SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Depo-Medrone with Lidocaine

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Methyprednisolone BP 4%, Lidocaine Hydrochloride BP 1%

3 PHARMACEUTICAL FORM

White, sterile aqueous suspension for injection

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Corticosteroid (glucocorticoid). Depo-Medrone with Lidocaine is indicated in conditions requiring a glucocorticoid effect: e.g. anti-inflammatory or antirheumatic. It is recommended for local use where the added anaesthetic effect would be considered advantageous.

Depo-Medrone with Lidocaine may be used as follows:

Intra-articular administration Rheumatoid arthritis

Osteo-arthritis with an inflammatory component

Periarticular administration Epicondylitis

Intrabursal administration Subacromial bursitis Prepatellar bursitis Olecranon bursitis

Tendon sheath administration

Tendinitis

Tenosynovitis

Epicondylitis

Therapy with Depo-Medrone with Lidocaine does not obviate the need for the conventional measures usually employed. Although this method of treatment will ameliorate symptoms, it is in no sense a cure and the hormone has no effect on the cause of the inflammation.

4.2 Posology and method of administration

Depo-Medrone with Lidocaine should not be mixed with any other preparation as flocculation of the product may occur. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever suspension and container permit. Depo-Medrone with Lidocaine may be used by any of the following routes: intra-articular, periarticular, intrabursal, and into the tendon sheath. It must not be used by the intrathecal or intravenous routes (see Contra-indications and Side-effects)

Adults

Intra-articular: Rheumatoid arthritis, osteo-arthritis. The dose of Depo-Medrone with Lidocaine depends on the size of the joint and the severity of the condition. Repeated injections, if needed, may be given at intervals of one to five or more weeks depending upon the degree of relief obtained from the initial injection. A suggested dosage guide is: large joint (knee, ankle, shoulder), 0.5 - 2 ml (20 - 80 mg of steroid); medium joint (elbow, wrist), 0.25 - 1 ml (10 - 40mg of steroid); small joint (metacarpophalangeal, interphalangeal, stemoclavicular, acromioclavicular), 0.1 -0.25 ml (4 - 10 mg of steroid).

Periarticular: Epicondylitis. Infiltrate 0.1 - 0.75 ml (4 - 30 mg of steroid) into the affected area.

Intrabursal: Subdeltoid bursitis, prepatellar bursitis, olecranon bursitis. For administration directly into bursae, 0.1 - 0.75 ml (4 - 30 mg of steroid). In most acute cases, repeat injections are not needed.

Into the tendon sheath: Tendinitis, tenosynovitis, epicondylitis. For administration directly into the tendon sheath, 0.1 - 0.75 ml (4 - 30 mg of steroid). In recurrent or chronic conditions, repeat injections may be necessary.

Children:

For infants and children, the recommended dosage should be reduced, but dosage should be governed by the severity of the condition rather than by strict adherence to the ratio indicated by age or body weight.

Elderly:

When used according to instructions, there is no information to suggest that a change in dosage is warranted in the elderly. However, treatment of elderly patients, particularly if long-term, should be planned bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age and close clinical supervision is required (see Other special warnings and precautions).

Special precautions should be observed when administering Depo-Medrone with

Lidocaine:

Intra-articular injections should be made using precise, anatomical localisation into the synovial space of the joint involved. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves. Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal and hip joints. The spinal joints, unstable joints and those devoid of synovial space are not suitable. Treatment failures are most frequently the result of failure to enter the joint space. Intra-articular injections should be made with care as follows: ensure correct positioning of the needle into the synovial space and aspirate a few drops of joint fluid. The aspirating syringe should then be replaced by another containing Depo-Medrone with Lidocaine. To ensure position of the needle synovial fluid should be aspirated and the injection made.

After injection the joint is moved slightly to aid mixing of the synovial fluid and the suspension. Subsequent to therapy care should be taken for the patient not to overuse the joint in which benefit has been obtained. Negligence in this matter may permit an increase in joint deterioration that will more than offset the beneficial effects of the steroid.

