Murine irritation & redness relief 0.012% w / v eye drops

1. Name Of The Medicinal Product

Murine irritation & redness relief.

2. Qualitative And Quantitative Composition

Naphazoline hydrochloride 0.012 %w/v

Also contains Benzalkonium Chloride

For full list of excipients, see section 6.1

3. Pharmaceutical Form

Eye drops solution (eye drops)

Clear, colourless liquid.

4. Clinical Particulars

4.1 Therapeutic Indications

Redness and minor irritations of the eye caused by, for example, dusty atmosphere, wind, swimming, smoke, air pollutants, and close work.

4.2 Posology And Method Of Administration

Ocular

Adults and children 12 years and over

The recommended dosage is one or two drops into each eye two or three times daily.

Children under 12 years: Not recommended. There is no recorded experience with the product in this age group.

4.3 Contraindications

Glaucoma, corneal damage, acute iritis and other serious eye disease.

Hypersensitivity to any ingredient.

Do not use at the same time as contact lenses. It is generally recommended that a short interval be allowed between the use of Murine and replacement of contact lenses, and that the duration of this 'short interval' should be about 15 minutes.

This product should not be used prior to peripheral iridectomy in eyes susceptible to angle closure because mydriatic action may precipitate angle block.

4.4 Special Warnings And Precautions For Use

Murine should not be used if there is an eye condition characterised by continued redness, pain or blurring of vision.

Murine should not be used if there is raised pressure inside the eyeball (glaucoma), damage to the corneas, inflammation of the iris (acute iritis) or any other serious eye disease.

If there is any eye pain, vision changes, continued redness or irritation of the eye, or if the condition worsens or persists for more than 24 hours, use of the product should be discontinued and the doctor or pharmacist should be informed.

Discontinue use prior to use of anaesthetics which sensitise the myocardium to sympathomimetics (e.g. cyclopropane, halothane).

As with other symptathomimetics, use with caution in the presence of hypertension, diabetes, hyperthyroidism, cardiovascular abnormalities and arteriosclerosis.

Contains benzalkonium chloride which may cause eye irritation. Avoid contact with soft contact lenses, remove contact lenses prior to application and wait at least 15 minutes before re-insertion; known to discolour soft contact lenses.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Currently there is no information regarding the use of Murine and the absorption of concomitant ocular products. However, patients should be advised to leave a short interval between the administration of Murine and other ocular products. It is generally recommended that this interval should be of about 15 minutes duration.

4.6 Pregnancy And Lactation

No special precautions.

4.7 Effects On Ability To Drive And Use Machines

Do not drive or operate machinery if vision is blurred.

4.8 Undesirable Effects

May cause slight dilation of pupil.

4.9 Overdose

Overdose or accidental administration by mouth may cause depression of CNS, reduction of body temperature, bradycardia, sweating, drowsiness and coma, particularly in children. Hypertension may be followed by rebound hypotension. In addition, overdosage may cause increased redness of the eye. Treatment of side-effects is symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: S01GA01

Naphazoline is a sympathomimetic agent with marked alpha-adrenergic activity. It is a vasoconstrictor with a rapid and prolonged action in reducing swelling and congestion when applied to mucous membranes.

5.2 Pharmacokinetic Properties

Absorbed following instillation into conjunctival sacs.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Benzalkonium chloride, boric acid (E284), borax (E285), purified water and disodium edetate.

6.2 Incompatibilities

None known

6.3 Shelf Life

Unopened: 24 months

Opened: 1 month

6.4 Special Precautions For Storage

Do not store above 25°C. Do not refrigerate or freeze.

6.5 Nature And Contents Of Container

10 ml of liquid in a plastic bottle, drop-forming plug and cap.

6.6 Special Precautions For Disposal And Other Handling

Do not use if the solution changes colour or becomes cloudy.

7. Marketing Authorisation Holder

Prestige Brands (UK) Limited

3 Scotlands Drive

Farnham Common

Slough

Berkshire SL2 3ES

United Kingdom

8. Marketing Authorisation Number(S)

PL18259/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

15 October 2003

10. Date Of Revision Of The Text

5^th May 2010

11 DOSIMETRY (IF APPLICABLE)

Not applicable

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Not applicable

Recent History:

5^th May 2010 – 0034 - Type IB Az Group – Sections 2, 3, 4.2, 5.1

31^st March 2010 – 0033 - Type IB A.2.b – Section 1

Mysoline 250mg Tablets

1. Name Of The Medicinal Product

'Mysoline'

2. Qualitative And Quantitative Composition

Primidone Ph. Eur. 250 mg

3. Pharmaceutical Form

White uncoated oral tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

'Mysoline' is indicated in the management of grand mal and psychomotor (temporal lobe) epilepsy. It is also of value in the management of focal or Jacksonian seizures, myoclonic jerks and akinetic attacks.

Management of essential tremor.

4.2 Posology And Method Of Administration

Epilepsy: Treatment must always be planned on an individual basis. In many patients it will be possible to use 'Mysoline' alone, but in some, 'Mysoline' will need to be combined with other anticonvulsants or with supporting therapy.

'Mysoline' is usually given twice daily. Begin with 125 mg once daily late in the evening. Every 3 days increase the daily dosage by 125 mg until the patient is receiving 500 mg daily. Thereafter, every 3 days increase the daily dosage by 250 mg in adults or 125 mg in children under 9 years - until control is obtained or the maximum tolerated dosage is being given. This may be as much as 1.5 g a day in adults; 1 g a day in children.

Average daily maintenance doses:

	Tablets (250mg)	Milligrams
Adults and children over 9 years	3 to 6	750 to 1500
Children 6 to 9 years	3 to 4	750 to 1000
Children 2 to 5 years	2 to 3	500 to 750
Children up to 2 years	1 to 2	250 to 500

The total daily dose is usually best divided and given in two equal amounts, one in the morning and the other in the evening. In certain patients, it may be considered advisable to give a larger dose when the seizures are more frequent. For instance: 1) if the attacks are nocturnal then all or most of the day's dose may be given in the evening; 2) if the attacks are associated with some particular event such as menstruation, a slight increase in the appropriate dose is often beneficial.

Elderly patients: It is advisable to monitor elderly patients with reduced renal function who are receiving primidone.

Patients on other anticonvulsants: Where a patient's attacks are not sufficiently well controlled with other anticonvulsants, or disturbing side effects have arisen, 'Mysoline' may be used to augment or replace existing treatment. First add 'Mysoline' to the current anticonvulsant treatment by the method of gradual introduction described previously. When a worthwhile effect has been achieved and the amount of 'Mysoline' being given has been built up to at least half the estimated requirement, withdrawal of the previous treatment can then be attempted. This should be done gradually over a period of 2 weeks, during which time it may be necessary to increase the 'Mysoline' dosage to maintain control.

Withdrawal of previous treatment should not be too rapid or status epilepticus may occur. Where phenobarbitone formed the major part of the previous treatment, however, both its withdrawal and 'Mysoline' substitution should be made earlier, so as to prevent excessive drowsiness from interfering with accurate assessment of the optimum dosage of 'Mysoline'.

Essential tremor: Initially a dose of 50 mg daily should be introduced using 'Mysoline' Suspension. The daily dose should be increased gradually over a 2 to 3 week period until remission of symptoms or the highest dose tolerated up to a maximum of 750 mg daily.

Patients with essential tremor who have not previously been exposed to anticonvulsants, or other drugs known to induce increased hepatic enzyme activity, may experience acute symptoms of tolerance to 'Mysoline', frequently characterised by vertigo, unsteadiness and nausea. It is, therefore, essential to start such patients at a low dosage (initially 50 mg daily) increasing very slowly up to the maximum tolerated dose or that which produces remission of tremor (up to 750mg daily).

4.3 Contraindications

Patients who exhibit hypersensitivity or an allergic reaction to primidone, to a constituent of the formulation or to phenobarbitone, should not receive the drug. Primidone should not be administered to patients with acute intermittent porphyria.

