Calamine and Glycerin Cream (Boots Company plc)

1. Name Of The Medicinal Product

Calamine and Glycerin Cream

2. Qualitative And Quantitative Composition

Active Ingredients	% w/w
Zinc Oxide Ph Eur	5
Calamine BP	15
Glycerin Ph Eur	5

3. Pharmaceutical Form

Cream

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of sunburn, windburn, rough, dry hands, chapped and tender skin and for the relief of skin irritation.

4.2 Posology And Method Of Administration

For topical application

Adults and Children:

To be applied gently to the affected parts when required.

4.3 Contraindications

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

For external use only.

Keep all medicines out of the reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant drug interactions known.

4.6 Pregnancy And Lactation

The safety of Calamine and Glycerin Cream during pregnancy and lactation has not been established but its use during these periods is not considered to constitute a hazard.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

Occasional hypersensitivity or irritant reactions.

4.9 Overdose

Symptoms of overdosage include anorexia, nausea, vomiting, epigastric discomfort and diarrhoea. Treatment consists of symptomatic measures only.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Calamine has a mild astringent action on the skin. Zinc oxide has mild astringent, soothing and protective qualities.

Glycerol has emollient properties.

5.2 Pharmacokinetic Properties

Not available.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Polawax A31

Paraffin light liquid

Isopropyl myristate

Polysorbate 80

Bentonite

Sodium citrate gran

Water purified

Liquefied phenol

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

An internally lacquered collapsible tube with latex welt having a polypropylene or polythene cap, in a cardboard carton.

Pack size: 35 gm.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham NG2 3AA

8. Marketing Authorisation Number(S)

PL 00014/5129R

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of First Authorisation:	9 November 1984
Last Renewal:	22 December 1994

10. Date Of Revision Of The Text

December 2002

Calcium Folinate 10 mg / mL Injection

1. Name Of The Medicinal Product

Calcium Folinate 10 mg/mL Injection

2. Qualitative And Quantitative Composition

Each vial of 10 ml solution contains 10 mg/ml of folinic acid provided as calcium folinate.

For excipients, see 6.1.

3. Pharmaceutical Form

Solution for Injection

4. Clinical Particulars

4.1 Therapeutic Indications

Calcium folinate is indicated

a) to diminish the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy and overdose in adults and children. In cytotoxic therapy, this procedure is commonly known as “Calcium Folinate Rescue”;

b) in combination with 5-fluorouracil in cytotoxic therapy.

4.2 Posology And Method Of Administration

For intravenous and intramuscular administration only. In the case of intravenous administration, no more than 160 mg of calcium folinate should be injected per minute due to the calcium content of the solution.

For intravenous infusion, calcium folinate may be diluted with 0.9% sodium chloride solution or 5% glucose solution before use. Refer also to sections 6.3 and 6.6.

Calcium folinate rescue in methotrexate therapy:

Since the calcium folinate rescue dosage regimen depends heavily on the posology and method of the intermediate- or high-dose methotrexate administration, the methotrexate protocol will dictate the dosage regimen of calcium folinate rescue. Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate.

The following guidelines may serve as an illustration of regimens used in adults, elderly and children:

Calcium folinate rescue has to be performed by parenteral administration in patients with malabsorption syndromes or other gastrointestinal disorders where enteral absorption is not assured. Dosages above 25-50 mg should be given parenterally due to saturable enteral absorption of calcium folinate.

Calcium folinate rescue is necessary when methotrexate is given at doses exceeding 500 mg/m² body surface and should be considered with doses of 100 mg – 500 mg/m² body surface.

Dosage and duration of calcium folinate rescue primarily depend on the type and dosage of methotrexate therapy, the occurrence of toxicity symptoms, and the individual excretion capacity for methotrexate. As a rule, the first dose of calcium folinate is 15 mg (6-12 mg/m²) to be given 12-24 hours (24 hours at the latest) after the beginning of methotrexate infusion. The same dose is given every 6 hours throughout a period of 72 hours. After several parenteral doses treatment can be switched over to the oral form.

In addition to calcium folinate administration, measures to ensure the prompt excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the calcium folinate rescue treatment. Renal function should be monitored through daily measurements of serum creatinine.

Forty-eight hours after the start of the methotrexate infusion, the residual methotrexate-level should be measured. If the residual methotrexate-level is >0.5 µmol/l, calcium folinate dosages should be adapted according to the following table:

Residual methotrexate blood level 48 hours after the start of the methotrexate administration:	Additional calcium folinate to be administered every 6 hours for 48 hours or until levels of methotrexate are lower than 0.05 µmol/l:
> 0.5 µmol/l	15 mg/m²
> 1.0 µmol/l	100 mg/m²
> 2.0 µmol/l	200 mg/m²

In combination with 5-fluorouracil in cytotoxic therapy:

Different regimens and different dosages are used, without any dosage having been proven to be the optimal one.

