SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Methylprednisolone 1 g powder for solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains methylprednisolone sodium succinate 1326 mg equivalent to 1000 mg of methylprednisolone. Each ml of reconstituted solution contains 62.5mg of methylprednisolone.

Excipient(s) with known effect:

Each vial contains 2.459 mmol (56.6mg) sodium.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection.

White or almost white, sterile, lyophilized powder.

Reconstituted solution:

Clear and colourless or pale brown solution. pH: 7.0 - 8.0

Osmolality: 294.5 - 325.5 mOsmol/kg

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Methylprednisolone is indicated for the treatment of conditions in which rapid and intense corticosteroid effect is required such as:

• Dermatological diseases

Severe erythema multiforme (Stevens-Johnson syndrome)

•    Allergic states Bronchial asthma

Severe seasonal and perennial allergic rhinitis

Angioneurotic oedema

Anaphylaxis

•    Gastro-intestinal diseases Ulcerative colitis Crohn’s disease

•    Respiratory diseases Aspiration of gastric contents

Fulminant or disseminated tuberculosis (with appropriate antituberculosis chemotherapy)

•    Neurological disorders

Secondary cerebral oedema caused by cerebral tumour

Acute exacerbations of multiple sclerosis superimposed on a relapsing-

remitting background.

•    Miscellaneous

T.B.C meningitis (with appropriate anti-tuberculosis chemotherapy) Transplantation

4.2 Posology and method of administration

Methylprednisolone may be administered intravenously or intramuscularly, the preferred method for emergency use being intravenous injection given over a suitable time interval.

When Methylprednisolone is administered in high doses intravenously, it should be given over a period of at least 30 minutes. Doses up to 250 mg should be given intravenously over a period of at least five minutes.

Undesirable effects may be minimized by using the lowest effective dose for the minimum period (see Section 4.4).

Adults: Dosage should be varied according to the severity of the condition, the initial dose should be between 10 to 500 mg. In the treatment of graft rejection reactions following transplantation, a dose of up to 1 g/day may be required. Although doses and protocols have varied in studies using methylprednisolone sodium succinate in the treatment of graft rejection reactions, the published literature supports the use of doses of this level, with 500 mg to 1 g most commonly used for acute rejection. Treatment at these doses should be limited to a 48-72 hours period until the patient’s condition has stabilized, as prolonged high dose corticosteroid therapy can cause serious corticosteroid induced side effects (see Sections 4.4 and 4.8).

Paediatric population: In the treatment of high dose indications, such as haematological, rheumatic, renal and dermatological conditions, a dosage of 30 mg/kg/day to a maximum of 1 g/day is recommended. This dosage may be repeated in three consecutive cycles on a daily basis or on every second day. In the treatment of graft rejection reactions following transplantation, a dosage of 10 to 20 mg/kg/day for up to 3 days, to a maximum of 1 g/day, is recommended. For the treatment of asthmatic states a dosage of 1 to 4 mg/kg/day for 1-3 days is recommended.

Dosage may be reduced in infants and children, but should be governed more by the severity of the patient’s condition and his response to treatment than on age or body weight.

Older people: Methylprednisolone is primarily used in acute short term conditions. There is no information to suggest that a change in dosage is necessary in elderly patients. However, treatment of elderly patients 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 Section 4.4).

Detailed recommendations for adult dosage are as follows:

In anaphylactic reactions adrenaline or noradrenaline should be administered first for an immediate haemodynamic effect, followed by intravenous injection of Methylprednisolone (methylprednisolone sodium succinate) with other accepted procedures. There is evidence that corticosteroids through their prolonged haemodynamic effect are of value in preventing recurrent attacks of acute anaphylactic reactions.

In sensitivity reactions Methylprednisolone is capable of providing relief of symptoms within half to two hours. In patients with status asthmaticus Methylprednisolone may be given at a dose of 40 mg intravenously, repeated as dictated by the patient response. In some asthmatic patients it may be of advantage to administer the product as a slow drop infusion over a time period of several hours.

In graft rejection reactions following transplantation doses of up to 1 g per day have been used to suppress rejection crises. In case of acute rejection, doses of 500 mg to 1 g are commonly used. Treatment should be continued only until the patient’s condition has stabilized; usually not beyond 48-72 hours.

In cerebral oedema corticosteroids are used to reduce or prevent the cerebral oedema associated with brain tumours (primary or metastatic).

In patients with oedema due to tumour, tapering the dose of corticosteroid appears to be important in order to avoid a rebound increase in intracranial pressure. If brain swelling does occur as the dose is reduced (intracranial bleeding having been ruled out), restart larger and more frequent doses parenterally. Patients with certain malignant diseases may need to remain on oral corticosteroid therapy for months or even life. Similar or higher doses may be helpful to control cerebral oedema during radiation therapy.

