). The magnitude of pain relief after two hours and the duration of action of Dyloject were found to be similar to Voltarol^®.

Bioavailability

The relative bioavailability of Dyloject 75 mg/2 ml Solution for Injection after IM administration is approximately 100%. The absolute bioavailability of Dyloject 75 mg/2 ml Solution for Injection after IV administration relative to Voltarol^® Ampoules IV is approximately 100%.

The bioavailability of diclofenac after oral or rectal administration is approximately one half that of IM or IV administration, as these latter routes avoid “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 to 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

The terminal half-life of Dyloject 75 mg/2 ml Solution for Injection in plasma is 1.17 ± 0.32 hours. In comparative clinical studies, the rate of clearance was more rapid than for Voltarol^® Ampoules (IM: 1.17 ± 0.29 hours, IV: 1.23 ± 0.31 hours). For Dyloject and Voltarol^®, renal clearance and excretion were found to be bioequivalent. Total systemic clearance of diclofenac in plasma is 263 ± 56 ml/min (mean value ± SD). 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.

Previous studies with HPβCD at higher doses than what is present in Dyloject 75 mg (667 mg per dose) have shown that the terminal half-life following a single-dose of 2 g of HPβCD administered by a one-hour IV infusion is 1.5 ± 0.3 hours. HPβCD is primarily renally excreted with 93% to 101% excreted unchanged in the urine within 12 hours of administration. In subjects with severe renal impairment (creatinine clearance 19 ml/min), clearance of HPβCD was reduced 6-fold compared to subjects with normal renal function.

Characteristics in patients

Elderly: No relevant age-dependent differences in the drug's absorption, metabolism or excretion have been reported.

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 hydroxyl 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.

Nonclinical data on diclofenac, HPβCD and their combination in Dyloject revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction, and local tolerance studies with the following provisions for potential gastrointestinal toxicity and foetal risk of premature closure of the ductus arteriosus in late pregnancy.

A single oral dose of 0.1 mg/kg of diclofenac to pregnant rats on pregnancy day 21 caused a constriction of the ductus arteriosus in the offspring, a known effect of prostaglandin-inhibiting drugs. Administration of diclofenac in late pregnancy is therefore not recommended.

In the 4-week IV toxicity studies conducted with diclofenac in rats (3, 7 and 15 mg/kg/day) and diclofenac and HPβCD in monkeys (3, 15 and 60 mg/kg/day and 533 mg/kg/day respectively) observed effects were essentially similar for both species and were all considered expected. Diclofenac induced a low incidence of mortality/premature sacrifice (due to peritonitis), gastrointestinal toxicity and regenerative anaemia in rats at a dose level of 15 mg/kg/day. Recovery was complete after a 9-week treatment-free period.

In monkeys, diclofenac caused gastrointestinal toxicity, regenerative anaemia and exacerbation of minor tail skin lesions at dose levels of 15 and 60 mg/kg/day. Resolution of these findings could not be assessed in the 60 mg/kg/day dose group, due to premature sacrifice. Findings attributed to HPβCD included very mild to mild renal tubular vacuolization in rats and very mild to mild granular appearance of the renal tubular cells in the medullar rays in monkeys. Following a relatively long treatment-free period as compared to the duration of treatment, partial and complete recovery of HPβCD-associated findings has been demonstrated in rats and monkeys, respectively.

The No Adverse Effect Level for HPβCD-related effects after 4 weeks of administration is lower than 26.6 mg HPβCD/kg/day in both species.

The solubilising agent HPβCD has been found to produce pancreatic hyperplasia and neoplasia when administered orally to rats at doses of 500, 2000 or 5000 mg/kg per day for 25 months. Adenocarcinomas of the exocrine pancreas produced in the treated animals were not seen in the untreated group and are not reported in the historical controls. These findings were not observed in the mouse carcinogenicity study, nor in a 12-month toxicity study in dogs or in a 2-year toxicity study in female cynomolgous monkeys.

In the Dyloject nonclinical studies diclofenac and HPβCD alone and in combination were not mutagenic or clastogenic. Diclofenac has shown no carcinogenic potential. The adenocarcinomas observed in the exocrine pancreas in the 2-year oral carcinogenicity study with HPβCD in rats were not considered a clinical hazard for Dyloject because HPβCD is not genotoxic. Dyloject is intended for short-term treatment only, and no pancreatotrophic changes were observed in the 4 week intravenous studies in rats and monkeys described above.

Dyloject 75 mg/2 ml Solution for Injection also contain

• Hydroxypropylbetadex (HPβCD)

• Monothioglycerol

• Water for Injection

• Sodium hydroxide and/or hydrochloric acid (to adjust pH)

• Nitrogen

The vials used IM or IV as a bolus should not be mixed with other injection solutions.

30 months.

Store below 30°C. Do not freeze. Keep vials in the outer carton in order to protect from light.

Keep Dyloject out of reach and sight of children.

The vials are 2 ml Ph. Eur. Type I borosilicate glass vials with 13 mm caps. The vials contain colourless liquid and are supplied in packs of 10.

The dose should be freshly withdrawn from the vial and used immediately. Once withdrawn, the dose should not be stored.

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

Therabel Pharma UK Limited

Compass House, Vision Park

Chivers Way, Histon

Cambridge CB24 9AD

United Kingdom

PL 25053/0001

30/10/2007

22/09/2009