Calcichew Forte Chewable Tablets

1. Name Of The Medicinal Product

Calcichew Forte Chewable Tablets

2. Qualitative And Quantitative Composition

Per tablet: Calcium carbonate 2500mg equivalent to 1g of elemental calcium.

Contains sorbitol, 780mg; isomalt, 124mg; and aspartame, 2mg.

For a full list of excipients see Section 6.1.

3. Pharmaceutical Form

Chewable tablet.

Round, white, uncoated and convex tablets. May have small specks.

4. Clinical Particulars

4.1 Therapeutic Indications

Calcichew Forte Chewable Tablets are to be chewed as a supplemental source of calcium in the correction of dietary deficiencies or when normal requirements are high.

Calcichew Forte Chewable Tablets may be used as an adjunct to conventional therapy in the prevention and treatment of osteoporosis. They may be used as a phosphate binding agent in the management of renal failure in patients on renal dialysis.

4.2 Posology And Method Of Administration

Oral.

Adults and elderly:

Adjunct to osteoporosis therapy	One tablet to be chewed daily.
Dietary deficiency	One tablet to be chewed daily.
Osteomalacia	1-3 tablets daily is recommended.

Children:

Dietary deficiency	One tablet to be chewed daily.
Phosphate Binder:
Adults, children and elderly:	Dose as required by the individual patient depending on serum phosphate level.

The tablets should be taken just before, during or just after each meal.

The tablets may be chewed or sucked.

Dosage in hepatic impairment:

No dose adjustment is required.

Dosage in renal impairment:

In patients with severe renal failure having a creatinine clearance of less than 25 ml/minute, dosage adjustments may be necessary dependent on serum calcium levels. See section 4.4.

4.3 Contraindications

• Severe hypercalcaemia and hypercalciuria, for example in hyperparathyroidism, vitamin D overdosage, decalcifying tumours such as plasmacytoma and skeletal metastases, in severe renal failure untreated by renal dialysis and in osteoporosis due to immobilisation.

• Nephrolithiasis

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

4.4 Special Warnings And Precautions For Use

Calcichew Forte chewable tablets contain aspartame (a source of phenylalanine) and should be avoided by patients with phenylketonuria.

Calcichew 500 mg Chewable Tablets contain sorbitol (E420) and isomalt (E953). Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

In renal insufficiency the tablets should be given only under controlled conditions for hyperphosphataemia. Caution should be exercised in patients with a history of renal calculi.

During high dose therapy and especially during concomitant treatment with vitamin D or nutrients (such as milk), there is a risk of hypercalcaemia with subsequent kidney function impairment and milk-alkali syndrome. In these patients, serum calcium levels should be followed and renal function should be monitored.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Thiazide diuretics reduce the urinary excretion of calcium. Due to increased risk of hypercalcaemia, serum calcium should be regularly monitored during concomitant use of thiazide diuretics.

Systemic corticosteroids reduce calcium absorption. During concomitant use, it may be necessary to increase the dose of Calcichew Forte Chewable Tablets.

Calcium carbonate may interfere with the absorption of concomitantly administered tetracycline preparations. For this reason, tetracycline preparations should be administered at least two hours before, or four to six hours after, oral intake of calcium.

Hypercalcaemia may increase the toxicity of cardiac glycosides during treatment with calcium. Patients should be monitored with regard to electrocardiogram (ECG) and serum calcium levels.

The efficacy of levothyroxine can be reduced by the concurrent use of calcium, due to decreased levothyroxine absorption. Administration of calcium and levothyroxine should be separated by at least four hours.

The absorption of quinolone antibiotics may be impaired if administered concomitantly with calcium. Quinolone antibiotics should be taken two hours before or after intake of calcium.

If a bisphosphonate or sodium fluoride is used concomitantly, this preparation should be administered at least three hours before the intake of Calcichew Forte Chewable Tablets since gastrointestinal absorption may be reduced.

Oxalic acid (found in spinach and rhubarb) and phytic acid (found in whole cereals) may inhibit calcium absorption through formation of insoluble calcium salts. The patient should not take calcium products within two hours of eating foods high in oxalic acid and phytic acid.

4.6 Pregnancy And Lactation

The adequate daily intake (including food and supplementation) for normal pregnant and lactating women is 1000-1300 mg calcium. During pregnancy, the daily intake of calcium should not exceed 1500 mg. Significant amounts of calcium are secreted in milk during lactation. Calcichew Forte Chewable Tablets can be used during pregnancy in case of a calcium deficiency.

4.7 Effects On Ability To Drive And Use Machines

There are no data about the effect of this product on driving capacity. An effect is, however, unlikely.

4.8 Undesirable Effects

Adverse reactions are listed below, by system organ class and frequency. Frequencies are defined as: uncommon (

Metabolism and nutrition disorders

Uncommon: Hypercalcaemia and hypercalciuria.

Very rare: Seen usually only in overdose, see 4.9: Milk-alkali syndrome

Gastrointestinal disorders

Rare: Constipation, dyspepsia, flatulence, nausea, abdominal pain and diarrhoea.

Skin and subcutaneous disorders

Rare: Pruritus, rash and urticaria.

4.9 Overdose

Overdose can lead to hypercalcaemia. Symptoms of hypercalcaemia may include anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, mental disturbances, polydipsia, polyuria, bone pain, nephrocalcinosis, nephrolithiasis and in severe cases, cardiac arrhythmias. Extreme hypercalcaemia may result in coma and death. Persistently high calcium levels may lead to irreversible renal damage and soft tissue calcification.

Milk-alkali syndrome (frequent urge to urinate; continuing headache; continuing loss of appetite; nausea or vomiting; unusual tiredness or weakness; hypercalcaemia, alkalosis and renal impairment). The milk-alkali syndrome of hypercalcaemia, alkalosis and renal impairment still occur in patients who ingest large amounts of calcium and absorbable alkali; it is not uncommon as a cause of hypercalcaemia requiring hospitalisation. The syndrome has also been reported in a patient taking recommended doses of antacids containing calcium carbonate for chronic epigastric discomfort, and in a pregnant woman taking high, but not grossly excessive, doses of calcium (about 3 g of elemental calcium daily). Metastatic calcification can develop.

Treatment of hypercalcaemia: The treatment with calcium must be discontinued. Treatment with thiazide diuretics, lithium, vitamin A, vitamin D and cardiac glycosides must also be discontinued. Treatment: rehydration, and, according to severity of hypercalcaemia, isolated or combined treatment with loop diuretics, bisphosphonates, calcitonin and corticosteroids should be considered. Serum electrolytes, renal function and diuresis must be monitored. In severe cases, ECG and CVP should be followed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Calcium

ATC-code: A12A A04

An adequate intake of calcium is of importance during growth, pregnancy and breastfeeding.

5.2 Pharmacokinetic Properties

Absorption: The amount of calcium absorbed through the gastrointestinal tract is approximately 30% of the swallowed dose.

Distribution and metabolism: 99% of the calcium in the body is concentrated in the hard structure of bones and teeth. The remaining 1% is present in the intra- and extracellular fluids. About 50% of the total blood-calcium content is in the physiologically active ionised form with approximately 10% being complexed to citrate, phosphate or other anions, the remaining 40% being bound to proteins, principally albumin.

Elimination: Calcium is eliminated through faeces, urine and sweat. Renal excretion depends on glomerular filtration and calcium tubular reabsorption.