4.4 Special Warnings And Precautions For Use

'Mysoline' should be given with caution and may be required in reduced dosage in children, the elderly, debilitated patients or those with impaired renal, hepatic or respiratory function.

Primidone is a potent CNS depressant and is partially metabolised to phenobarbitone. After prolonged administration there is a potential for tolerance, dependence and a withdrawal reaction on abrupt cessation of treatment.

Exceptionally, as with phenytoin and phenobarbitone, megaloblastic anaemia may develop requiring discontinuation of primidone. This condition may respond to treatment with folic acid and/or vitamin B12. There have been isolated reports of other blood dyscrasias.

Mysoline has the potential to harm the foetus, see section 4.6 before considering use during pregnancy.

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for primidone.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Both primidone and its major metabolite phenobarbitone are metabolized by, and also induce, liver enzyme activity, principally the CYP 450 3A4 enzyme system..

Agents which inhibit the CYP 450 3A4 enzyme system, such as chloramphenicol, felbamate, nelfinavir*, metronidazole and sodium valproate may result in increased plasma levels of concomitantly administered primidone and its metabolite phenobarbitone.

In addition, St. John's Wort* induces the CYP450 enzyme system and may result in a reduction of plasma levels of concomitantly administered primidone and of its major metabolite phenobarbitone.

Theophylline protein binding may affect phenobarbitone binding, affecting free phenobarbitone levels.

Mysoline therapy may also lead to altered pharmacokinetics in concomitantly administered drugs, whose metabolism may be increased and lead to lowered plasma levels and/or a shorter half-life. These drugs include androgens*, beta-antagonists, carbamazepine, cyclosporin, cloazepine, chloramphenicol, corticosteroids/glucocorticosteroids, cyclophosphamide, dicoumarins, digitoxin*, doxycycline, ethosuxamide, etoposide, felbamate, granisetron, lamotrigine, losartan, methadone*, metronidazole, mainserin, montelukast*, nelfinavir*, nimodipine, oral-contraceptives, oxcarbazepine, phenytoin, quinidine, rocuronium, sodium valproate, tiagabine, theophyllines, topiramate, tricyclic antidepressants, vecuronium, warfarin and zonisamide.

Mysoline inhibits the glucoronidation of paracetamol* and may increase the hepatotoxicity of paracetamol.

The CNS depressant effect of Mysoline is additive to those of other CNS depressants such as alcohol, opiates and barbiturates.

The above interactions are potentially clinically significant.

* No formal interaction studies have been performed. The inclusion of the drug is based on reports of their influence or dependence upon enzyme systems influenced by, or of relevance to the metabolic pathways of primidone or its major metabolite, phenobarbitone.

4.6 Pregnancy And Lactation

Pregnancy: Primidone is suspected to have caused serious birth defects when administered during pregnancy. In infants born of epileptic mothers treated with primidone, there have been reports of congenital abnormalities including congenital heart disease, cleft palate and conditions associated with maternal folate deficiency, including spina bifida, microencephaly and anencephaly. Mysoline should not be used during pregnancy unless clearly necessary to manage epilepsy in the mother where withdrawal of therapy may cause risks or where alternative anti-epileptic managements are unsuitable.

Withdrawal symptoms may occur in the newly born whose mothers have received 'Mysoline' during late pregnancy.

Long-term anticonvulsant therapy can be associated with decreased serum folate levels. As folic acid requirements are also increased during pregnancy, regular screening of patients at risk is advised, and treatment with folic acid and Vitamin B12, although controversial, should be considered.

Anticonvulsant therapy in pregnancy has occasionally been associated with coagulation disorders in the neonates. For this reason pregnant patients should be given Vitamin K1 through the last month of pregnancy up to the time of delivery. In the absence of such pretreatment, 10 mg Vitamin K1 may be given to the mother at the time of delivery and 1 mg should be given immediately to the neonate at risk.

Lactation: During breast feeding the baby should be monitored for sedation.

4.7 Effects On Ability To Drive And Use Machines

As with most other anticonvulsants, patients who drive vehicles or operate machinery should be made aware of the possibility of impaired reaction time.

4.8 Undesirable Effects

If adverse effects do appear, the most common side effects are drowsiness and listlessness but these generally occur only in the beginning of treatment.

Visual disturbances, nausea, headache, dizziness, vomiting, nystagmus and ataxia have been reported but are usually transient even when pronounced. On occasions an idiosyncratic reaction may occur which involves these symptoms in an acute and severe form necessitating withdrawal of treatment.

Common ( >1/100)	General	Drowsiness
	Central and peripheral nervous system	Listlessness, ataxia, visual disturbances, nystagmus
	Gastrointestinal	Nausea
Less common (1/100 - 1/1000)	General	Headache, dizziness
	Gastrointestinal	Vomiting
	Dermatological	Allergic reactions particularly affecting the skin can include maculopapular, morbilliform or scarlatiniform rashes.
Rare (< 1/1000)	Central and peripheral nervous system	Personality changes, which may include psychotic reactions.
	Haematological	Megaloblastic anaemia, blood dyscrasias
	Hepatic	Elevations in hepatic enzymes, including gamma-glutamyl transferase (gamma GT) and alkaline phosphatase.
	Musculoskeletal	Arthralgia, osteomalacia.   As with phenobarbitone, Dupuytren's contracture has been reported
	Dermatological	Severe reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis and lupus erythematosus.

Vitamin D supplementation may be needed during long-term Mysoline therapy, since vitamin D catabolism may be increased.

Exceptionally, as with phenytoin and phenobarbitone, megaloblastic anaemia may develop requiring discontinuation of primidone. This condition may respond to treatment with folic acid and/or Vitamin B12.

4.9 Overdose

Primidone is metabolised extensively to phenobarbitone and overdosage leads to varying degrees of CNS depression which, depending on the dose ingested, may include ataxia, loss of consciousness, respiratory depression and coma.

Crystalluria may occur in overdosage and could be used as a helpful diagnostic aid where primidone overdosage is suspected.

Depending on the severity of intoxication, therapy should include aspiration of stomach contents, administration of activated charcoal, administration of intravenous fluids, forced alkaline diuresis (striving for a urine pH of 8.0), and general supportive measures. In more life threatening circumstances, haemoperfusion (if the patient is hypotensive) or haemodialysis are effective.

There is no specific antidote.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The activity of 'Mysoline' is due to the anticonvulsant properties of three active moieties, namely primidone itself and its two major metabolites phenobarbitone and phenylethylmalonamide. The relative contribution of these three moieties to the clinical anticonvulsant effect has not been firmly established. Although the precise mode of action of 'Mysoline' is unknown, in common with other anticonvulsants, effects on the neuronal membrane particularly with respect to alteration of ionic fluxes are likely to play a fundamental role.

'Mysoline', as with other anticonvulsants, can induce liver enzymes.

5.2 Pharmacokinetic Properties

'Mysoline' is absorbed rapidly from the gastrointestinal tract, peak plasma levels being attained approximately 3 hours after ingestion. Primidone is well distributed in all organs and tissues: it crosses the blood-brain and placental barriers and is excreted in breast milk. The pharmacokinetics of primidone are complex because of biotransformation into two metabolites, phenobarbitone and phenylethylmalonamide, that have anticonvulsant activity and complex pharmacokinetic properties. Primidone has a plasma half-life of approximately 10 hours which is considerably shorter than those of its principal metabolites.

Primidone and phenylethylmalonamide are bound to plasma proteins to only a small extent, whereas approximately half of phenobarbitone is bound. Approximately 40% of the drug is excreted unchanged in urine.

5.3 Preclinical Safety Data

Primidone is a drug on which extensive clinical experience has been obtained. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Carmellose calcium Ph. Eur.

Gelatin Ph. Eur.

Magnesium stearate Ph. Eur.

Povidone Ph. Eur.

Purified water Ph. Eur.

Stearic acid Ph. Eur.

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

HDPE bottle (100 tablets).

6.6 Special Precautions For Disposal And Other Handling

To be taken as directed by the prescriber.