The following are suggested dosage schedules for oedemas due to brain tumour:

Schedule (1)	Dose (mg)	Route	Interval	Duration
			(in hours)
Pre-operative:	20	im	3-6
During surgery:	20 to 40	iv	Hourly

Post operative:	20	im	3	24 hours
	16	im	3	24 hours
	12	im	3	24 hours
	8	im	3	24 hours
	4	im	3	24 hours
	4	Im	6	24 hours
	4	im	12	24 hours

Schedule (2)	Dose (mg)	Route	Interval (in hours)	Duration
Pre-operative:	40	im	6	2-3
Post operative	40	Im	6	3-5
	20	Oral	6	1
	12	Oral	6	1
	8	Oral	8	1
	4	Oral	12	1
	4	Oral		1

Aim: to discontinue therapy after a total of 10 days.

In the treatment of acute exacerbations of multiple sclerosis in adults, the recommended dose is 1 g daily for 3 days. Methylprednisolone should be given as an intravenous infusion over at least 30 minutes.

In other indications, initial dosage will vary from 10 to 500 mg depending on the clinical problem being treated. Larger doses may be required for short-term management of severe, acute conditions. The initial dose, up to 250 mg, should be given intravenously over a period of at least 5 minutes, doses exceeding 250 mg should be given intravenously over a period of at least 30 minutes. The subsequent doses may be given intravenously or intramuscularly at intervals as dictated by the patient’s response and clinical condition. Corticosteroid therapy is an adjunct to - and not a replacement of - conventional therapy.

For instruction on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to methylprednisolone, other corticosteroids or any of the components of product,

-    Systemic infections (unless specific anti-infective therapy is employed)

-    In septic shock

-    Cerebral oedema associated with malaria.

-    Systemic fungal infections

4.4 Special warnings and precautions for use

Warnings and precautions:

•    Undesirable effects may be minimised by using the lowest effective dose for the minimum period of time. Frequent patient control is required to appropriately adjust the dose depending on disease activity (see Section 4.2).

•    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 longer 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 been applied for a time period of maximum 3 weeks is appropriate if the treating physician considers a relapse of the disease to be unlikely. Abrupt withdrawal of doses up to 32 mg daily of methylprednisolone for maximum 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 treatment lasting 3 weeks or less:

•    Patients who have received repeated courses of systemic corticosteroid treatment, particularly if applied for longer than 3 weeks

•    When a short course has been prescribed within one year of cessation of longterm 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 receiving repeated doses in the evening.

•    Data from a clinical study conducted to establish the efficacy of Methylprednisolone in septic shock, suggests that a higher mortality occurred in patients who entered the study with elevated serum creatinine levels or who developed a secondary infection after therapy began. Therefore this product should not be used in the treatment of septic syndrome or septic shock.

•    There have been a few reports of cardiac arrhythmias and/or circulatory collapse and/or cardiac arrest associated with the rapid intravenous administration of large doses of methylprednisolone-sodium-succinate (greater than 500 mg administered over a period of less than 10 minutes). Bradycardia has been reported during or after the administration of large doses of methylprednisolone sodium succinate, however this may be independent of the infusion rate and duration.

•    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 recognized.

•    Varicella is of serious concern since this normally unserious illness may be fatal in immuno-suppressed patients. Patients (or parents of children) without a definite history of varicella should be advised to avoid close personal contact with varicella or herpes zoster and if exposed they should seek urgent medical attention. Passive immunization with varicella/zoster immunoglobulin (VZIG) is necessary for exposed non-immunised patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; immunization should be performed within 10 days of exposure to varicella. If a diagnosis of varicella is confirmed, the illness necessitates specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

•    Exposure to patients with measles should be avoided. Medical advice should be sought immediately if exposure occurs. Prophylaxis with normal intramuscular immunoglobulin may be needed.

•    Live vaccines should not be given to patients with a decreased immune response. The antibody response to other vaccines may also be decreased.

•    The use of Methylprednisolone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate anti-tuberculosis regimen. 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 chemo-prophylaxis.

•    Rarely anaphylactoid reactions have been reported following parenteral Methylprednisolone therapy. Physicians administering the drug should be prepared to handle and treat these conditions. Appropriate precautionary measures should be taken prior to administration, especially when the patient has history of drug allergy.

•    Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see Section 4.8).

•    Corticosteroids should not be used for the management of head injury or stroke because it is unlikely to be of benefit and may even be harmful.

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:

•    Osteoporosis (post-menopausal females are particularly at risk)

•    Hypertension or congestive heart failure.

•    Existing or previous history of severe affective disorders (especially previous steroid psycosis).