Intrabursal injections should be made as follows: the area around the injection site is prepared in a sterile way and a wheal at the site made with 1 percent procaine hydrochloride solution. A 20 to 24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied. In the treatment of tenosynovitis and tendinitis, care should be taken to inject Depo-Medrone with Lidocaine into the tendon sheath rather than into the substance of the tendon. Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with Depo-Medrone with Lidocaine.

4.3 Contraindications

Depo-Medrone with Lidocaine is contra-indicated where there is known hypersensitivity to components or to any local anaesthetics of the amide type and in systemic infection unless anti-infective therapy is employed.

Due to its potential for neurotoxicity, Depo-Medrone with Lidocaine must not be given by the intrathecal route. In addition, as the product is a suspension it must not be given by the intravenous route (see Side-effects).

4.4 Special warnings and precautions for use

1.    Undesirable effects may be minimised by using the lowest effective dose for the minimum period. Frequent patient review is required to appropriately titrate the dose against disease activity (see Dosage and administration).

2.    Patients should carry 'Steroid Treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

3.    Depo-Medrone with Lidocaine vials are intended for single dose use only. Any multidose use of the product may lead to contamination.

4.    Depo-Medrone with Lidocaine is not recommended for epidural, intranasal, intra-ocular, or any other unapproved route of administration. See Side-effects section for details of side-effects reported from some non-recommended routes of administration.

5.    Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with Depo-Medrone with Lidocaine.

6.    While crystals of adrenal steroids in the dermis suppress inflammatory reactions, their presence may cause disintegration of the cellular elements and physiochemical changes in the ground substance of the connective tissue. The resultant infrequently occurring dermal and/or subdermal changes may form depressions in the skin at the injection site and the possibility of depigmentation. The degree to which this reaction occurs will vary with the amount of adrenal steroid injected. Regeneration is usually complete within a few months or after all crystals of the adrenal steroid have been absorbed. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra-articular injection should include precautions against injection or leakage into the dermis.

7.    Systemic absorption of methylprednisolone occurs following intraarticular injection of Depo-Medrone with Lidocaine. Systemic as well as local effects can therefore be expected.

8.    Intra-articular corticosteroids are associated with a substantially increased risk of inflammatory response in the joint, particularly bacterial infection introduced with the injection. Charcot-like arthropathies have been reported particularly after repeated injections. Appropriate examination of any joint fluid present is necessary to exclude any bacterial infection, prior to injection.

9 Following a single dose of Depo-Medrone with Lidocaine, plasma cortisol levels are reduced and there is evidence of hypothalamic-pituitary-adrenal axis (HPA) suppression. This suppression lasts for a variable period of up to 4 weeks. The usual dynamic tests of HPA axis function can be used to diagnose evidence of impaired activity (e.g. Synacthen test).

10.    Adrenal cortical atrophy develops during prolonged therapy and may persist for months after stopping treatment. In patients who have received more than physiological doses of systemic corticosteroids (approximately 6 mg methylprednisolone) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids, but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose of 6 mg methylprednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 32 mg daily of methylprednisolone for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

•    Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.

•    When a short course has been prescribed within one year of cessation of long-term therapy (months or years).

•    Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.

•    Patients receiving doses of systemic corticosteroid greater than 32 mg daily of methylprednisolone.

•    Patients repeatedly taking doses in the evening.

11.    Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

12.    Because rare instances of anaphylactic reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of drug allergy.

13.    Corticosteroids may mask some signs of infection, and new infections may appear during their use. Suppression of the inflammatory response and immune function increases the susceptibility to fungal, viral and bacterial infections and their severity. The clinical presentation may often be atypical and may reach an advanced stage before being recognised.

14.    Chickenpox is of serious concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunization with varicella/zoster immunoglobin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

15.    Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.

16.    If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

17.    This product contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.

18.    Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see Side-effects).

19.    The following precautions apply for parenteral corticosteroids: Following intra-articular injection, a marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.