5.3 Preclinical Safety Data

There is no information of relevance to the safety assessment in addition to what is stated in other parts of the SmPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sorbitol (E420)

Povidone

Magnesium stearate

Aspartame (E951)

Orange flavour:

Isomalt (E953)

Flavouring (orange)

Mono, di-fatty acid glycerides

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 30ºC.

Keep the container tightly closed to protect from moisture.

6.5 Nature And Contents Of Container

WiMo Box of 28, 30, 56, 60, 90 and 100 tablets. Not all pack sizes may be marketed.

It is a high density polyethylene cylindrical bottle with high density polyethylene screw cap and medium density polyethylene tamper-evident liner.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Shire Pharmaceuticals Limited

Hampshire International Business Park

Chineham

Basingstoke

Hampshire RG24 8EP

United Kingdom

8. Marketing Authorisation Number(S)

PL 08557/0022

9. Date Of First Authorisation/Renewal Of The Authorisation

2 January 1992

10. Date Of Revision Of The Text

09-Jun-2010

Carnitor 1 g Solution for Injection

1. Name Of The Medicinal Product

Carnitor 1 g Solution for Injection

2. Qualitative And Quantitative Composition

L-carnitine inner salt 1 g

3. Pharmaceutical Form

A clear, colourless or light straw- coloured solution

4. Clinical Particulars

4.1 Therapeutic Indications

Indicated for the treatment of primary and secondary carnitine deficiency in adults, children, infants and neonates.

Secondary carnitine deficiency in haemodialysis patients.

Secondary carnitine deficiency should be suspected in long-term haemodialysis patients who have the following conditions:

1. Severe and persistent muscle cramps and/or hypotensive episodes during dialysis.

2. Lack of energy causing a significant negative effect on the quality of life.

3. Skeletal muscle weakness and/or myopathy.

4. Cardiomyopathy.

5. Anaemia of uraemia unresponsive to or requiring large doses of erythropoietin.

6. Muscle mass loss caused by malnutrition.

4.2 Posology And Method Of Administration

For slow intravenous administration over 2-3 minutes

Adults, Children, infants and neonates

It is advisable to monitor therapy by measuring free and acyl carnitine levels in both plasma and urine.

The management of inborn errors of metabolism:

The dosage required depends upon the specific inborn error of metabolism concerned and the severity of presentation at the time of treatment. However, the following can be considered as a general guide.

In acute decompensation, dosages of up to 100 mg/kg/day in 3-4 divided doses are recommended. Higher doses have been used although an increase in adverse events, primarily diarrhoea, may occur.

Secondary carnitine deficiency in haemodialysis patients:

It is strongly recommended that, before initiating therapy with Carnitor, plasma carnitine is measured. Secondary carnitine deficiency is suggested by a plasma ratio of acyl to free carnitine of greater than 0.4 and/or when free carnitine concentrations are lower than 20 μmol/litre.

A dose of 20mg per kg should be administered as an intravenous bolus at the end of each dialysis session (assuming three sessions per week). The duration of intravenous treatment should be at least three months, which is the time usually required to restore normal muscle levels of free carnitine. The overall response should be assessed by monitoring plasma acyl to free carnitine levels and by evaluating the patient's symptoms. When carnitine supplementation has been stopped there will be a progressive decline in carnitine levels. The need for a repeat course of therapy can be assessed by plasma carnitine assays at regular intervals and by monitoring the patient's symptoms.

Haemodialysis - maintenance therapy:

If significant clinical benefit has been gained by the first course of intravenous Carnitor then maintenance therapy can be considered using 1 g per day of Carnitor orally. On the day of the dialysis, oral Carnitor has to be administered at the end of the session.

4.3 Contraindications

Hypersensitivity to any of the constituents of the product.

4.4 Special Warnings And Precautions For Use

While improving glucose utilisation, the administration of L-carnitine to diabetic patients receiving either insulin or hypoglycaemic oral treatment may result in hypoglycaemia. Plasma glucose levels in these subjects must be monitored regularly in order to adjust the hypoglycaemic treatment immediately, if required.

The safety and efficacy of oral L-carnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral L-carnitine in patients with severely compromised renal function or in end stage renal disease (ESRD) patients on dialysis may result in an accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are usually excreted in the urine. This situation has not been observed following intravenous administration of L-carnitine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There are no known interactions.

4.6 Pregnancy And Lactation

Reproductive studies were performed in rats and rabbits. There was no evidence of a teratogenic effect in either species. In the rabbit but not in the rat, there was a statistically insignificant greater number of post implantation losses at the highest dose tested (600 mg/kg daily) as compared with control animals. The significance of these findings for man is unknown. There is no experience of use in pregnant patients with primary systemic carnitine deficiency.

Taking into account the serious consequences to a pregnant woman who has primary systemic carnitine deficiency stopping treatment, the risk to the mother of discontinuing treatment seems greater than the theoretical risk to the foetus if treatment is continued.

Levocarnitine is a normal component of human milk. Use of levocarnitine supplementation in nursing mothers has not been studied.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Various mild gastro-intestinal complaints have been reported during the long-term administration of oral levocarnitine, these include transient nausea and vomiting, abdominal cramps and diarrhoea.

Decreasing the dosage often diminishes or eliminates drug-related patient body odour or gastro-intestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration and after any dosage increase.

4.9 Overdose

There have been no reports of toxicity from levocarnitine overdosage. Overdosage should be treated with supportive care.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: A16AA01 (Amino acids and derivatives)

L-Carnitine is present as a natural constituent in animal tissues, micro-organisms and plants. In man the physiological metabolic requirements are met both by the consumption of food containing carnitine and the endogenous synthesis in the liver and kidneys from lysine with methionine serving as the methyl donor. Only the L-isomer is biologically active, playing an essential role in lipid metabolism as well as in the metabolism of ketone bodies as branched chain-amino-acids. L-Carnitine as a factor is necessary in the transport of long-chain fatty acids into the mitochondria – facilitating the oxidation of fatty acids rather than their incorporation into triglycerides. By releasing CoA from its thioesters, through the action of CoA; carnitine acetyl transferase, L-carnitine also enhances the metabolic flux in the Kreb's cycle; with the same mechanism it stimulates the activity of pyruvate dehydrogenase and in skeletal muscle, the oxidation of branched chain-amino acids. L-Carnitine is thus involved, directly or indirectly in several pathways so that its availability should be an important factor controlling not only the oxidative utilisation of fatty acids and ketone bodies but also that of glucose and some amino acids.

5.2 Pharmacokinetic Properties

The absorbed L-carnitine is transported to various organ systems via the blood. The presence of membrane-bound proteins in several tissues including red blood cells that bind carnitine, suggest that a transport system in the blood and a cellular system for the collective uptake is present in several tissues. Tissue and serum carnitine concentration depends on several metabolic processes, carnitine biosynthesis and dietary contributions, transport into and out of tissues, degradation and excretion may all affect tissue carnitine concentrations.

Absorption

L-Carnitine is absorbed by the mucosal cells of the small intestine and enters the blood stream relatively slowly; the absorption is probably associated with an active transluminal mechanism.

The apparent systemic availability after oral administration is limited (<10%) and variable.

Distribution

Absorbed L-carnitine is transported to various organ systems via the blood; it is thought that a transport system in the blood and a cellular system for selective uptake is involved.

Excretion

L-Carnitine is excreted mainly in the urine and is variable. The excretion is directly proportional to the blood levels.