7. Marketing Authorisation Holder

Acorus Therapeutics Limited

Office Village

Chester Business Park

Chester

Cheshire

CH4 9QZ.

UK

8. Marketing Authorisation Number(S)

PL 20132/0005

9. Date Of First Authorisation/Renewal Of The Authorisation

14 August 2004

10. Date Of Revision Of The Text

April 2009

11 DOSIMETRY (IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Mydrilate 1.0% Eye Drops

1. Name Of The Medicinal Product

Mydrilate 1.0 % Eye Drops

2. Qualitative And Quantitative Composition

Cyclopentolate Hydrochloride BP 1.0 % w/v.

3. Pharmaceutical Form

Eye drops.

4. Clinical Particulars

4.1 Therapeutic Indications

(i) Diagnostic purposes for fundoscopy and cycloplegic refraction.

(ii) Dilating the pupil in inflammatory conditions of the iris and uveal tract.

4.2 Posology And Method Of Administration

(i) Refraction / Fundoscopy

Adults (and the elderly):

One drop of 0.5 % solution instilled into the eye, repeated after 15 minutes if necessary, approximately 40 minutes before examination.

Deeply pigmented eyes may require the use of a 1 % solution.

NB: Maximum effect is reached after 30-60 minutes.

Children 6-16 years:

One drop of 1 % solution instilled into the eye, repeated after 15 minutes if necessary, approximately 40 minutes before examination.

Children under 6 years:

One or two drops of 1 % solution instilled into the eye, repeated after 15 minutes if necessary, approximately 40 minutes before examination.

(ii) For Uveitis, Iritis and Iridocyclitis:

Adults and the elderly:

One or two drops of 0.5 % solution instilled into the eye up to 4 times daily or as required.

Deeply pigmented eyes may require the use of a 1 % solution.

Children:

At the discretion of the physician

Do not use during the first three months of life due to possible association between the cycloplegia produced and the development of amblyopia and also the increased risks of systemic toxicity in neonates.

Cycloplegia following administration is quick in onset and short-lived. Maximal cycloplegia is achieved within 15 - 45 minutes of instillation and lasts on average about 20 minutes. Recovery normally takes place in about 4 hours, but very occasionally some effect persists for up to 24 hours.

Mydriasis is produced very rapidly and an average pupil diameter of 7 mm is usually reached 15 - 30 minutes after instillation of one drop of 0.5 % solution. Complete recovery from the mydriatic effect generally occurs spontaneously in not more than 20 hours.

No specific information on the use of this product in the elderly is available. Clinical trials have included patients over 65 years and no adverse reactions specific to this age group have been reported.

4.3 Contraindications

(i) Use in narrow-angle glaucoma or those with a tendency towards glaucoma e.g. patients with a shallow anterior chamber.

(ii) Hypersensitivity to cyclopentolate hydrochloride, benzalkonium chloride or any other components of the formulation.

(iii) This preparation contains benzalkonium chloride and should not be used whilst soft contact lenses are being worn.

(iv) Use in patients with paralytic ileus.

(v) Use in children with organic brain syndromes, including congenital or neuro-developmental abnormalities, particularly those predisposing to epileptic seizures.

4.4 Special Warnings And Precautions For Use

Because of the risk of precipitating angle-closure glaucoma in the elderly and others prone to raised intraocular pressure, an estimate of the depth of the anterior chamber should be made before use, particularly if therapy is likely to be intense or protracted.

Caution should be observed when drugs of this group are administered to patients with prostatic enlargement, coronary insufficiency or cardiac failure, or ataxia. Atropine-like effects have been reported as side-effects.

Extreme caution is advised for use in children and individuals susceptible to belladonna alkaloids because of the increased risk of systemic toxicity.

Patients should be warned of the oral toxicity of this preparation, and advised to wash their hands after use. If accidentally swallowed, patients should be advised to seek medical attention.

Use with caution in an inflamed eye as the hyperaemia greatly increases the rate of systemic absorption through the conjunctiva.

To reduce systemic absorption the lacrimal sac should be compressed at the medial canthus by digital pressure for at least two minutes after instillation of the drops.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The effects of anti-muscarinic agents may be enhanced by the concomitant administration of other drugs with anti-muscarinic properties such as some antihistamines, butyrophenones, phenothiazines, tricyclic antidepressants and amantadine.

4.6 Pregnancy And Lactation

There is insufficient evidence as to drug safety in pregnancy and lactation. This product should not be used during pregnancy unless it is considered essential by a physician.

4.7 Effects On Ability To Drive And Use Machines

May cause blurred vision, difficulty in focusing and sensitivity to light. Patients should be warned not to drive or engage in other hazardous activities (including climbing ladders and scaffolding) unless vision is clear. Complete recovery from the effects of Mydrilate Eye Drops may take up to 24 hours.

4.8 Undesirable Effects

(i) Local:

Increased intraocular pressure, transient stinging, and sensitivity to light secondary to pupillary dilation. Prolonged administration may lead to local irritation, hyperaemia, oedema and conjunctivitis.

(ii) Systemic:

Systemic anticholinergic toxicity is manifested by dryness of the mouth, flushing, dryness of the skin, bradycardia followed by tachycardia with palpitations and arrhythmias, urinary urgency, difficulty and retention, reduction in the tone and motility of the gastrointestinal tract leading to constipation.

(iii) Vomiting, giddiness and staggering may occur, a rash may be present in children, abdominal distension in infants. Psychotic reactions, behavioural disturbances and cardio-respiratory collapse may occur in children.

4.9 Overdose

Systemic toxicity may occur following topical use, particularly in children. It is manifested by flushing and dryness of the skin (a rash may be present in children), blurred vision, a rapid and irregular pulse, fever, abdominal distension in infants, convulsions and hallucinations and the loss of neuromuscular co-ordination.

Treatment is supportive (there is no evidence that physostigmine is superior to supportive management). In infants and small children the body surface must be kept moist. If accidentally ingested, induce emesis or perform gastric lavage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Cyclopentolate is an anti-muscarinic agent used topically in the eye as a mydriatic and cycloplegic. The effects are similar to those of atropine, but with a more rapid onset and a shorter duration of action.

5.2 Pharmacokinetic Properties

None stated.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Boric acid

Potassium chloride

Benzalkonium chloride solution

Purified water.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store at 2-8^oC. Refrigerate, do not freeze. Protect from light. Do not dilute or dispense from any container other than the original bottle. Discard one month after opening.

6.5 Nature And Contents Of Container

5 ml dropper bottle of 1.0 % solution.

Bottle:	LE 6601 PH (LDPE) Natural colour
Cap:	Melochem White colour

6.6 Special Precautions For Disposal And Other Handling

When using the product for the first time, screw down the cap firmly on the bottle to pierce the seal at the tip of the plastic nozzle and unscrew the cap for use.

7. Marketing Authorisation Holder

Intrapharm Laboratories Ltd

60 Boughton Lane

Maidstone

Kent

ME15 9QS

United Kingdom

8. Marketing Authorisation Number(S)

PL 17509/0008

9. Date Of First Authorisation/Renewal Of The Authorisation

8 August 2001

10. Date Of Revision Of The Text

June 2003

11. Legal category

POM

MIRAPEXIN 3.15 mg prolonged-release tablets

1. Name Of The Medicinal Product

MIRAPEXIN 3.15 mg prolonged-release tablets

2. Qualitative And Quantitative Composition

Each prolonged-release tablet contains 4.5 mg pramipexole dihydrochloride monohydrate equivalent to 3.15 mg pramipexole.

Please note:

Pramipexole doses as published in the literature refer to the salt form.

Therefore, doses will be expressed in terms of both pramipexole base and pramipexole salt (in brackets).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged-release tablet.

The tablets are white to off-white, of oval shape, and have a code embossed (one side with the code P5, and one side with the Boehringer Ingelheim company symbol).

4. Clinical Particulars

4.1 Therapeutic Indications

MIRAPEXIN is indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or “on off” fluctuations).