No additional benefit derives from the intramuscular administration of Depo-

Medrone with Lidocaine. Where parenteral corticosteroid therapy for

sustained systemic effect is desired, plain Depo-Medrone should be used.

Local injection of a steroid into a previously infected joint is to be avoided.

Corticosteroids should not be injected into unstable joints.

Sterile technique is necessary to prevent infections or contamination.

Special precautions:

Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

1.    Osteoporosis (post-menopausal females are particularly at risk).

2.    Hypertension or congestive heart failure.

3.    Existing or previous history of severe affective disorders (especially previous steroid psychosis).

4.    Diabetes mellitus (or a family history of diabetes).

5.    History of tuberculosis.

6.    Glaucoma (or a family history of glaucoma).

7.    Previous corticosteroid-induced myopathy.

8.    Liver failure or cirrhosis.

9.    Renal insufficiency.

10.    Epilepsy.

11.    Peptic ulceration.

12.    Fresh intestinal anastomoses.

13.    Predisposition to thrombophlebitis.

14.    Abscess or other pyogenic infections.

15.    Ulcerative colitis.

16.    Diverticulitis.

17.    Myasthenia gravis.

18.    Ocular herpes simplex, for fear of corneal perforation.

19.    Hypothyroidism.

20.    Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5 Interaction with Other Medicaments and Other Forms of Interaction that can increase the risk of side effects),

although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

Use in children: Corticosteroids cause growth retardation in infancy, childhood and adolescence which may be irreversible. Treatment should be limited to the minimum dosage for the shortest possible time.

Use in the elderly: The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

4.5 Interaction with other medicinal products and other forms of interaction

1.	Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Since concurrent administration of these agents results in a mutual inhibition of metabolism, it is possible that convulsions and other adverse effects associated with the individual use of either drug may be more apt to occur.
2.	Drugs that induce hepatic enzymes, such as rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, and aminoglutethimide enhance the metabolism of cortico steroids and its therapeutic effects may be reduced.
3.	Drugs such as erythromycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance.
4.	Steroids may reduce the effects of anticholinesterases in myasthenia gravis. The desired effects of hypoglycaemic agents (including insulin), antihypertensives and diuretics are antagonised by corticosteroids, and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced.
5.	The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is

	required to avoid spontaneous bleeding.
6.	The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication. Salicylates and non-steroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids in hypothrombinaemia.
7.	Steroids have been reported to interact with neuromuscular blocking agents such as pancuronium with partial reversal of the neuromuscular block.

4.6 Fertility, Pregnancy and lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, methyiprednisolone does cross the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate in man, however, when administered for long periods or repeatedly during pregnancy, corticosteroids may increase the risk of intrauterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential, however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

The use of local anaesthetics such as lidocaine during labour and delivery may be associated with adverse effects on mother and foetus. Lidocaine readily crosses the placenta.

Lactation

Corticosteroids are excreted in small amounts in breast milk, however, doses of up to 40 mg daily of methylprednisolone are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression, but the benefits of breastfeeding are likely to outweigh any theoretical risk.

It is not known whether lidocaine is excreted in human breast milk.

4.7 Effects on ability to drive and use machines

None stated.

4.8 Undesirable effects

The incidence of predictable undesirable side-effects associated with the use of corticosteroids, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and duration of treatment (See other special warnings and precautions).

Side-effects for the Depo-Medrone component may be observed including:

PARENTERAL CORTICOSTEROID THERAPY - Anaphylactic reaction or allergic reactions, hypopigmentation or hyperpigmentation, subcutaneous and cutaneous atrophy, sterile abscess, post injection flare (following intraarticular use), charcot-like arthropathy.

GASTRO-INTESTINAL - Dyspepsia, peptic ulceration with perforation and haemorrhage, abdominal distension, oesophageal ulceration, oesophageal candidiasis, acute pancreatitis, perforation of bowel.

Increases in alanine transaminase (ALT, SGPT) aspartate transaminase (AST, SGOT) and alkaline phosphatase have been observed following corticosteroid treatment. These changes are usually small, not associated with any clinical syndrome and are reversible upon discontinuation.