Metabolism

L-Carnitine is metabolised to a very limited extent.

5.3 Preclinical Safety Data

L-Carnitine is a naturally occurring body substance in human beings, plants and animals. Carnitor products are used to bring the level of L-carnitine in the body up to those found naturally. Appropriate pre-clinical studies have been undertaken and show no signs of toxicity at normal therapeutic doses.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Hydrochloric acid 10%

Water for injection

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Store below 25^oC.

Store in the original carton in order to protect from light.

6.5 Nature And Contents Of Container

Ph.Eur. Type 1 clear glass ampoules of 5 ml capacity.

The ampoules are packed in cardboard outer cartons containing 5 ampoules.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Sigma-Tau Industrie Farmaceutiche Riunite SpA,

Viale Shakespeare 47-00144,

Rome, Italy.

8. Marketing Authorisation Number(S)

PL 08381/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

30 November 1999

10. Date Of Revision Of The Text

November 2008

Celluvisc 0.5% w / v, eye drops, solution

CELLUVISC 0.5% w/v, eye drops, solution, unit dose

Carmellose sodium

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription from pharmacies. Please use CELLUVISC carefully according to the instructions below to get the best results.

• Keep this leaflet. You may need to read it again.


• Ask your pharmacist if you need more information or advice.


• You must contact a doctor if your symptoms worsen or do not improve.


• If any of the side effects gets serious, or if you notice any side effect not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What CELLUVISC is and what it is used for


• 2. Before you use CELLUVISC


• 3. How to use CELLUVISC


• 4. Possible side effects


• 5. How to store CELLUVISC


• 6. Further information

What Celluvisc Is And What It Is Used For

CELLUVISC is a substitute for tears, and contains the lubricant called carmellose sodium. It is used for the treatment of the symptoms of dry eye (such as soreness, burning, irritation or dryness) caused by your not producing enough tears to keep the eye wet.

Before You Use Celluvisc

Do not use CELLUVISC

• If you are hypersensitive (allergic) to carmellose sodium or any of the other ingredients of CELLUVISC. These are listed at the end of this leaflet in section 6 "Further information".

Take special care with CELLUVISC

• If irritation, pain, redness or changes in vision occur or if you feel your condition is getting worse, stop taking this medicine and consult your doctor or pharmacist.

Using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

If you are using other eye drops, leave at least 15 minutes between putting in the other drops and CELLUVISC.

Pregnancy and breast-feeding

You can use CELLUVISC if you are pregnant and when you are breast-feeding.

Driving and using machines

CELLUVISC does not usually cause blurred (unclear) vision. If you do experience temporary blurring, do not drive or use machines until your sight is clear.

Read all the information in this leaflet before using CELLUVISC.

If you are unsure about anything, discuss it with your doctor, nurse or pharmacist.

How To Use Celluvisc

Follow these instructions unless the pharmacist or your doctor gave you different advice.

The usual dose is 1-2 drops of CELLUVISC in the affected eye/each affected eye, 4 times a day or as often as needed.

You do not need to remove contact lenses before using CELLUVISC.

Make sure that the single-dose container is intact before use. The solution should be used immediately after opening. To avoid contamination, do not let the open-end of the single-dose container touch your eye or anything else. Wash your hands before use.

• 1. Tear one single-dose container from the strip.


• 2. Hold the single-dose container upright (with the top uppermost) and twist off the top.


• 3. Gently pull down the lower eyelid to form a pocket. Turn the single-dose container upside down and squeeze it to release one drop into each eye. Blink your eyes a few times.

Do not re-use the single-dose container even if there is some solution left. It is most important that you throw it away and do not keep it.

If you use more CELLUVISC than you should, it will not cause you any harm. If you are worried, talk to your doctor or pharmacist.

If you forget to use CELLUVISC, use a single drop in each eye that needs treatment as soon as you remember, and then go back to your regular routine. Do not use a large number of drops to make up for forgetting to put drops in your eye or eyes earlier.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines, CELLUVISC can cause side (unwanted) effects, although not everybody gets them.

You may have a feeling of burning, for a short time.

If this side effect goes on for some time or worries you, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Celluvisc

Keep out of the reach and sight of children.

Do not store above 25°C.

Do not use CELLUVISC after the expiry date (use by date) which is stated on the single-dose container tab and the carton after EXP:. The expiry date refers to the last day of that month.

Used CELLUVISC eye drop containers can be disposed of as household waste. Any unused containers can be returned to the pharmacist or he can tell you how to dispose of them safely (in order to protect the environment).

Further Information

What CELLUVISC contains

• The active ingredient is carmellose sodium 5 mg/ml.


• The other ingredients are sodium chloride, sodium lactate, potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, and purified water. Small amounts of sodium hydroxide or hydrochloric acid may be added to bring the solution to the correct pH (a measure of the acidity or alkalinity of the solution).

The ingredients and the amount used in CELLUVISC were chosen to match what appears in tears produced naturally by the eye.

What CELLUVISC looks like and contents of the pack

CELLUVISC is a clear, colourless to pale yellow solution in a small see-through (bubble-like) casing (known as a 'single-dose container'). The single-dose container has a twist-off top. Each single-dose container contains 0.4 ml of solution.

Each pack contains 5, 30 or 90 single-dose containers. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Allergan Pharmaceuticals Ireland

Castlebar Road

Westport

County Mayo

Ireland

For any further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

Allergan Limited

1st Floor Marlow International

The Parkway, Marlow

Buckinghamshire

SL7 1YL

United Kingdom

Tel.:01628 494026

E-mail:uk_medinfo@allergan.com

This leaflet was last approved on 2nd October 2006

Carbaglu

1. Name Of The Medicinal Product

Carbaglu 200 mg dispersible tablets

2. Qualitative And Quantitative Composition

Each tablet contains 200 mg of carglumic acid.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Dispersible tablet

The tablets are white and elongated with three score marks.

The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of hyperammonaemia due to N-acetylglutamate synthase deficiency.

4.2 Posology And Method Of Administration

Carbaglu treatment should be initiated under the supervision of a physician experienced in the treatment of metabolic disorders.

Based on clinical experience, the treatment may be started as early as the first day of life.

The initial daily dose should be 100 mg/kg, up to 250 mg/kg if necessary.

It should then be adjusted individually in order to maintain normal ammonia plasma levels (see section 4.4).

In the long term, it may not be necessary to increase the dose according to body weight as long as adequate metabolic control is achieved; daily doses range from 10 mg/kg to 100 mg/kg.

Carglumic acid responsiveness test

It is recommended to test individual responsiveness to carglumic acid before initiating any long term treatment. As examples

- In a comatose child, start with a dose of 100 to 250 mg/kg/day and measure ammonia plasma concentration at least before each administration; it should normalise within a few hours after starting Carbaglu.

- In a patient with moderate hyperammonaemia, administer a test dose of 100 to 200 mg/kg/day for 3 days with a constant protein intake and perform repeated determinations of ammonia plasma concentration (before and 1 hour after a meal); adjust the dose in order to maintain normal ammonia plasma levels.

Based on pharmacokinetic data and clinical experience, it is recommended to divide the total daily dose into two to four doses to be given before meals or feedings. The breaking of the tablets in halves allows most of the required posology adjustments. Occasionally, the use of quarter tablets may also be useful to adjust the posology prescribed by the physician.