4.2 Posology And Method Of Administration

Posology

MIRAPEXIN prolonged-release tablets are a once-a-day oral formulation of pramipexole.

Initial treatment

Doses should be increased gradually from a starting dose of 0.26 mg of base (0.375 mg of salt) per day and then increased every 5 - 7 days. Providing patients do not experience intolerable undesirable effects, the dose should be titrated to achieve a maximal therapeutic effect.

Ascending dose schedule of MIRAPEXIN prolonged-release tablets
Week	Daily dose (mg of base)	Daily dose (mg of salt)
1	0.26	0.375
2	0.52	0.75
3	1.05	1.5

If a further dose increase is necessary the daily dose should be increased by 0.52 mg of base (0.75 mg of salt) at weekly intervals up to a maximum dose of 3.15 mg of base (4.5 mg of salt) per day. However, it should be noted that the incidence of somnolence is increased at doses higher than 1.05 mg of base (1.5 mg of salt) per day (see section 4.8).

Patients already taking MIRAPEXIN tablets may be switched to MIRAPEXIN prolonged-release tablets overnight, at the same daily dose. After switching to MIRAPEXIN prolonged-release tablets, the dose may be adjusted depending on the patient's therapeutic response (see section 5.1).

Maintenance treatment

The individual dose of pramipexole should be in the range of 0.26 mg of base (0.375 mg of salt) to a maximum of 3.15 mg of base (4.5 mg of salt) per day. During dose escalation in pivotal studies, efficacy was observed starting at a daily dose of 1.05 mg of base (1.5 mg of salt). Further dose adjustments should be done based on the clinical response and the occurrence of adverse reactions. In clinical trials approximately 5% of patients were treated at doses below 1.05 mg of base (1.5 mg of salt). In advanced Parkinson's disease, pramipexole doses higher than 1.05 mg of base (1.5 mg of salt) per day can be useful in patients where a reduction of the levodopa therapy is intended. It is recommended that the dose of levodopa is reduced during both the dose escalation and the maintenance treatment with MIRAPEXIN, depending on reactions in individual patients (see section 4.5).

Missed dose

When the intake of a dose is missed, MIRAPEXIN prolonged-release tablets should be taken within 12 hours after the regularly scheduled time. After 12 hours, the missed dose should be left out and the next dose should be taken on the following day at the next regularly scheduled time.

Treatment discontinuation

Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome. Pramipexole should be tapered off at a rate of 0.52 mg of base (0.75 mg of salt) per day until the daily dose has been reduced to 0.52 mg of base (0.75 mg of salt). Thereafter the dose should be reduced by 0.26 mg of base (0.375 mg of salt) per day (see section 4.4).

Dosing in patients with renal impairment

The elimination of pramipexole is dependent on renal function. The following dose schedule is suggested:

Patients with a creatinine clearance above 50 ml/min require no reduction in daily dose or dosing frequency.

In patients with a creatinine clearance between 30 and 50 ml/min, treatment should be started with 0.26 mg MIRAPEXIN prolonged-release tablets every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week. If a further dose increase is necessary, doses should be increased by 0.26 mg pramipexole base at weekly intervals up to a maximum dose of 1.57 mg pramipexole base (2.25 mg of salt) per day.

The treatment of patients with a creatinine clearance below 30 ml/min with MIRAPEXIN prolonged-release tablets is not recommended as no data are available for this patient population. The use of MIRAPEXIN tablets should be considered.

If renal function declines during maintenance therapy, the recommendations given above should be followed.

Dosing in patients with hepatic impairment

Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbed active substance is excreted through the kidneys. However, the potential influence of hepatic insufficiency on MIRAPEXIN pharmacokinetics has not been investigated.

Paediatric population

The safety and efficacy of MIRAPEXIN in children below 18 years has not been established. There is no relevant use of MIRAPEXIN prolonged-release tablets in the paediatric population in Parkinson's Disease.

Method of administration

The tablets should be swallowed whole with water, and must not be chewed, divided or crushed. The tablets may be taken either with or without food and should be taken each day at about the same time.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

When prescribing MIRAPEXIN in a patient with Parkinson's disease with renal impairment a reduced dose is suggested in line with section 4.2.

Hallucinations

Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients should be informed that (mostly visual) hallucinations can occur.

Dyskinesia

In advanced Parkinson's disease, in combination treatment with levodopa, dyskinesia can occur during the initial titration of MIRAPEXIN. If they occur, the dose of levodopa should be decreased.

Sudden onset of sleep and somnolence

Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported uncommonly. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with MIRAPEXIN. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction of the dose or termination of therapy may be considered. Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products or alcohol in combination with pramipexole (see sections 4.5, 4.7 and section 4.8).

Impulse control disorders and compulsive behaviours

Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson's disease, including MIRAPEXIN. Furthermore, patients and caregivers should be aware of the fact that other behavioural symptoms of impulse control disorders and compulsions such as binge eating and compulsive shopping can occur. Dose reduction/tapered discontinuation should be considered.

Patients with psychotic disorders

Patients with psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks. Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see section 4.5).

Ophthalmologic monitoring

Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.

Severe cardiovascular disease

In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the general risk of postural hypotension associated with dopaminergic therapy.

Neuroleptic malignant syndrome

Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy (see section 4.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Plasma protein binding

Pramipexole is bound to plasma proteins to a very low (< 20%) extent, and little biotransformation is seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by biotransformation, the potential for an interaction is limited, although an interaction with anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and levodopa.

Inhibitors/competitors of active renal elimination pathway

Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine and procainamide, may interact with pramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose should be considered when these medicinal products are administered concomitantly with MIRAPEXIN.

Combination with levodopa

When MIRAPEXIN is given in combination with levodopa, it is recommended that the dose of levodopa is reduced and the dose of other anti-parkinsonian medicinal products is kept constant while increasing the dose of MIRAPEXIN.

Because of possible additive effects, caution should be advised when patients are taking other sedating medicinal products or alcohol in combination with pramipexole (see sections 4.4, 4.7 and 4.8).

Antipsychotic medicinal products

Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see section 4.4), e.g. if antagonistic effects can be expected.

4.6 Pregnancy And Lactation

Pregnancy

The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3). MIRAPEXIN should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected. The excretion of pramipexole into breast milk has not been studied in women. In rats, the concentration of active substance-related radioactivity was higher in breast milk than in plasma.

In the absence of human data, MIRAPEXIN should not be used during breast-feeding. However, if its use is unavoidable, breast-feeding should be discontinued.

Fertility

No studies on the effect on human fertility have been conducted. In animal studies, pramipexole affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However, these studies did not indicate direct or indirect harmful effects with respect to male fertility.

4.7 Effects On Ability To Drive And Use Machines

MIRAPEXIN can have a major influence on the ability to drive and use machines.

Hallucinations or somnolence can occur.

Patients being treated with MIRAPEXIN and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see also sections 4.4, 4.5 and 4.8).

4.8 Undesirable Effects

Expected adverse reactions

The following adverse reactions are expected under the use of MIRAPEXIN: abnormal dreams, amnesia, behavioural symptoms of impulse control disorders and compulsions such as binge eating, compulsive shopping, hypersexuality and pathological gambling; cardiac failure, confusion, constipation, delusion, dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia, hypotension, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus, rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual impairment including diplopia, vision blurred and visual acuity reduced, vomiting, weight decrease including decreased appetite, weight increase.

Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,778 Parkinson's disease patients on pramipexole and 1,297 patients on placebo, adverse drug reactions were frequently reported for both groups. 67% of patients on pramipexole and 54% of patients on placebo reported at least one adverse drug reaction.

The adverse drug reactions reported in the table below are those events that occurred in 0.1% or more of patients treated with pramipexole and were reported significantly more often in patients taking pramipexole than placebo, or where the event was considered clinically relevant. The majority of adverse drug reactions were mild to moderate, they usually start early in therapy and most tended to disappear even as therapy was continued.