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

•    Patient history of tuberculosis.

•    Glaucoma (or a family history of glaucoma).

•    Previous corticosteroid-induced myopathy.

•    Liver failure or cirrhosis.

•    Renal insufficiency.

•    Epilepsy.

•    Peptic ulceration.

•    Fresh intestinal anastomoses.

•    Predisposition to thrombophlebitis.

•    Abscess or other pyogenic infections.

•    Ulcerative colitis.

•    Diverticulitis.

•    Myasthenia gravis.

•    Ocular herpes simplex, for fear of corneal perforation.

•    Hyperthyreoidism.

•    Recent myocardial infarction (myocardial rupture has been reported).

•    Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.

•    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)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/nursing people 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. In order to minimize suppression of the hypothalamo-pituitary-adrenal axis and growth retardation, treatment should be administered where possible as a single dose on alternate days.

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.

This medicinal product contains 2.46 mmol (or 56.6 mg) sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

• Convulsions have been reported with concurrent use of methylprednisolone and cyclosporine. Since concurrent administration of these agents results in mutual metabolic inhibition, convulsions and other adverse events

associated with the individual use of either drug may occur with a higher possibility.

•    Drugs that induce hepatic enzymes, such as rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, primidone and aminoglutethimide enhance the metabolism of corticosteroids and may therefore reduce their therapeutic effect.

•    Drugs which inhibit the CYP3A4 enzyme, such as cimetidine, erythromycin, ketoconazole, itraconazole, diltiazem and mibefradil, may decrease the rate of metabolism of corticosteroids and hence may increase the serum concentration.

•    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.

•    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.

•    The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication. Salicylates and nonsteroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids in hypothrombinaemia.

•    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, methylprednisolone does cross the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects 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 intra-uterine growth retardation. Hypoadrenalism may theoretically occur in neonates following perinatal 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.

Breast-feeding

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 infants. 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.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

Frequency grouping according to MedDRA:

-    Very common > 1/10

-    Common > 1/100 to < 1/10

-    Uncommon > 1/1,000 to <1/100

-    Rarely > 1/10,000 to < 1/1,000

-    Very rare < 1/10,000

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Metabolism and nutrition disorders:

Uncommon: sodium and fluid retention, potassium loss, manifestation of latent diabetes mellitus, increased insulin or oral antidiabetic requirement of diabetic patients.

Hypokalaemic alkalosis.

Cardiac disorders:

Myocardial rupture following a myocardial infarction.

Vascular disorders:

Uncommon: hypertension, increased clotting can cause thrombolytic complications.

Musculoskeletal and connective tissue disorders:

Common: muscle weakness, osteoporosis

Rare: aseptic bone necrosis (femur and humerus), tendon rupture.

Gastro-intestinal disorders:

Dyspepsia, abdominal distension, oesophageal ulceration, oesophageal candidiasis, acute pancreatitis, perforation of bowel, nausea, vomiting, bad taste.

General disorders and administration site conditions:

Common: delayed wound healing

Uncommon: skin and soft tissue atrophy by subcutaneous injection Rare: allergic dermatitis, contact dermatitis, angioneurotic oedema.

Nervous system disorders:

Common: convulsions

Rare: benign intracranial hypertension.

Endocrine disorders:

Common: inhibition of endogenous ACTH and cortisol secretion,

Cushing-like symptoms, growth suppression in infancy, childhood and adolescence, osteoporosis

Menstrual irregularity, amenorrhoea.

Eye disorders:

Uncommon: glaucoma, posterior cataracts.

Increased intraocular pressure, papilloedema with possible damage to the optic nerve, corneal and sclera thinning, exacerbation of ophthalmic viral or fungal disease.

Immune system disorders:

Common: increased suscepitibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, may suppress reactions to skin tests, recurrence of dormant tuberculosis (see section 4.4). Rare: hypersensitivity, suppression of responses to skin tests, allergic reactions, sometimes anaphylactic, with bronchospasm.

Psychiatric disorders:

Very common: 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, seizures 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. Respiratory, thoracic and mediastinal disorders:

4.9 Overdose

Clinical signs are not known. Methylpredisolone can be removed by dialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: corticosteroids for systemic use, plain. Glucocorticoids ATC: H02A B04

Mechanism of action

The active ingredient of Methylprednisolone solution for injection is the methylprednisolone. Methylprednisolone is a synthetic glucocorticoid. Methylprednisolone is a synthetic analog of a glucocorticoid steroid, it acts as a potent anti-inflammtory steroid. The principle uses of methylprednisolone and its derivatives are as anti-inflammatory or immunosuppressant agents.