The tablets must be dispersed in a minimum of 5-10 ml of water and ingested immediately or administered by fast push through a syringe via a nasogastric tube.

The suspension has a slightly acidic taste.

4.3 Contraindications

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

Breast-feeding during the use of carglumic acid is contraindicated (see sections 4.6 and 5.3).

4.4 Special Warnings And Precautions For Use

Therapeutic monitoring

Plasma levels of ammonia and amino acids should be maintained within normal limits.

As very few data on the safety of carglumic acid are available, systematic surveillance of liver, renal, cardiac functions and haematological parameters is recommended.

Nutritional management

Protein restriction and arginine supplementation may be indicated in case of low protein tolerance.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No specific interaction studies have been performed.

4.6 Pregnancy And Lactation

For carglumic acid no clinical data on exposed pregnancies are available.

Animal studies have revealed minimal developmental toxicity (see section 5.3). Caution should be exercised when prescribing to pregnant women.

Although it is not known whether carglumic acid is secreted into human milk, it has been shown to be present in the milk of lactating rats (see section 5.3). Therefore, breast-feeding during the use of carglumic acid is contraindicated. (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.

4.8 Undesirable Effects

Clinical experience has been collected in about 170 patient-years.

Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies are defined as: very common (

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

Investigations	Uncommon : increased transaminases
Skin and subcutaneous tissue disorders	Common : increased sweating

4.9 Overdose

In one patient treated with carglumic acid, where the dose was increased up to 750 mg/kg/day, symptoms of intoxication occurred which can be characterised as a sympathomimetic reaction: tachycardia, profuse sweating, increased bronchial secretion, increased body temperature and restlessness. These symptoms resolved once the dose was reduced.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Amino acids and derivatives; ATC code: A16AA05

Carglumic acid is a structural analogue of N-acetylglutamate, which is the naturally occurring activator of carbamoyl phosphate synthetase, the first enzyme of the urea cycle.

Carglumic acid has been shown in vitro to activate liver carbamoyl phosphate synthetase. Despite a lower affinity of carbamoyl phosphate synthetase for carglumic acid than for N-acetylglutamate, carglumic acid has been shown in vivo to stimulate carbamoyl phosphate synthetase and to be much more effective than N-acetylglutamate in protecting against ammonia intoxication in rats. This could be explained by the following observations:

i) The mitochondrial membrane is more readily permeable for carglumic acid than for N-acetylglutamate

ii) Carglumic acid is more resistant than N-acetylglutamate to hydrolysis by aminoacylase present in the cytosol.

Other studies have been conducted in rats under different experimental conditions leading to increased ammonia availability (starvation, protein-free or high-protein diet). Carglumic acid was shown to decrease blood ammonia levels and increase urea levels in blood and urine, whereas the liver content of carbamoyl phosphate synthetase activators was significantly increased.

In patients with N-acetylglutamate synthase deficiency, carglumic acid was shown to induce a rapid normalisation of plasma ammonia levels, usually within 24 hours. When the treatment was instituted before any permanent brain damage, patients exhibited normal growth and psychomotor development.

5.2 Pharmacokinetic Properties

The pharmacokinetics of carglumic acid has been studied in healthy male volunteers using both radiolabelled and unlabelled product.

Absorption

After a single oral dose of 100 mg/kg body weight, approximately 30% of carglumic acid is estimated to be absorbed. At that dose-level, in 12 volunteers given Carbaglu tablets, plasma concentration peaked at 2.6 μg/ml (median; range 1.8-4.8) after 3 hours (median; range 2-4).

Distribution

The plasma elimination curve of carglumic acid is biphasic with a rapid phase over the first 12 hours after administration followed by a slow phase (terminal half life up to 28 hours).

Diffusion into erythrocytes is non existent. Protein binding has not been determined.

Metabolism

A proportion of carglumic acid is metabolised. It is suggested that depending on its activity, the intestinal bacterial flora may contribute to the initiation of the degradation process, thus leading to a variable extent of metabolism of the molecule. One metabolite that has been identified in the faeces is glutamic acid. Metabolites are detectable in plasma with a peak at 36-48 hours and a very slow decline (half-life around 100 hours).

The end product of carglumic acid metabolism is carbon dioxide, which is eliminated through the lungs.

Elimination

After a single oral dose of 100 mg/kg body weight, 9% of the dose is excreted unchanged in the urine and up to 60% in the faeces.

Plasma levels of carglumic acid were measured in patients of all age categories, from newborn infants to adolescents, treated with various daily doses (7 – 122 mg/kg/day). Their range was consistent with those measured in healthy adults, even in newborn infants. Whatever the daily dose, they were slowly declining over 15 hours to levels around 100 ng/ml.

5.3 Preclinical Safety Data

Safety pharmacology studies have shown that Carbaglu administered orally at doses of 250, 500, 1000 mg/kg had no statistically significant effect on respiration, central nervous system and cardiovascular system.

Carbaglu showed no significant mutagenic activity in a battery of genotoxicity tests performed in vitro (Ames test, human lymphocyte metaphase analysis) and in vivo (micronucleus test in rat).

Single doses of carglumic acid up to 2800 mg/kg orally and 239 mg/kg intravenously did not induce any mortality or abnormal clinical signs in adult rats. In newborn rats receiving daily carglumic acid by oral gavage for 18 days as well as in young rats receiving daily carglumic acid for 26 weeks, the No Observed Effect Level (NOEL) was established at 500 mg/kg/day and the No Observed Adverse Effect Level (NOAEL) was established at 1000 mg/kg/day.

No adverse effects have been observed on male or female fertility. In rats and rabbits no evidence has been seen of embryotoxicity, foetotoxicity or teratogenicity up to maternotoxic doses leading to fifty times exposure as compared to humans in rats and seven times in rabbits. Carglumic acid is secreted in the milk of lactating rats and although developmental parameters were unaffected, there were some effects on body weight / body weight gain of pups breast-fed by dams treated with 500 mg/kg/day and a higher mortality of pups from dams treated with 2000/kg/day, a dose that caused maternotoxicity. The maternal systemic exposures after 500 and 2000 mg/kg/day were twenty five times and seventy times the expected human exposure.

No carcinogenicity study has been conducted with carglumic acid.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Microcrystalline cellulose

sodium laurilsulfate

hypromellose

croscarmellose sodium

silica colloidal anhydrous

sodium stearyl fumarate

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

30 months

After first opening of the tablet container: 1 month

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C)

After first opening of the tablet container:

Do not refrigerate.

Do not store above 30°C.

Keep the container tightly closed in order to protect from moisture.

6.5 Nature And Contents Of Container

5- or 60- polypropylene tablet containers closed by a polyethylene cap with a desiccant unit.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Orphan Europe

Immeuble “Le Wilson”

F-92058 Paris La Défense

France

8. Marketing Authorisation Number(S)

EU/1/02/246/002 (60 dispersible tablets)

EU/1/02/246/003 (5 dispersible tablets)

9. Date Of First Authorisation/Renewal Of The Authorisation

24 January 2003

24 January 2008

10. Date Of Revision Of The Text

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

Cetirizine hydrochloride 10 mg film-coated tablets

1. Name Of The Medicinal Product

Cetirizine hydrochloride 10 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 10 mg cetirizine hydrochloride.

Excipient: 155.2 mg lactose monohydrate/ film-coated tablet

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White to off-white, film-coated, off-rectangular tablets, debossed with 'X' on one side with '20' on the other side. Score line between '2' and '0'.