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (

The most commonly (

System Organ Class	Adverse Drug Reaction
Infections and infestations
Uncommon	pneumonia
Psychiatric disorders
Common	abnormal dreams, behavioural symptoms of impulse control disorders and compulsions; confusion, hallucinations, insomnia
Uncommon	binge eating1, compulsive shopping, delusion, hyperphagia1, hypersexuality, libido disorder, paranoia, pathological gambling, restlessness
Nervous system disorders
Very common	dizziness, dyskinesia, somnolence
Common	headache
Uncommon	amnesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Common	visual impairment including diplopia, vision blurred and visual acuity reduced
Cardiac disorders
Uncommon	cardiac failure1
Vascular disorders
Common	hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon	dyspnoea, hiccups
Gastrointestinal disorders
Very common	nausea
Common	constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon	hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common	fatigue, peripheral oedema
Investigations
Common	weight decrease including decreased appetite
Uncommon	weight increase

¹This side effect has been observed in post-marketing experience. With 95 % certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 2,762 patients with Parkinson's Disease treated with pramipexole.

Somnolence

Pramipexole is commonly associated with somnolence and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes (see also section 4.4).

Libido disorders

Pramipexole may uncommonly be associated with libido disorders (increased or decreased).

Impulse control disorders and compulsive behaviours

Patients treated with dopamine agonists for Parkinson's disease, including MIRAPEXIN, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation. See also section 4.4.

In a cross-sectional, retrospective screening and case-control study including 3,090 Parkinson's disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had symptoms of an impulse control disorder during the past six months. Manifestations observed include pathological gambling, compulsive shopping, binge eating, and compulsive sexual behaviour (hypersexuality). Possible independent risk factors for impulse control disorders included dopaminergic treatments and higher doses of dopaminergic treatment, younger age (

Cardiac failure

In clinical studies and post-marketing experience cardiac failure has been reported in patients with pramipexole. In a pharmacoepidemiological study pramipexole use was associated with an increased risk of cardiac failure compared with non-use of pramipexole (observed risk ratio 1.86; 95% CI, 1.21-2.85).

4.9 Overdose

There is no clinical experience with massive overdose. The expected adverse reactions would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hyperkinesia, hallucinations, agitation and hypotension. There is no established antidote for overdose of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent may be indicated. Management of the overdose may require general supportive measures, along with gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram monitoring.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists, ATC code: N04BC05.

Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily of dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsic activity.

Pramipexole alleviates parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and turnover.

In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with healthy volunteers, where MIRAPEXIN prolonged-release tablets were titrated faster (every 3 days) than recommended up to 3.15 mg pramipexole base (4.5 mg of salt) per day, an increase in blood pressure and heart rate was observed. Such effect was not observed in patient studies.

In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson's disease. Placebo-controlled clinical trials included approximately 1,800 patients of Hoehn and Yahr stages I – V treated with pramipexole. Out of these, approximately 1,000 were in more advanced stages, received concomitant levodopa therapy, and suffered from motor complications.

In early and advanced Parkinson's disease, efficacy of pramipexole in controlled clinical trials was maintained for approximately six months. In open continuation trials lasting for more than three years there were no signs of decreasing efficacy.

In a controlled double blind clinical trial of 2 year duration, initial treatment with pramipexole significantly delayed the onset of motor complications, and reduced their occurrence compared to initial treatment with levodopa. This delay in motor complications with pramipexole should be balanced against a greater improvement in motor function with levodopa (as measured by the mean change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally higher in the escalation phase with the pramipexole group. However, there was no significant difference during the maintenance phase. These points should be considered when initiating pramipexole treatment in patients with Parkinson's disease.

The safety and efficacy of MIRAPEXIN prolonged-release tablets in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of three randomised, controlled trials. Two trials were conducted in patients with early Parkinson's disease and one trial was conducted in patients with advanced Parkinson's disease.

Superiority of MIRAPEXIN prolonged-release tablets over placebo was demonstrated after 18 weeks of treatment on both the primary (UPDRS Parts II+III score) and the key secondary (CGI-I and PGI-I responder rates) efficacy endpoints in a double-blind placebo-controlled trial including a total of 539 patients with early Parkinson's disease. Maintenance of efficacy was shown in patients treated for 33 weeks. MIRAPEXIN prolonged-release tablets were non-inferior to pramipexole immediate release tablets as assessed on the UPDRS Parts II+III score at week 33.

In a double-blind placebo-controlled trial including a total of 517 patients with advanced Parkinson's disease who were on concomitant levodopa therapy superiority of MIRAPEXIN prolonged-release tablets over placebo was demonstrated after 18 weeks of treatment on both the primary (UPDRS Parts II+III score) and the key secondary (off-time) efficacy endpoints.

The efficacy and tolerability of an overnight switch from MIRAPEXIN tablets to MIRAPEXIN prolonged-release tablets at the same daily dose were evaluated in a double-blind clinical study in patients with early Parkinson's disease.

Efficacy was maintained in 87 of 103 patients switched to MIRAPEXIN prolonged-release tablets. Out of these 87 patients, 82.8% did not change their dose, 13.8% increased and 3.4% decreased their dose.

In half of the 16 patients who did not meet the criterion for maintained efficacy on UPDRS Part II+III score, the change from baseline was considered not clinically relevant.

Only one patient switched to MIRAPEXIN prolonged-release tablets experienced a drug-related adverse event leading to withdrawal.

The European Medicines Agency has waived the obligation to submit the results of studies with MIRAPEXIN in all subsets of the paediatric population in Parkinson's Disease (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic Properties

Pramipexole is completely absorbed following oral administration. The absolute bioavailability is greater than 90%.

In a Phase I trial, where pramipexole immediate release and prolonged-release tablets were assessed in fasted state, the minimum and peak plasma concentration (C_min, C_max) and exposure (AUC) of the same daily dose of MIRAPEXIN prolonged-release tablets given once daily and MIRAPEXIN tablets given three times a day were equivalent.

The once daily administration of MIRAPEXIN prolonged-release tablets causes less frequent fluctuations in the pramipexole plasma concentration over 24 hours compared to the three times daily administration of pramipexole immediate release tablets.

The maximum plasma concentrations occur at about 6 hours after administration of MIRAPEXIN prolonged-release tablets once daily. Steady state of exposure is reached at the latest after 5 days of continuous dosing.

Concomitant administration with food does generally not affect the bioavailability of pramipexole. Intake of a high fat meal induced an increase in peak concentration (C_max) of about 24% after a single dose administration and about 20% after multiple dose administrations and a delay of about 2 hours in time to reach peak concentration in healthy volunteers. Total exposure (AUC) was not affected by concomitant food intake. The increase in C_max is not considered clinically relevant. In the Phase III studies that established safety and efficacy of MIRAPEXIN prolonged-release tablets, patients were instructed to take study medication without regard to food intake.

While body weight has no impact on the AUC, it was found to influence the volume of distribution and therefore the peak concentrations C_max. A decreased body weight by 30 kg results in an increase in C_max of 45%. However, in Phase III trials in Parkinson's disease patients no clinically meaningful influence of body weight on the therapeutic effect and tolerability of MIRAPEXIN prolonged-release tablets was detected.

Pramipexole shows linear kinetics and a small inter-patient variation of plasma levels. In humans, the protein binding of pramipexole is very low (< 20%) and the volume of distribution is large (400 l). High brain tissue concentrations were observed in the rat (approx. 8-fold compared to plasma).

Pramipexole is metabolised in man only to a small extent.

Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of ¹⁴C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately 400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.

5.3 Preclinical Safety Data

Repeated dose toxicity studies showed that pramipexole exerted functional effects, mainly involving the CNS and female reproductive system, and probably resulting from an exaggerated pharmacodynamic effect of pramipexole.

Decreases in diastolic and systolic pressure and heart rate were noted in the minipig, and a tendency to a hypotensive effect was discerned in the monkey.

The potential effects of pramipexole on reproductive function have been investigated in rats and rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at maternally toxic doses. Due to the selection of animal species and the limited parameters investigated, the adverse effects of pramipexole on pregnancy and male fertility have not been fully elucidated.