Methylprednisolone injection can be used intravenously or intramuscularly for the treatment of pathological states where quick and intensive hormone effect is desired; methylprednisolone has a strong antiphlogistic, immunosuppressive and anti-allergic effect.

Pharmacodynamic effects

Glucocorticoids are widely used due to their anti-inflammatory and immunosuppressive effects. They inhibit the onset of both early and late symptoms of inflammation.

In humans they reduce the proliferative response to certain mitogens and antigens. Due to their effect production of lymphokins is reduced, which in turn results in reduction of mobilization and activation of macrophages (immune suppression).

Glucocorticoids reduce protein synthesis and increase protein catabolism mainly in the muscles. They have a permissive effect on lipolysis induced by cathecolamins or other hormones, the reason of which is the increase of intracellular cAMP-levels. They also posses a slight mineral corticoid activity, at the mineral corticoid receptor level. They induce a certain degree of Na+ retention and K+ loss.

Pharmacokinetic properties

Absorption

The active substance in Methylprednisolone injection is present in the form of the sodium succinate salt, which is in vivo quickly hydrolysed to methylprednisolone.

40 mg Methylprednisolone given in i.v. bolus, after 25 minutes produces a peak plasma concentration of 42 - 47 pg/100 ml, while 40 mg given i.m. produces a peak plasma concentration of 34 pg/100 ml after 120 minutes. (Almost equivalent methylprednisolone effectivity is achieved with both application methods)

Distribution

As with endogenous corticosteroids, about 90% of exogenously administered corticosteroids, such as methylprednisolone, bind to corticosteroid-binding globulin (CBG) produced by the liver.

The half-life of methylprednisolone in the circulation is normally 3-3.5 hours; reduced in obese patients. The half-life of methylprednisolone can be increased when a large amount is administered, when patient is stressed, or when hypothyroidism, or liver disease are present.

Metabolism and Excretion

The renal excretion of unchanged glucocorticoids is only 1-20%. The liver is the principal site of glucocorticoid catabolism and methylprednisolone can be metabolized in many other tissues, including the placenta.

Subjects with hepatic insufficiency

Although the rate of hepatic inactivation of glucocorticoids is depressed in liver disease, the metabolism of corticosteroids is not significantly altered, and dose adjustments are not necessary.

5.3 Preclinical safety data

Administration of corticosteroid to pregnant animals caused foetal damage. Cleft palate, retardation of intrauterine growth, and inhibition of brain growth and development were observed.

List of excipients

Excipients:

Sodium hydroxide

Sodium dihydrogen phosphate dihydrate Disodium hydrogen phosphate anhydrous

6.2 Incompatibilities

In order to avoid compatibility and stability problems, methylprednisolone powder for injection must not be mixed with other medicinal products or diluents except those mentioned in section 6.6 and should be administered on its own through the infusion pump.

6.3 Shelf life

2 years

Chemical and physical in use stability has been demonstrated for 8 hours at 25°C and for 24 hours in a refrigerator at 2-8°C.

From a microbiological point of view once opened, the product may be stored for a maximum of 24 hours at 2-8°C. Other in-use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Keep vial in the original pack in order to protect from light

For precautions for storage following reconstitution see section 6.3.

6.5    Nature and contents of container

Clear glass vial sealed with a rubber stopper, aluminium cap and a white coloured plastic disc.

Pack size: 1, 3 and 10 vials.

Not all pack sizes may be marketed

6.6    Special precautions for disposal

The product should only be used within the expiry period indicated on the packaging material.

Keep out of reach of children!

The injectable solution should be prepared according to the following prescriptions:

Parenteral drug products should wherever possible be visually inspected for particulate matter and discoloration prior to administration.

Dilution should be made using sterile water for injection.

a.) Preparation of the injection: The diluent should be added to the sterile

powder under aseptic conditions.

Reconstitution table

Presentation	Solvent quantity (ml)	Quantity of dissolved product (ml)	Nominal conc. (mg/ml)
40 mg/vial	1	1	40
125 mg/ vial	2	2	62.5
500 mg/ vial	7.8	8	62.5
1000 mg/ vial	15.6	16	62.5

b.) Preparation of infusion solution: Sterile powder should be diluted as described above. The initially prepared solution may be diluted with 5% dextrose in water, isotonic saline solution, or 5% dextrose in 0,9% saline solution. To avoid compatibility problems with other drugs Methylprednisolone should be administered separately, and only with the solutions mentioned above.

Any unused product or waster should be disposed of in accordance with local requirements.

Comments:

Prescription only medicine.

7 MARKETING AUTHORISATION HOLDER

Teva UK Limited,

Brampton Road,

Hampden Park Eastbourne,

BN22 9AG United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/1315

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/09/2011

10 DATE OF REVISION OF THE TEXT

17/07/2012