The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

In adults and paediatric patients 6 years and above:

• Cetirizine is indicated for the relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis.

• Cetirizine is indicated for the relief of symptoms of chronic idiopathic urticaria.

4.2 Posology And Method Of Administration

Oral use.

Children aged from 6 to 12 years: 5mg twice daily (a half tablet twice daily).

Adults and adolescents over 12 years of age: 10mg once daily (1 tablet).

The tablets need to be swallowed with a glass of liquid.

Elderly subjects: data do not suggest that the dose needs to be reduced in elderly subjects provided that the renal function is normal.

Patients with moderate to severe renal impairment: there are no data to document the efficacy/safety ratio in patients with renal impairment. Since cetirizine is mainly excreted via renal route (see section 5.2), in cases no alternative treatment can be used, the dosing intervals must be individualized according to renal function. Refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CL_cr) in ml/min is needed. The CL_cr (ml/min) may be estimated from serum creatinine (mg/dl) determination using the following formula:

Dosing adjustments for adult patients with impaired renal function

Group	Creatinine clearance (ml/min)	Dosage and frequency
Normal		10mg once daily
Mild	50 – 79	10mg once daily
Moderate	30 – 49	5mg once daily
Severe	< 30	5mg once every 2 days
End-stage renal disease-Patients undergoing dialysis	< 10	Contra-indicated

In paediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient, his age and his body weight.

Patients with hepatic impairment: no dose adjustment is needed in patients with solely hepatic impairment.

Patients with hepatic impairment and renal impairment: dose adjustment is recommended (see Patients with moderate to severe renal impairment above).

4.3 Contraindications

• Hypersensitivity to the active substance, to any of the excipients, to hydroxyzine or to any piperazine derivatives.

• Patients with severe renal impairment at less than 10 ml/min creatinine clearance.

4.4 Special Warnings And Precautions For Use

At therapeutic doses, no clinically significant interactions have been demonstrated with alcohol (for a blood alcohol level of 0.5 g/L). Nevertheless, precaution is recommended if alcohol is taken concomitantly.

Caution in epileptic patients and patients at risk of convulsions is recommended.

The use of the film-coated tablet formulation is not recommended in children aged less than 6 years since this formulation does not allow for appropriate dose adaptation.

Allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.

Cetirizine 10 mg film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Due to the pharmacokinetic, pharmacodynamic and tolerance profile of cetirizine, no interactions are expected with this antihistamine. Actually, neither pharmacodynamic nor significant pharmacokinetic interaction was reported in drug-drug interactions studies performed, notably with pseudoephedrine or theophylline (400 mg/day).

The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased.

4.6 Pregnancy And Lactation

Pregnancy

For cetirizine very rare clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women.

Lactation

Cetirizine is excreted in human milk at concentrations representing 0.25 to 0.90 those measured in plasma, depending on sampling time after administration. Therefore, caution should be exercised when prescribing cetirizine to lactating women.

4.7 Effects On Ability To Drive And Use Machines

Objective measurements of driving ability, sleep latency and assembly line performance have not demonstrated any clinically relevant effects at the recommended dose of 10mg.

Patients intending to drive, engaging in potentially hazardous activities or operating machinery should not exceed the recommended dose and should take their response to the medicinal product into account. In these sensitive patients, concurrent use with alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.

4.8 Undesirable Effects

Clinical studies have shown that cetirizine at the recommended dosage has minor undesirable effects on the CNS, including somnolence, fatigue, dizziness and headache. In some cases, paradoxical CNS stimulation has been reported.

Although cetirizine is a selective antagonist of peripheral H₁-receptors and is relatively free of anticholinergic activity, isolated cases of micturition difficulty, eye accommodation disorders and dry mouth have been reported.

Instances of abnormal hepatic function with elevated hepatic enzymes accompanied by elevated bilirubin have been reported. Mostly this resolves upon discontinuation of the treatment with cetirizine hydrochloride.

Clinical trials:

Double blind controlled clinical or pharmacoclinical trials comparing cetirizine to placebo or other antihistamines at the recommended dosage (10mg daily for cetirizine), of which quantified safety data are available, included more than 3200 subjects exposed to cetirizine.

From this pooling, the following adverse events were reported for cetirizine 10mg in the placebo-controlled trials at rates of 1.0% or greater:

Adverse event (WHO-ART)	Cetirizine 10mg (n= 3260)	Placebo (n= 3061)
Body as a whole- general disorders
Fatigue	1.63%	0.95%
Central and peripheral nervous system disorders
Dizziness	1.10%	0.98%
Headache	7.42%	8.07%
Gastro-intestinal system disorders
Abdominal pain	0.98%	1.08%
Dry mouth	2.09%	0.82%
Nausea	1.07%	1.14%
Psychiatric disorders
Somnolence	9.63%	5.00%
Respiratory system disorders
Pharyngitis	1.29%	1.34%

Although statistically more common than under placebo, somnolence was mild to moderate in the majority of cases. Objective tests as demonstrated by other studies have demonstrated that usual daily activities are unaffected at the recommended daily dose in healthy young volunteers.

Adverse drug reactions at rates of 1% or greater in children aged from 6 months to 12 years, included in placebo-controlled clinical or pharmacological trials are:

Adverse event (WHO-ART)	Cetirizine (n= 1656)	Placebo (n= 1294)
Gastro-intestinal system disorders
Diarrhoea	1.0%	0.6%
Psychiatric disorders
Somnolence	1.8%	1.4%
Respiratory system disorders
Rhinitis	1.4%	1.1%
Body as a whole- general disorders
Fatigue	1.0%	0.3%

Post-marketing experience

In addition to the adverse effects reported during clinical studies and listed above, isolated cases of the following adverse drug reactions have been reported in post-marketing experience. For these less frequently reported undesirable effects, the estimated frequencies (uncommon:

Investigations:

Rare: weight increased

Cardiac disorders:

Rare: tachycardia

Blood and lymphatic disorders:

Very rare: thrombocytopenia

Nervous system disorders:

Uncommon: paraesthesia

Rare: convulsions, movement disorders

Very rare: dysgeusia, syncope, tremor, dystonia, dyskinesia

Not known: amnesia, memory impairment

Eye disorders:

Very rare: accommodation disorder, blurred vision, oculogyration

Gastrointestinal disorders:

Uncommon: diarrhoea

Renal and urinary disorders:

Very rare: dysuria, enuresis

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, rash

Rare: urticaria.

Very rare: angioneurotic oedema, fixed drug eruption

General disorders and administration site conditions:

Uncommon: asthenia, malaise

Rare: oedema

Immune system disorders

Rare: hypersensitivity

Very rare: anaphylactic shock

Hepato-billiary disorders:

Rare: hepatic function abnormal (increased transaminases, alkaline phosphatase, γ-GT and bilirubin)

Psychiatric disorders:

Uncommon: agitation

Rare: aggression, confusion, depression, hallucination, insomnia

Very rare: tics

4.9 Overdose

Symptoms:

Symptoms observed after an overdose of cetirizine are mainly associated with CNS effects or with effects that could suggest an anticholinergic effect.

Adverse events reported after an intake of at least 5 times the recommended daily dose are: confusion, diarrhoea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor, and urinary retention.

Management:

There is no known specific antidote to cetirizine.

Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage should be considered following ingestion of a short occurrence.