A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats. The relevance for humans is unknown.

Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding is not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of salt) and higher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was not observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study or in any other species investigated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Hypromellose 2208

Maize starch

Carbomer 941

Colloidal anhydrous silica

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Store in the original package in order to protect from moisture.

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

6.5 Nature And Contents Of Container

OPA/aluminium/PVC-aluminium blisters.

Each blister strip contains 10 prolonged-release tablets.

Cartons containing 1, 3 or 10 blister strips (10, 30 or 100 prolonged-release tablets).

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Boehringer Ingelheim International GmbH

Binger Strasse 173

D-55216 Ingelheim am Rhein

Germany

8. Marketing Authorisation Number(S)

EU/1/97/051/025-027

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 23 February 1998

Date of latest renewal: 23 February 2008

10. Date Of Revision Of The Text

17 June 2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

MYFORTIC gastro-resistant tablets

1. Name Of The Medicinal Product

Myfortic ^® 180 mg gastro-resistant tablets

Myfortic ^® 360 mg gastro-resistant tablets

2. Qualitative And Quantitative Composition

Each gastro-resistant tablet contains 180mg or 360 mg mycophenolic acid (as mycophenolate sodium).

Excipients:

Lactose, anhydrous: 45 mg or 90 mg per tablet.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Gastro-resistant tablet

180mg: Lime green, film-coated round tablet, with bevelled edges and the imprint (debossing) “C” on one side.

360mg: Pale orange red film-coated ovaloid tablet, with imprint (debossing) “CT” on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Myfortic is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adult patients receiving allogeneic renal transplants.

4.2 Posology And Method Of Administration

Treatment with Myfortic should be initiated and maintained by appropriately qualified transplant specialists.

The recommended dose is 720 mg administered twice daily (1,440 mg daily dose). This dose of mycophenolate sodium corresponds to 1 g mycophenolate mofetil administered twice daily (2 g daily dose) in terms of mycophenolic acid (MPA) content.

For additional information about the corresponding therapeutic doses of mycophenolate sodium and mycophenolate mofetil, see sections 4.4 and 5.2.

In de novo patients, Myfortic should be initiated within 72 hours following transplantation.

Myfortic can be taken with or without food. Patients may select either option but must adhere to their selected option (see section 5.2).

In order to retain the integrity of the enteric coating, Myfortic tablets should not be crushed.

Where crushing of Myfortic tablets is necessary, avoid inhalation of the powder or direct contact of the powder with skin or mucous membrane.

Children and adolescents

Insufficient data are available to support the efficacy and safety of Myfortic in children and adolescents. Limited pharmacokinetic data are available for paediatric renal transplant patients (see section 5.2).

Elderly

The recommended dose in elderly patients is 720 mg twice daily.

Patients with renal impairment

In patients experiencing delayed renal graft function post-operatively, no dose adjustments are needed (see section 5.2).

Patients with severe renal impairment (glomerular filtration rate <25 ml·min^-1·1.73 m^-2) should be carefully monitored and the daily dose of Myfortic should not exceed 1,440 mg.

Patients with hepatic impairment

No dose adjustments are needed for renal transplant patients with severe hepatic impairment.

Treatment during rejection episodes

Renal transplant rejection does not lead to changes in mycophenolic acid (MPA) pharmacokinetics; dosage modification or interruption of Myfortic is not required.

4.3 Contraindications

Hypersensitivity to mycophenolate sodium, mycophenolic acid or mycophenolate mofetil or to any of the excipients (see section 6.1).

Myfortic is contraindicated in women who are breastfeeding (see section 4.6).

For information on use in pregnancy and lactation and contraceptive requirements, see section 4.6.

4.4 Special Warnings And Precautions For Use

Patients receiving immunosuppressive regimens involving combinations of drugs, including Myfortic, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.8). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As general advice to minimise the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Patients receiving Myfortic should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.

Patients treated with immunosuppressants, including Myfortic, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Among the opportunistic infections are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives (which include mycophenolate mofetil and mycophenolate sodium) in combination with other immunosuppressants. The mechanism for MPA derivatives induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of therapy. Changes to Myfortic therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection (see Section 4.8).

Patients receiving Myfortic should be monitored for blood disorders (e.g. neutropenia or anemia – see section 4.8), which may be related to MPA itself, concomitant medications, viral infections, or some combination of these causes. Patients taking Myfortic should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If blood disorders occur (e.g. neutropenia with (absolute neutrophil count <1.5 x 10³/µl or anemia) it may be appropriate to interrupt or discontinue Myfortic.

Patients should be advised that during treatment with MPA vaccinations may be less effective and the use of live attenuated vaccines should be avoided (see section 4.5).

Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.

Because MPA derivatives have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration and haemorrhage and perforation, Myfortic should be administered with caution in patients with active serious digestive system disease.

It is recommended that Myfortic not be administered concomitantly with azathioprine because concomitant administration of these drugs has not been evaluated.

Mycophenolic acid (as sodium salt) and mycophenolate mofetil should not be indiscriminately interchanged or substituted because of their different pharmacokinetic profiles.

Myfortic has been administered in combination with corticosteroids and ciclosporin.

There is limited experience with its concomitant use with induction therapies such as anti-lymphocyte globulin or basiliximab. The efficacy and safety of the use of Myfortic with other immunosuppressive agents (for example, tacrolimus) have not been studied.

Myfortic contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The concomitant administration of Myfortic and drugs which interfere with enterohepatic circulation, for example cholestyramine or activated charcoal, may result in sub-therapeutic systemic MPA exposure and reduced efficacy.

Myfortic is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. Therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

Myfortic therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning Myfortic therapy, during therapy and for six weeks following therapy discontinuation (see section 4.6).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The following interactions have been reported between MPA and other medicinal products:

Aciclovir and ganciclovir

The potential for myelosuppression in patients receiving both Myfortic and aciclovir or ganciclovir has not been studied. Increased levels of mycophenolic acid glucuronide (MPAG) and aciclovir/ganciclovir may be expected when aciclovir/ganciclovir and Myfortic are administered concomitantly, possibly as a result of competition for the tubular secretion pathway.

The changes in MPAG pharmacokinetics are unlikely to be of clinical significance in patients with adequate renal function. In the presence of renal impairment, the potential exists for increases in plasma MPAG and aciclovir/ganciclovir concentrations; dose recommendations for aciclovir/ganciclovir should be followed and patients carefully observed.

Gastroprotective agents:

Magnesium-aluminium containing antacids:

MPA AUC and C_max have been shown to decrease by approximately 37% and 25%, respectively, when a single dose of magnesium-aluminium containing antacids is given concomitantly with Myfortic. Magnesium aluminium-containing antacids may be used intermittently for the treatment of occasional dyspepsia. However the chronic, daily use of magnesium-aluminium containing antacids with Myfortic is not recommended due to the potential for decreased mycophenolic acid exposure and reduced efficacy.

Proton pump inhibitors:

In healthy volunteers, no changes in the pharmacokinetics of MPA were observed following concomitant administration of Myfortic and pantoprazole given at 40 mg twice daily during the four previous days. No data are available with other proton pump inhibitors given at high doses.

Oral contraceptives

Interaction studies between MMF and oral contraceptives indicate no interaction. Given the metabolic profile of MPA, no interactions would be expected for Myfortic and oral contraceptives.

Cholestyramine and drugs that bind bile acids

Caution should be used when co-administering drugs or therapies that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to decrease MPA exposure and thus reduce the efficacy of Myfortic.

Ciclosporin

When studied in stable renal transplant patients, ciclosporin pharmacokinetics were unaffected by steady state dosing of Myfortic. When co-administered with mycophenolate mofetil, ciclosporin is known to decrease the exposure of MPA. When co-administered with Myfortic, ciclosporin may decrease the concentration of MPA as well (by approximately 20%, extrapolated from mycophenolate mofetil data), but the exact extent of this decrease is unknown because such an interaction has not been studied. However, as efficacy studies were conducted in combination with ciclosporin, this interaction does not modify the recommended posology of Myfortic. In case of interruption or discontinuation of ciclosporin, Myfortic dosage should be re-evaluated depending on the immunosuppressive regimen.