ANTI-INFLAMMATORY AND IMMUNOSUPPRESSIVE EFFECTS -Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, may suppress reactions to skin tests, recurrence of dormant tuberculosis (see Other special warnings and precautions).

MUSCULOSKELETAL - Proximal myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture, aseptic necrosis, muscle weakness.

FLUID AND ELECTROLYTE DISTURBANCE - Sodium and water retention, potassium loss, hypertension, hypokalaemic alkalosis, congestive heart failure in susceptible patients.

DERMATOLOGICAL - Impaired healing, petechiae and ecchymosis, thin fragile skin, skin atrophy, bruising, striae, telangiectasia, acne.

ENDOCRINE/METABOLIC - Suppression of the hypothalamo-pituitary-adrenal axis; growth suppression in infancy, childhood and adolescence; menstrual irregularity and amenorrhoea. Cushingoid facies, hirsutism, weight gain, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, negative nitrogen and calcium balance. Increased appetite.

NEUROPSYCHIATRIC - A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood psychological dependence and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported for all corticosteroids. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions was estimated to be 56%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown. Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri) has been reported, usually after treatment withdrawal of methylprednisolone.

OPHTHALMIC - Increased intra-ocular pressure, glaucoma, papilloedema, cataracts with possible damage to the optic nerve, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal disease, exophthalmos.

GENERAL - Leucocytosis, hypersensitivity including anaphylaxis, thromboembolism, nausea, vertigo.

WITHDRAWAL SYMPTOMS - Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. However, this is more applicable to corticosteroids with an indication where continuous therapy is given (see Other special warnings and precautions).

A 'withdrawal syndrome' may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

Side-effects for the Lidocaine component include:

CENTRAL NERVOUS SYSTEM - Lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensation of heat, cold, numbness, twitching, tremors, convulsions, loss of consciousness, respiratory depression, respiratory arrest.

CARDIOVASCULAR SYSTEM - Bradycardia, hypotension, cardiovascular collapse, cardiac arrest.

ALLERGIC REACTIONS - Cutaneous lesions, urticaria, oedema, anaphylactic reactions.

CERTAIN SIDE-EFFECTS REPORTED WITH SOME NON RECOMMENDED ROUTES OF ADMINISTRATION:

Intrathecal:    Usual systemic corticoid adverse reactions, headache,

meningismus, meningitis, paraplegia, spinal fluid abnormalities, nausea, vomiting, sweating, arachnoiditis, convulsions.

Extradural: Wound dehiscence, loss of sphincter control.

Intranasal: Permanent/temporary blindness, allergic reactions, rhinitis.

Ophthalmic (Subconjunctival): Redness and itching, abscess, slough at injection site, residue at injection site, increased intra-ocular pressure, decreased vision - blindness, infection.

Miscellaneous: Scalp, tonsillar fauces, sphenopalatine ganglion: blindness.

4.9 Overdose

There is no clinical syndrome of acute overdosage with Depo-Medrone with Lidocaine. Following overdosage the possibility of adrenal suppression should be guarded against by gradual diminution of dose levels over a period of time. In such event the patient may require to be supported during any further traumatic episode.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Methylprednisolone acetate is a synthetic glucocorticoid with the actions and use of natural corticosteroids. However the slower metabolism of the synthetic corticosteroid with their lower protein-binding affinity may account for their increased potency compared with the natural corticosteroids.

Lidocaine has the actions of a local anaesthetic.

5.2 Pharmacokinetic properties

No pharmacokinetic studies have been performed with the combination product of methylprednisolone and lidocaine, however, data are provided from pharmacokinetic studies performed with the individual product components methylprednisolone and lidocaine.

Absorption:

Methylprednisolone:

One in-house study of eight volunteers determined the pharmacokinetics of a single 40 mg intramuscular dose of Depo-Medrone. The average of the individual peak plasma concentrations was 14.8 ± 8.6 ng/mL, the average of the individual peak times (tmax) was 7.25 ± 1.04 hours, and the average area under the curve (AUC) was

1354.2 ± 424.1 ng/mL x hrs (Day 1-21).