Cetirizine is not effectively removed by dialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Piperazine derivatives, ATC code: R06AE07

Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of peripheral H₁-receptors. In vitro receptors binding studies have shown no measurable affinity for other than H₁-receptors.

In addition to its anti-H₁ effect, cetirizine was shown to display anti-allergic activities: at a dose of 10mg once or twice daily, it inhibits the late phase recruitment of eosinophils, in the skin and conjunctiva of atopic subjects submitted to allergen challenge.

Studies in healthy volunteers show that cetirizine, at doses of 5 and 10mg strongly inhibits the wheal and flare reactions induced by very high concentrations of histamine into the skin, but the correlation with efficacy is not established.

In a 35-day study in children aged 5 to 12, no tolerance to the antihistaminic effect (suppression of wheal and flare) of cetirizine was found. When a treatment with cetirizine is stopped after repeated administration, the skin recovers its normal reactivity to histamine within 3 days.

In a six-week, placebo-controlled study of 186 patients with allergic rhinitis and concomitant mild to moderate asthma, cetirizine 10mg once daily improved rhinitis symptoms and did not alter pulmonary function. This study supports the safety of administering cetirizine to allergic patients with mild to moderate asthma.

In a placebo-controlled study, cetirizine given at the high daily dose of 60mg for seven days did not cause statistically significant prolongation of QT interval.

At the recommended dosage, cetirizine has demonstrated that it improves the quality of life of patients with perennial and seasonal allergic rhinitis.

5.2 Pharmacokinetic Properties

The steady-state peak plasma concentrations is approximately 300 ng/ml and is achieved within 1.0 ± 0.5 h. No accumulation is observed for cetirizine following daily doses of 10 mg for 10 days. The distribution of pharmacokinetic parameters such as peak plasma concentration (C_max) and area under curve (AUC), is unimodal in human volunteers.

The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased. The extent of bioavailability is similar when cetirizine is given as solutions, capsules or tablets.

The apparent volume of distribution is 0.50 l/kg. Plasma protein binding of cetirizine is 93 ± 0.3%. Cetirizine does not modify the protein binding of warfarin.

Cetirizine does not undergo extensive first pass metabolism. About two third of the dose are excreted unchanged in urine. The terminal half-life is approximately 10 hours.

Cetirizine exhibits linear kinetics over the range of 5 to 60mg.

Special populations

Elderly: Following a single 10mg oral dose, half-life increased by about 50% and clearance decreased by 40% in 16 elderly subjects compared to the normal subjects. The decrease in cetirizine clearance in these elderly volunteers appeared to be related to their decreased renal function.

Children, infants and toddlers: The half-life of cetirizine was about 6 hours in children of 6-12 years and 5 hours in children 2-6 years. In infants and toddlers aged 6 to 24 months, it is reduced to 3.1 hours.

Renally impaired patients: The pharmacokinetics of the drug were similar in patients with mild impairment (creatinine clearance higher than 40ml/min) and healthy volunteers. Patients with moderate renal impairment had a 3-fold increase in half-life and a 70% decrease in clearance compared to healthy volunteers.

Patients on haemodialysis (creatinine clearance less than 7 ml/min) given a single oral 10mg dose of cetirizine had a 3-fold increase in half-life and a 70% decrease in clearance compared to normals. Cetirizine was poorly cleared by haemodialysis. Dosing adjustment is necessary in patients with moderate or severe renal impairment (see section 4.2).

Hepatically impaired patients: Patients with chronic liver disease (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20mg of cetirizine as a single dose had a 50% increase in half-life along with a 40% decrease in clearance compared to healthy subjects.

Dosing adjustment is only necessary in hepatically impaired patients if concomitant renal impairment is present.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or toxicity to reproduction.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Lactose monohydrate

Crospovidone

Starch, pregelatinised (maize)

Magnesium stearate

Film-coat:

Hypromellose

Titanium dioxide

Macrogol 400

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Blister pack: 1 year

HDPE bottle pack: 18 months

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

PVC-PVDC Aluminium blisters: 1,2, 7, 10, 14, 15, 20, 21, 30, 50, 60, 90, 98 and 100 film-coated tablets.

HDPE bottle: 250 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Aurobindo Pharma (Malta) Limited

46/2, South street, Valletta, VLT 11, Malta

8. Marketing Authorisation Number(S)

PL 32256/0036

9. Date Of First Authorisation/Renewal Of The Authorisation

03/07/2009

10. Date Of Revision Of The Text

17/06/2011

Ceplene 0.5 mg / 0.5 ml solution for injection

Ceplene 0.5 mg/0.5 ml

solution for injection

Histamine

Read all of this leaflet carefully before you start using this medicine.

• Keep this leaflet. You may need to read it again.


• If you have further questions, please ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects become serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1. What Ceplene is and what it is used for

2. Before you use Ceplene

3. How to use Ceplene

4. Possible side effects

5. How to store Ceplene

6. Further information, instructions for self-injection of Ceplene

What Ceplene Is And What It Is Used For

What Ceplene is

Ceplene belongs to a group of medicines called immunomodulatory medicines. These medicines help the body's immune system fight diseases like cancer by improving the immune system's natural role in fighting disease. The active substance in Ceplene is histamine; it is identical to a naturally occurring substance in the body. It is used together with low doses of interleukin-2 (IL-2), another medicine which helps the immune system to fight diseases like cancer.

What Ceplene is used for

Ceplene is used, together with IL-2 to treat a particular type of leukaemia called acute myeloid leukaemia (AML). It is used to maintain the remission (the period during which the disease is less severe or not detectable). As your doctor has discussed with you, acute myeloid leukaemia is a cancer of blood forming cells in the bone marrow. Ceplene with IL-2 will help your immune system attack any remaining cancer cells after a previous cancer treatment.

During your treatment, you will always use IL-2 AND Ceplene. Ask your doctor if you have any questions about Ceplene or IL-2.

Before You Use Ceplene

Do NOT use Ceplene

• If you are allergic (hypersensitive) to histamine or any of the other ingredients of Ceplene.


• If you have severe heart problems.


• If you are receiving one of the following medicines:
  
  
  • Steroids such as prednisone and dexamethasone. They are used to inhibit activity of the immune system (immunosuppressant) and to reduce inflammation.
  • Clonidine, a medicine used to reduce high blood pressure.
  • H₂ blockers such as cimetidine, ranitidine, famotidine or nizatidine which are used to treat stomach ulcers, indigestion (dyspepsia) or heartburn.


• If you have received a stem cell transplant (a kind of bone marrow transplant) from a donor.


• If you are pregnant.


• If you are breast-feeding.

Take special care with Ceplene

• Ceplene and IL-2 are not to be injected at the same time. IL-2 has to be injected first. Ceplene must be injected 1 to 3 minutes later.


• Ceplene must be injected slowly in the layer of tissue just under the skin (subcutaneously), over a period of approximately 5 to 15 minutes. Rapid injection can cause a drop in your blood pressure and make you feel faint or even pass out.


• You will start your treatment with Ceplene in the clinic under supervision of a doctor. You must be monitored to check how you respond to treatment. Your doctor will check your blood pressure, pulse rate and lung function. Your doctor will also carry out some blood tests during treatment.