Tacrolimus

In a calcineurin cross-over study in stable renal transplant patients, steady-state Myfortic pharmacokinetics were measured during both Neoral and tacrolimus treatment. Mean MPA AUC was 19% higher (90% CI: -3, +47), whereas mean MPAG AUC was about 30% lower (90% CI: 16, 42) on tacrolimus compared to Neoral treatment. In addition, MPA AUC intra-subject variability was doubled when switching from Neoral to tacrolimus. Clinicians should note this increase both in MPA AUC and variability, and adjustments to Myfortic dosing should be dictated by the clinical situation. Close clinical monitoring should be performed when a switch from one calcineurin inhibitor to another is planned.

Live attenuated vaccines

Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished.

4.6 Pregnancy And Lactation

Pregnancy

Myfortic therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning Myfortic therapy, during Myfortic therapy and for six weeks after discontinuing therapy. Patients should be instructed to consult their physician immediately should pregnancy occur.

The use of Myfortic is not recommended during pregnancy and should be reserved for cases where no alternative treatment is available.

There is limited data from the use of Myfortic in pregnant women. However, congenital malformations including ear malformations, i.e. abnormally formed or absent external/middle ear, have been reported in children of patients exposed to mycophenolate in combination with other immunosuppressants during pregnancy. Cases of spontaneous abortions have been reported in patients exposed to mycophenolic acid compounds. Studies in animals have shown reproductive toxicity (see section 5.3).

Lactation

MPA is excreted in milk in lactating rats. It is unknown whether Myfortic is excreted in human breast milk. Because of the potential for serious adverse reactions to MPA in breast-fed infants, Myfortic is contra-indicated in women who are breast-feeding (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. The mechanism of action and pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.

4.8 Undesirable Effects

The following undesirable effects cover adverse drug reactions from clinical trials:

Malignancies

Patients receiving immunosuppressive regimens involving combinations of drugs, including MPA, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Lymphoproliferative disease or lymphoma developed in 2 de novo (0.9%) patients and in 2 maintenance patients (1.3%) receiving Myfortic for up to 1 year. Non-melanoma skin carcinomas occurred in 0.9% of de novo and 1.8% of maintenance patients receiving Myfortic for up to 1 year; other types of malignancy occurred in 0.5% of de novo and 0.6% of maintenance patients.

Opportunistic infections

All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load (see section 4.4). The most common opportunistic infections in de novo renal transplant patients receiving Myfortic with other immunosuppressants in controlled clinical trials of renal transplant patients followed for 1 year were cytomegalovirus (CMV), candidiasis and herpes simplex. CMV infection (serology, viraemia or disease) was reported in 21.6% of de novo and in 1.9% of maintenance renal transplant patients.

Elderly patients

Elderly patients may generally be at increased risk of adverse drug reactions due to immunosuppression.

Other adverse drug reactions

Table 1 below contains adverse drug reactions possibly or probably related to Myfortic reported in the controlled clinical trials in renal transplant patients, in which Myfortic was administered together with ciclosporin microemulsion and corticosteroids at a dose of 1,440 mg/day for 12 months. It is compiled according to MedDRA system organ class.

Adverse reactions are listed according to the following categories:

Very common Common Uncommon Rare Very rare

( ( ( ( (<1/10,000)

Table 1

Cardiac disorders
	Uncommon:	Tachycardia, pulmonary oedema, ventricular extrasystoles
Blood and lymphatic system disorders
	Very common	Leukopenia
	Common:	Anaemia, thrombocytopenia
	Uncommon:	Lymphocele*, lymphopenia*, neutropenia*, lymphadenopathy*
Nervous system disorders
	Common	Headache
	Uncommon:	Tremor, insomnia*
Eye disorders
	Uncommon:	Conjunctivitis*, vision blurred*
Respiratory, thoracic and mediastinal disorders
	Common	Cough
	Uncommon:	Pulmonary congestion*, wheezing*
Gastrointestinal disorders
	Very common	Diarrhoea
	Common:	Abdominal distension, abdominal pain, constipation, dyspepsia, flatulence, gastritis, loose stools, nausea, vomiting
	Uncommon:	Abdominal tenderness, gastrointestinal haemorrhage, eructation, halitosis*, ileus*, lip ulceration*, oesophagitis*, subileus*, tongue discolouration*, dry mouth*, gastro-oesophageal reflux disease*, gingival hyperplasia*, pancreatitis, parotid duct obstruction*, peptic ulcer*, peritonitis*
Renal and urinary disorders
	Common	Increased blood creatinine
	Uncommon:	Haematuria*, renal tubular necrosis*, urethral complications
Skin and subcutaneous tissue disorders
	Uncommon:	Alopecia, contusion*
Musculoskeletal and connective tissue disorders
	Uncommon:	Arthritis*, back pain*, muscle cramps
Metabolism and nutrition disorders
	Uncommon:	Anorexia, hyperlipidaemia, diabetes mellitus*, hypercholesterolaemia*, hypophosphataemia
Infections and infestations
	Very common	Viral, bacterial and fungal infections
	Common	Upper respiratory tract infections, pneumonia
	Uncommon	Wound infection, sepsis*, osteomyelitis*
Neoplasms benign, malignant and unspecified (including cysts and polyps)
	Uncommon	Skin papilloma*, basal cell carcinoma*, Kaposi´s sarcoma*, lymphoproliferative disorder, squamous cell carcinoma*
General disorders and administration site conditions
	Common	Fatigue, pyrexia
	Uncommon	Influenza like illness, oedema lower limb*, pain, rigors*, thirst*, weakness*
Hepato-biliary disorders
	Common	Hepatic function tests abnormal
Reproductive system and breast disorders
	Uncommon	Impotence*
Psychiatric disorders
	Uncommon	Abnormal dreams*, delusional perception*

* event reported in a single patient (out of 372) only.

Note: renal transplant patients were treated with 1,440 mg Myfortic daily up to one year. A similar profile was seen in the de novo and maintenance transplant population although the incidence tended to be lower in the maintenance patients.

Rash has been identified as an adverse drug reaction from post marketing experience.

The following additional adverse reactions are attributed MPA derivatives as a class effect:

Gastrointestinal disorders:

colitis, CMV gastritis, intestinal perforation, gastric ulcers, duodenal ulcers.

Infections and infestations:

serious, life-threatening infections, including meningitis, infectious endocarditis, tuberculosis, and atypical mycobacterial infection. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Myfortic (see section 4.4).

Blood and lymphatic system disorders:

neutropenia, pancytopenia.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives (see section 4.4).

Isolated cases of abnormal neutrophil morphology, including acquired Pelger-Huet anomaly, have been observed in patients treated with MPA derivatives. These changes are not associated with impaired neutrophil function. These changes may suggest a 'left shift' in maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that received Myfortic.

4.9 Overdose

No case of overdose has been reported. Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety MPA. This is in large part due to the very high plasma protein binding of MPA, 97%. By interfering with enterohepatic circulation of MPA, bile acid sequestrants, such as cholestyramine, may reduce the systemic MPA exposure.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: immunosuppressant, ATC code: L04AA06

MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilize salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

5.2 Pharmacokinetic Properties

Absorption

Following oral administration, mycophenolate sodium is extensively absorbed. Consistent with its enteric coated design, the time to maximal concentration (T_max) of MPA was approximately 1.5-2 hours. Approximately 10% of all morning pharmacokinetic profiles showed a delayed T_max, sometimes up to several hours, without any expected impact on 24 hour/daily MPA exposure.

In stable renal transplant patients on ciclosporin based immunosuppression, the gastrointestinal absorption of MPA was 93% and the absolute bioavailability was 72%. Myfortic pharmacokinetics are dose proportional and linear over the studied dose range of 180 to 2,160 mg.