Lidocaine:

Pharmacokinetics of lidocaine after synovial absorption following intra-articular bolus injection in patients with knee joint arthroscopy was studied with different maximum concentration (Cmax) values reported. The C_max values are 2.18 pg/mL at 1 hour (serum) and 0.63 pg/mL at 0.5 hour (plasma) following administration of lidocaine doses of 7 mg/kg and 400 mg, respectively. Other reported serum C_max values are 0.69 pg/mL at 5 minutes and 0.278 pg/mL at 2 hours following administration of lidocaine doses of 25 mL of 1% and 20 mL of 1.5%, respectively.

Pharmacokinetic data of lidocaine after intra-bursa and intra-cyst administrations for local effect are not available.

Distribution:

Methylprednisolone:

Methylprednisolone is widely distributed into the tissues, crosses the blood-brain barrier, and is secreted in breast milk. Its apparent volume of distribution is approximately 1.4 L/kg. The plasma protein binding of methylprednisolone in humans is approximately 77%.

Lidocaine:

The plasma protein binding of lidocaine is concentration-dependent, and binding decreases as concentration increases. At concentrations of 1 to 5 pg/mL, 60%-80% lidocaine is protein bound. Binding is also dependent on the plasma concentration of the a1-acid glycoprotein.

Lidocaine has a volume of distribution at steady state of 91 L.

Lidocaine readily crosses the placenta, and equilibrium of unbound drug concentration is rapidly reached. The degree of plasma protein binding in the foetus is less than in the mother, which results in lower total plasma concentrations in the foetus.

Metabolism:

Methylprednisolone:

In humans, methylprednisolone is metabolized in the liver to inactive metabolites; the major ones are 20a-hydroxymethylprednisolone and 20p-hydroxymethylprednisolone. Metabolism in the liver occurs primarily via the CYP3A4. (For a list of drug interactions based on CYP3A4-mediated metabolism, see section 4.5.)

Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for the ATP-binding cassette (ABC) transport protein p-glycoprotein, influencing tissue distribution and interactions with other medicines modulated by P-gp.

Lidocaine:

Lidocaine is mainly metabolized by the liver. The main metabolites of lidocaine are monoethylglycine xylidide, glycinexylidide, 2,6-dimethylaniline, and 4-hydroxy-2,6-dimethylaniline. The lidocaine N-dealkylation to monoethylglycine xylidide is considered to be mediated by both CYP1A2 and CYP3A4. The metabolite 2,6-dimethylaniline is converted to 4-hydroxy-2,6-dimethylaniline by CYP2A6 and CYP2E1.

Elimination:

Methylprednisolone:

The mean elimination half-life for total methylprednisolone is in the range of 1.8 to

5.2 hours. Total clearance is approximately 5 to 6 mL/min/kg.

Lidocaine:

The clearance of lidocaine in plasma following intravenous bolus administration is 9 to 10 mL/min/kg.

The elimination half life of lidocaine following intravenous bolus injection is typically 1.5 to 2 hours.

The pharmacological actions of monoethylglycine xylidide and glycinexylidide are similar to but less potent than those of lidocaine. Monoethylglycine xylidide has a half life of approximately 2.3 hours and glycinexylidide has a half life of about 10 hours and may accumulate after long-term administration.

Only 3% of lidocaine is excreted unchanged by the kidneys. About 73% of lidocaine appears in the urine as 4-hydroxy-2,6-dimethylaniline metabolite.

Special Population

Methylprednisolone:

No pharmacokinetic studies have been performed for methylprednisolone in special populations.

Special Population

Lidocaine:

Hepatic impairment

Following intravenous administration, the half life of lidocaine has approximately 3fold increase in patients with liver impairment. Pharmacokinetic data of lidocaine after intra-articular, intra-bursa and intra-cyst administrations for local effect are not available in hepatic impairment.