• If you have had one of the following conditions you will be monitored in the hospital during the next treatment days or the next cycles of treatment:
  
  
  • bleeding ulcers,
  • stroke,
  • narrowing of the arteries (systemic peripheral arterial disease),
  • heart disease (for severe heart problems see above "Do NOT use Ceplene"),
  • a history of auto-immune disease (a disease where the immune system attacks the body's own cells or tissues, such as systemic lupus, rheumatoid arthritis, inflammatory bowel disease or psoriasis.


• If you are taking any other medicines mentioned under "Taking other medicines" or if you are to have an operation or special X-ray investigation requiring an injection, talk to your doctor.


• If you have an infection your doctor will closely monitor you.
  
  If you have had an infection within 14 days of starting this treatment which required you to take medicines to treat infections (antibiotics, antifungals or antivirals) your doctor will closely monitor you.


• If you have kidney problems, talk to your doctor before using this medicine.
  
  A decrease of blood pressure may occur.


• If you have liver problems, talk to your doctor before using this medicine. Your doctor may change your dose.

Children and adolescents

Ceplene use is not recommended in children and adolescents, as there is no information available about using this medicine in this age group.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

If you are taking any of the following medicines, please be sure to discuss this with your doctor or pharmacist before using Ceplene. Some of them must not be taken during treatment with Ceplene or may need special precautions:

• 
  Steroids such as prednisone and dexamethasone. They are used to inhibit activity of the immune system (immunosuppressant) and to reduce inflammation (see above "Do NOT use Ceplene").


• 
  H₂ blockers such as cimetidine, ranitidine, famotidine, or nizatidine which are used to treat stomach ulcers, indigestion (dyspepsia) or heartburn (see above “Do NOT use Ceplene”).


• 
  Antihistamines used to treat allergy.


• Certain anti-psychotics such as chlorpromazine, flupenthixol, thoridazine, clozapine and risperidone. They are used to treat mental conditions.


• 
  Tricyclic antidepressant medicines such as amitryptiline, imipramine or monoamine oxidase inhibitors, such as phenelzine, isocarboxazide, tranylcypromine or moclobemide. They are used to treat depression.


• 
  Malaria or medicines used to treat infections responsible for sleeping sickness.
  


• 
  Beta-blockers, such as propranolol, metoprolol, atenolol for angina and heart beat disorders or any treatment of high blood pressure (for example thiazide diuretics (bendrofluazide), ACE inhibitors (captropil), calcium antagonist (nifedipine) and alpha-blockers (prazosin).

Also, if you are to have an operation or special X-ray investigation requiring an injection, first make sure that your doctor knows that you are receiving Ceplene. Certain medicines used for an operation (for example neuromuscular blocking medicines and narcotic pain-killers) or dyes used for certain X-rays may interfere with this medicine.

Pregnancy and breast-feeding

There is no information about the use of Ceplene in pregnant women. Therefore, the treatment with Ceplene and IL-2 must not be used during pregnancy.

It is not known whether Ceplene appears in breast milk. Therefore Ceplene and IL-2 must not be used during breast-feeding.

For both men and women using this treatment, contraception must be used as it is important to not conceive a child while being treated with Ceplene and IL-2.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Do not drive or use machines within one hour after receiving a Ceplene injection as it may reduce blood pressure causing dizziness, light-headedness and blurred vision which can affect your ability to drive and operate machines.

How To Use Ceplene

Always use Ceplene exactly as your doctor has instructed. You should check with your doctor or pharmacist if you are not sure about this.

This treatment must be prescribed and supervised by a physician with knowledge of acute myeloid leukaemia.

Dosage

Since you will be using both IL-2 and Ceplene in a combined treatment, information about both dosages is provided:

Interleukin-2 (IL-2)

IL-2 is injected twice daily as a subcutaneous injection (in the layer of tissue just under the skin) 1 to 3 minutes before the injection of Ceplene. Each dose is calculated from your body weight. You should use 16,400 IU* per kg bodyweight. Your doctor will let you know how much it is and how to inject it.

*IU=international units, a measurement specifying the amount of IL-2

Ceplene

The usual dose of Ceplene is 0.5 ml (or 0.5 mg) twice a day given as a slow subcutaneous injection (in the layer of tissue just under the skin).

Ceplene must be injected 1 to 3 minutes after IL-2

The two medicines, IL-2 and Ceplene , are both injected twice a day, with a minimum of 6 hours between injections.

Treatment periods and treatment breaks

The treatment with IL-2 and Ceplene lasts for 81 weeks and is cyclic.

• For the first 18 weeks: you will use IL-2 and Ceplene daily for 3 weeks, followed by a 3 week break (no treatment at all).


• For the following 63 weeks: you will use IL-2 and Ceplene daily for 3 weeks, followed by a 6 week break (no treatment at all).

Injecting Ceplene yourself

Your doctor may decide that it would be more convenient for you to inject IL-2 and Ceplene yourself.

Your doctor or nurse will show you how to inject yourself. Do not try to inject yourself unless a qualified professional has trained you.

It is recommended that you always have someone with you when injecting this medicine, such as an adult family member, friend, or other care provider who could help you if you feel light-headed or faint.

For further instructions on how to inject this medicine yourself, please read the section "INSTRUCTIONS FOR SELF-INJECTION OF CEPLENE " at the end of this leaflet.

Your doctor may advise you that it is appropriate to use a syringe pump to regulate the injection of Ceplene. If you are using a syringe pump you must refer to the instructions provided by the pump manufacturer and the training provided by your doctor, nurse and/or pharmacist.

If you have used more Ceplene than you should

You must use this medicine exactly as it has been prescribed for you. If you accidentally inject more than you were told to, contact your doctor or pharmacist immediately.

If you forget a dose of Ceplene

Do not take any additional dose to make up for the forgotten doses. Continue with the treatment as prescribed. If you have missed one of your doses in a day, contact your doctor or pharmacist.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines, Ceplene can cause side effects, although not everybody gets them.

If you experience any side effects during or soon after the injection, tell your doctor.

Side effects observed when Ceplene is used as described in this package leaflet

Very common side effects (occurs in more than 1 in 10 people who use the medicine)

• Increase in the number of a certain type of white blood cells in the blood (eosinophilia) and decrease in the number of blood platelets (thrombocytopenia)


• Headache, dizziness and tiredness


• Altered taste (dysgeusia)


• Rapid heart beat (tachycardia)


• Flushing and low blood pressure (hypotension) leading to light-headedness and fainting


• Cough, difficulty in breathing (dyspnoea)


• Nausea, indigestion (dyspepsia) and diarrhoea


• Rash


• Joint and muscle pain (arthralgia and myalgia)


• Inflamed granulated skin at the injection site, fatigue, fever (pyrexia), injection site redness, feeling hot, itching at the injection site, flu-like symptoms, shivering (rigors), injection site inflammation and pain.

Common side effects (occurs in less than 1 in 10 people but more than 1 in 100 people who use the medicine)

• Loss of appetite


• Difficulty in sleeping (insomnia)


• Feeling your own heart beat (palpitations)


• Nasal congestion


• Vomiting, upper abdominal pain and dry mouth


• Abnormal redness of the skin (erythema), increased sweating, night sweats and itching (pruritus)


• Pain in limbs and back pain


• Hives, bruising, rash and swelling at the injection site, weakness and chest pain

Side effects observed when Ceplene was used in other types of treatment

Very common side effects (occurs in more than 1 in 10 people who use the medicine)

• Dry skin


• Anxiety


• Feeling of general discomfort or unease


• Accumulation of fluid in the body especially in the legs and loss of weight

Common side effects (occurs in less than 1 in 10 people but more than 1 in 100 people who use the medicine)

• Sensation of spinning (vertigo)


• Your body does not make enough thyroxine, a body chemical called a hormone (hypothyroidism)


• Decrease in the number of red blood cells (anaemia)


• Dehydration


• Depression


• Tingling, prickling or numbness of the skin (paraesthesis)


• Hot flushes


• Wheezing


• Constipation, swollen stomach, inflamed mouth


• Pain and formation of extra tissue in the skin around the injection site

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Ceplene

Keep out of the reach and sight of children.