Compared to the fasting state, administration of a single dose of Myfortic 720 mg with a high fat meal (55 g fat, 1,000 calories) had no effect on the systemic exposure of MPA (AUC), which is the most relevant pharmacokinetic parameter linked to efficacy. However there was a 33% decrease in the maximal concentration of MPA (C_max). Moreover, T_lag and T_max were on average 3-5 hours delayed, with several patients having a T_max of>15 hours. The effect of food on Myfortic may lead to an absorption overlap from one dose interval to another. However, this effect was not shown to be clinically significant.

Distribution

The volume of distribution at steady state for MPA is 50 litres. Both mycophenolic acid and mycophenolic acid glucuronide are highly protein bound (97% and 82%, respectively). The free MPA concentration may increase under conditions of decreased protein binding sites (uraemia, hepatic failure, hypoalbuminaemia, concomitant use of drugs with high protein binding). This may put patients at increased risk of MPA-related adverse effects.

Elimination

The half life of MPA is approximately 12 hours and the clearance is 8.6 l/h.

Metabolism

MPA is metabolised principally by glucuronyl transferase to form the phenolic glucuronide of MPA, mycophenolic acid glucuronide (MPAG). MPAG is the predominant metabolite of MPA and does not manifest biological activity. In stable renal transplant patients on ciclosporin-based immunosuppression, approximately 28% of the oral Myfortic dose is converted to MPAG by presystemic metabolism. The half life of MPAG is longer than that of MPA, approximately 16 hours and its clearance is 0.45 l/h.

Excretion

Although negligible amounts of MPA are present in the urine (<1.0%), the majority of MPA is eliminated in the urine as MPAG. MPAG secreted in the bile is available for deconjugation by gut flora. The MPA resulting from this deconjugation may then be reabsorbed. Approximately 6-8 hours after Myfortic dosing a second peak of MPA concentration can be measured, consistent with reabsorption of the deconjugated MPA. There is large variability in the MPA trough levels inherent to MPA preparations, and high morning trough levels (C₀> 10 µg/ml) have been observed in approximately 2% of patients treated with Myfortic. However, across studies, the AUC at steady state (0-12h) which is indicative of the overall exposure showed a lower variability than the one corresponding to C_trough.

Pharmacokinetics in renal transplant patients on ciclosporin based immunosuppression

Shown in Table 2 are mean pharmacokinetic parameters for MPA following the administration of Myfortic. In the early post transplant period, mean MPA AUC and mean MPA C_max were approximately one-half of the values measured six months post transplant.

Table 2 Mean (SD) pharmacokinetic parameters for MPA following oral administration of Myfortic to renal transplant patients on ciclosporin-based immunosuppression

Adult chronic, multiple dosing 720 mg BID (Study ERLB 301) n=48	Dose	Tmax* (h)	Cmax (μg/ml)	AUC 0-12 (μg x h/ml)
14 days post-transplant	720 mg	2	13.9 (8.6)	29.1 (10.4)
3 months post -transplant	720 mg	2	24.6 (13.2)	50.7 (17.3)
6 months post-transplant	720 mg	2	23.0 (10.1)	55.7 (14.6)
Adult chronic, multiple dosing 720 mg BID 18 months post-transplant (Study ERLB 302) n=18	Dose	Tmax* (h)	Cmax (μg/ml)	AUC 0-12 (μg x h/ml)
720 mg	1.5	18.9 (7.9)	57.4 (15.0)
Paediatric 450 mg/m2 single dose (Study ERL 0106) n=16	Dose	Tmax* (h)	Cmax (μg/ml)	AUC o- (μg x h/ml)
450 mg/m2	2.5	31.9 (18.2)	74.5 (28.3)

* median values

Renal impairment

MPA pharmacokinetics appeared to be unchanged over the range of normal to absent renal function. In contrast, MPAG exposure increased with decreased renal function; MPAG exposure being approximately 8 fold higher in the setting of anuria. Clearance of either MPA or MPAG was unaffected by haemodialysis. Free MPA may also significantly increase in the setting of renal failure. This may be due to decreased plasma protein binding of MPA in the presence of high blood urea concentration.

Hepatic impairment

In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.

Children and adolescents

Limited data are available on the use of Myfortic in children and adolescents. In Table 2 above the mean (SD) MPA pharmacokinetics are shown for stable paediatric renal transplant patients (aged 5-16 years) on ciclosporin-based immunosuppression. Mean MPA AUC at a dose of 450 mg/m² was similar to that measured in adults receiving 720 mg Myfortic. The mean apparent clearance of MPA was approximately 6.7 l/h/m².

Gender

There are no clinically significant gender differences in Myfortic pharmacokinetics.

Elderly

Pharmacokinetics in the elderly have not formally been studied. MPA exposure does not appear to vary to a clinically significant degree by age.

5.3 Preclinical Safety Data

The haematopoetic and lymphoid system were the primary organs affected in repeated-dose toxicity studies conducted with mycophenolate sodium in rats and mice. These effects occurred at systemic exposure levels which are equivalent to or less than the clinical exposure at the recommended dose of 1.44 g/day of Myfortic in renal transplant patients.

Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended doses.

The non-clinical toxicity profile of mycophenolic acid (as sodium salt) appears to be consistent with adverse events observed in human clinical trials which now provide safety data of more relevance to the patient population (see section 4.8).

Three genotoxicity assays (in vitro mouse lymphoma assay, micronucleus test in V79 Chinese hamster cells and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolic acid to cause chromosomal aberrations. These effects can be related to the pharmacodynamic mode of action, i.e. inhibition of nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity.

Mycophenolic acid (as sodium salt) was not tumourigenic in rats and mice. The highest dose tested in the animal carcinogenicity studies resulted in approximately 0.6-5 times the systemic exposure (AUC or C_max) observed in renal transplant patients at the recommended clinical dose of 1.44 g/day.

Mycophenolic acid (as sodium salt) had no effect on fertility of male or female rats up to dose levels at which general toxicity and embryotoxicity were observed.

In a teratology study performed with mycophenolic acid (as sodium salt) in rats, at a dose as low as 1 mg/kg, malformations in the offspring were observed, including anophthalmia, exencephaly and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the dose of 1.44 g/day of Myfortic (see section 4.6).

In a pre- and postnatal development study in rat, mycophenolic acid (as sodium salt) caused developmental delays (abnormal pupillary reflex in females and preputial separation in males) at the highest dose of 3 mg/kg that also induced malformations.

Mycophenolic acid (as sodium salt) showed a phototoxic potential in an in vitro 3T3 NRU phototoxicity assay.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core

Maize starch

Povidone

Crospovidone

Lactose, anhydrous

Silica, colloidal anhydrous

Magnesium stearate

Coating

Hypromellose phthalate

Titanium dioxide (E 171)

Iron oxide yellow (E 172)

Indigo Carmine (E 132) (180mg only)

Iron oxide red (E 172) (360mg only)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

30 months.

6.4 Special Precautions For Storage

Do not store above 30°C.

Store in the original package in order to protect from moisture and light.

6.5 Nature And Contents Of Container

The tablets are packed in polyamide/aluminium/PVC/aluminium blister packs of 10 tablets per blister in quantities of 20, (180mg only), 50, 100, 120 and 250 tablets per carton.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

In order to retain the integrity of the enteric coating, Myfortic tablets should not be crushed (see section 4.2).

Mycophenolic acid has demonstrated teratogenic effects in rats and rabbits (see section 4.6). Where crushing of Myfortic tablets is necessary, avoid inhalation of the powder or direct contact of the powder with skin or mucous membrane.

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

7. Marketing Authorisation Holder

Novartis Pharmaceuticals UK Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

United Kingdom

8. Marketing Authorisation Number(S)

Myfortic 180mg gastro-resistant tablets: PL 00101/0664

Myfortic 360mg gastro-resistant tablets: PL 00101/0665

9. Date Of First Authorisation/Renewal Of The Authorisation

10/10/2008

10. Date Of Revision Of The Text

28/10/2010

LEGAL CATEGORY:

POM