Renal impairment

Mild to moderate renal impairment (CLcr 30-60 mL/min) does not affect lidocaine pharmacokinetics but may increase the accumulation of glycinexylidide metabolite following intravenous administration. However, lidocaine clearance decreases about half and its half life is approximately doubled with increased accumulation of glycinexylidide metabolite in patients with severe renal impairment (Clcr <30 mL/min).

The pharmacokinetics of lidocaine and its main metabolite of monoethylglycine xylidide are not altered significantly in haemodialysis patients who receive an intravenous dose of lidocaine.

Pharmacokinetic data of lidocaine after intra-articular, intra-bursa and intra-cyst administrations for local effect are not available in renal impairment.

No dosing adjustments are necessary in renal failure. Methylprednisolone is haemodialysable.

5.3 Preclinical safety data

Methvlprednisolone

Based on conventional studies of safety pharmacology and repeated dose toxicity, no unexpected hazards were identified. The toxicities seen in the repeated-dose studies were those expected to occur with continued exposure to exogenous adrenocortical steroids.

Mutagenic potential:

There was no evidence of a potential for genetic and chromosome mutations when tested in limited studies performed in bacteria and mammalian cells.

Carcinogenic potential:

Long-term studies in animals have not been performed to evaluate carcinogenic potential, as the drug is indicated for short-term treatment only. There were no signs indicative of carcinogenic activity in studies conducted to date.

Reproductive toxicity:

Reproductive fertility studies in animals have not been performed to evaluate specifically the potential of impairment of fertility. There is no evidence that corticosteroids impair fertility.

An increased frequency of cleft palate was observed among the offspring of mice treated during pregnancy with methylprednisolone in doses similar to those typically used for oral therapy in humans.

An increased frequency of cardiovascular defects and decreased body weight were observed among the offspring of pregnant rats treated with methylprednisolone in a dose that was similar to that used for oral therapy in humans but was toxic to the mothers. In contrast, no teratogenic effect was noted in rats with doses <1-18 times those typically used for oral therapy in humans in another study. High frequencies of foetal death and a variety of central nervous system and skeletal anomalies were reported in the offspring of pregnant rabbits treated with methylprednisolone in doses less than those used in humans. The relevance of these findings to the risk of malformations in human infants born to mothers treated with methylprednisolone in pregnancy is unknown. Safety margins for the reported teratogenic effects are unknown.

Lidocaine

Carcinogenic potential:

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Mutagenic potential:

Genotoxicity studies were carried out with lidocaine and its metabolites. The Salmonella microsomal assay (Salmonella typhimurium strains TA100, TA98, and TA1538 with 1, 10, 100 and 500 mg/plate), with or without metabolic activation, with lidocaine and its metabolites monoethylglycinexylidine, N-hydroxylidocaine, N-

hydroxy-monoethylglycinexylidine, 2,6-xylidine, 2,6-

dimethylphenylhydroxylamine, did not reveal any mutagenic activity. However, metabolite 2,6-dimethylaniline, has been shown to have mutagenic and carcinogenic potential.

Reproductive toxicity:

Methvlprednisolone plus Lidocaine Carcinogenic potential:

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

The toxicity of lidocaine was not significantly altered in rats that were treated with the combination of lidocaine and methylprednisolone.

Mutagenic potential:

Genotoxicity studies have not been conducted with the combination of methylprednisolone and lidocaine (see above for genotoxicity as it pertains to the individual drugs).

Reproductive toxicity:

Reproductive toxicity studies have not been conducted with the combination of methylprednisolone and lidocaine (see above for reproductive toxicity as it pertains to the individual drugs).

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium chloride, myristyl-garnma-picolinium chloride, benzyl alcohol, macrogol, sodium hydroxide, hydrochloric acid and water for injection.

6.2 Incompatibilities

None.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

Store below 25 °C. Protect from freezing.

6.5 Nature and contents of container

Glass vials with rubber cap containing 1 or 2 ml of suspension.