Do not use Ceplene after the expiry date which is stated on the carton and vial label.

The expiry date refers to the last day of that month.

Do not freeze.

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Ceplene contains

• The active substance is histamine. One vial contains 0.5 mg histamine dihydrochloride in 0.5 ml
  solution.


• The other ingredients are water for injections and sodium chloride, and it may also contain sodium hydroxide and/or hydrochloric acid for pH adjustment.

What Ceplene looks like

Ceplene is a clear, colourless liquid. It is provided in a glass vial with a grey rubber stopper and a blue peel flip off aluminium tamper evident over seal.

Ceplene is available in pack sizes of 14 single-use vials.

Marketing Authorisation Holder

EpiCept GmbH

Goethestrasse 4

D-80336 München

Germany

Manufacturer

Catalent UK Packaging Ltd

Lancaster Way

Wingates Industrial Park

Westhoughton

Bolton

Lancashire

BL5 3XX

United Kingdom

This leaflet was last approved in 10/2008

This medicine has been authorised under "Exceptional circumstances". This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicine. The European Medicines Agency (EMEA) will review any new information on this medicine every year and this package leaflet will be updated as necessary. Detailed information on this medicine is available on the European Medicines Agency (EMEA) website: http://www.emea.europa.eu. There are also links to other websites about rare diseases and treatments.

Instructions For Self-Injection Of Ceplene

This section contains information on how to give yourself an injection of Ceplene.

For general information about the dosage and how to use Ceplene and IL-2, please see Section 3, "HOW TO USE CEPLENE".

Read the following instructions carefully. It is important that you do not try to give yourself the injection unless you have received special training from your doctor or nurse. If you are not sure about how to give yourself the injection or you have any questions, please ask your doctor or nurse for help.

If you feel faint or dizzy during or after the injections, tell your doctor before injecting your next dose. Your doctor may want to increase the time you take to complete your injection, or change your dose.

You will have to inject Ceplene and IL-2 twice a day by subcutaneous injection (in the layer of tissue just under the skin), according to the directions provided by your doctor.

Always inject IL-2 first. Ceplene must be injected 1 to 3 minutes later.

Ceplene must not be mixed with any other products and must not be diluted.

Your doctor will explain to you how to prepare and inject IL-2.

It is recommended that you always have someone with you when injecting Ceplene, such as an adult family member, friend, or other care provider to help you if you feel light-headed or faint.

Preparation For Injection Of Ceplene

To prepare a dose of Ceplene you will need the following:

• 1 vial of Ceplene solution (0.5ml)


• 1 sterile syringe with needle


• 1 alcohol wipe

Method

1. Take 1 vial out of the carton. Check the expiry date (EXP) on the vial label.

2. Do not use if the date has passed the last day of the month shown.

3. Wash your hands thoroughly with soap and water.

4. Double check the vial label to make sure you are using the correct medicine. The solution must be clear and colourless. If not, use another vial and inform your doctor or pharmacist.

5. Remove the plastic cap from the vial, exposing the stopper with the inner rubber circle.

6. Use an alcohol wipe to clean the rubber part of the stopper. Do not touch the stopper with your hands.

7. Pick up the sterile syringe. Notice the numbered marks on it. Each mark (0.1, 0.2, 0.3, etc) represents one-tenth of a millilitre (0.1 ml). With the needle cover on, pull back the plunger and draw air into the syringe to the level (number of millilitres) instructed by your doctor. See Figure 1.

8. Pull the needle cover straight off. With the vial standing on a flat surface, insert the needle straight through the rubber stopper into the vial.

9. Push the plunger of the syringe down to inject air into the vial. See Figure 2.

10. Holding both the vial and the syringe, turn the vial upside down. Adjust the syringe so that the tip of the needle is slightly above the rubber stopper but still within the solution. See Figure 3.

11. Slowly pull back the plunger to draw the solution into the syringe, filling it to the level (number of millilitres) instructed by your doctor. If bubbles appear in the syringe, push the solution slowly back into the vial and withdraw the solution again.

12. Take the needle out of the vial. Do not lay the syringe down or let the needle touch anything.

13. Replace the cover on the needle. Place the syringe on a clean flat surface.

14. There may be a small amount of solution left in the vial.

This is to be returned to the pharmacist for disposal.

15. Double check the syringe to make sure that you have withdrawn the correct amount.

16. Take the syringe and follow the "INSTRUCTIONS FOR INJECTION" information below.

Instructions For Injection

You will usually inject two doses of 0.5 ml in a day, unless your doctor has prescribed a lower dose for you.

For injection you will need the following:

• 1 prepared syringe for your IL-2 injection (refer to the IL-2 package leaflet and your doctor's dose instructions)


• 1 prepared syringe containing Ceplene


• Alcohol wipe(s)


• A timer, clock or watch with a second hand


• A puncture-proof container so you can dispose of used syringes safely

Method

1. Find a comfortable, well-lit place to sit and where you can lie back. Place the pre-prepared syringes containing IL-2, Ceplene and an opened alcohol wipe where you can reach them. For your safety it is very important that you are sitting where you can lean back or lie flat when you perform the injections.

2. Inject IL-2 as you have been instructed.

3. Wait 1 to 3 minutes.

4. Decide where you will inject Ceplene.

You may choose the inner or outer thighs, arms or stomach. Ceplene and IL-2 must not be injected into the same region. For example, if you inject IL-2 in the left arm, you could inject Ceplene into the left or right thigh, the stomach, or the right arm. Always vary the site that you inject. For possible injection sites, see Figure 4.

5. Make sure that the area of the skin you selected is exposed. Use an alcohol wipe to clean it. Allow the area to dry for 10 seconds.

6. Pinch up a section of the cleaned skin between your thumb and forefinger, without squeezing it. See Figure 5.

7. Hold needle either vertically (90°) or at a 45° angle to the skin and insert it under the skin as far as it will go in one quick motion. The needle must be inserted under the skin, but not into any blood vessels below the skin, See Figure 6.

8. Slightly pull back the plunger. If blood appears, do not inject Ceplene because the needle has entered a blood vessel. Withdraw and discard the syringe as instructed. Obtain new supplies and start the procedure over again, even if 3 minutes have passed after injection of IL-2.


9. Notice the numbered marks on each syringe. Each mark (0.1, 0.2, 0.3, etc.) represents one-tenth of a millilitre (0.1 ml).


10. Push down the syringe plunger and inject one-tenth of a millilitre (0.1 ml) every minute, or more slowly if instructed to do so by your doctor. See Figure 7.

11. Never inject Ceplene any faster or all at once.

12. When the syringe is empty remove the needle from your skin.

13. Apply gentle pressure with the alcohol wipe over the injection site without rubbing it

14. Remain seated or lying down for 20 minutes after injecting Ceplene.

15. Dispose of the syringe in the puncture-proof container as instructed.

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