The following regimens have been used in adults and elderly in the treatment of advanced or metastatic colorectal cancer and are given as examples. There are no data on the use of these combinations in children:

Bimonthly regimen: Calcium folinate 200 mg/m² by intravenous infusion over two hours, followed by bolus 400 mg/m² of 5-FU and 22-hour infusion of 5-FU (600 mg/m²) for 2 consecutive days, every 2 weeks on days 1 and 2.

Weekly regimen: Calcium folinate 20 mg/m² by bolus i.v. injection or 200 to 500 mg/m² as i.v. infusion over a period of 2 hours plus 500 mg/m² 5-fluorouracil as i.v. bolus injection in the middle or at the end of the calcium folinate infusion.

Monthly regimen: Calcium folinate 20 mg/m² by bolus i.v. injection or 200 to 500 mg/m² as i.v. infusion over a period of 2 hours immediately followed by 425 or 370 mg/m² 5-fluorouracil as i.v. bolus injection during five consecutive days.

For the combination therapy with 5-fluorouracil, modification of the 5-fluorouracil dosage and the treatment-free interval may be necessary depending on patient condition, clinical response and dose limiting toxicity as stated in the product information of 5-fluorouracil. A reduction of calcium folinate dosage is not required.

The number of repeat cycles used is at the discretion of the clinician.

Antidote to the folic acid antagonists trimetrexate, trimethoprim, and pyrimethamine:

Trimetrexate toxicity:

• Prevention: Calcium folinate should be administered every day during treatment with trimetrexate and for 72 hours after the last dose of trimetrexate. Calcium folinate can be administered either by the intravenous route at a dose of 20 mg/m² for 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m², or by oral route with four doses of 20 mg/m² administered at equal time intervals. Daily doses of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.

• Overdosage (possibly occurring with trimetrexate doses above 90 mg/m² without concomitant administration of calcium folinate): after stopping trimetrexate, calcium folinate 40 mg/m² IV every 6 hours for 3 days.

Trimethoprim toxicity:

• After stopping trimethoprim, 3-10 mg/day calcium folinate until recovery of a normal blood count.

Pyrimethamine toxicity:

• In case of high dose pyrimethamine or prolonged treatment with low doses, calcium folinate 5 to 50 mg/day should be simultaneously administered, based on the results of the peripheral blood counts.

4.3 Contraindications

• Known hypersensitivity to calcium folinate, or to any of the excipients.

• Pernicious anaemia or other anaemias due to vitamin B12 deficiency.

Regarding the use of calcium folinate with methotrexate or 5-fluorouracil during pregnancy and lactation, see section 4.6, “Pregnancy and Lactation” and the summaries of product characteristics for methotrexate- and 5-fluorouracil- containing medicinal products.

4.4 Special Warnings And Precautions For Use

Calcium folinate should only be given by intramuscular or intravenous injection and must not be administered intrathecally. When folinic acid has been administered intrathecally following intrathecal overdose of methotrexate death has been reported.

General

Calcium folinate should be used with methotrexate or 5-fluorouracil only under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.

Calcium folinate treatment may mask pernicious anaemia and other anaemias resulting from vitamin B12 deficiency.

Many cytotoxic medicinal products – direct or indirect DNA synthesis inhibitors – lead to macrocytosis (hydroxycarbamide, cytarabine, mecaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.

In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides there is a risk to increase the frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs. Clinical monitoring, possibly monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic drug during calcium folinate administration and after discontinuation is recommended (see also section 4.5 Interactions).

Calcium folinate/5-fluorouracil

Calcium folinate may enhance the toxicity risk of 5-fluorouracil, particularly in elderly or debilitated patients. The most common manifestations are leucopenia, mucositis, stomatitis and/or diarrhoea, which may be dose limiting. When calcium folinate and 5-fluorouracil are used in combination, the 5- fluorouracil dosage has to be reduced more in cases of toxicity than when 5-fluorouracil is used alone.

Combined 5-fluorouracil/calcium folinate treatment should neither be initiated nor maintained in patients with symptoms of gastrointestinal toxicity, regardless of the severity, until all of these symptoms have completely disappeared.

Because diarrhoea may be a sign of gastrointestinal toxicity, patients presenting with diarrhoea must be carefully monitored until the symptoms have disappeared completely, since a rapid clinical deterioration leading to death can occur. If diarrhoea and/or stomatitis occur, it is advisable to reduce the dose of 5-FU until symptoms have fully disappeared. Especially the elderly and patients with a low physical performance due to their illness are prone to these toxicities. Therefore, particular care should be taken when treating these patients.

In elderly patients and patients who have undergone preliminary radiotherapy, it is recommended to begin with a reduced dosage of 5-fluorouracil.

Calcium folinate must not be mixed with 5-fluorouracil in the same IV injection or infusion.

Calcium levels should be monitored in patients receiving combined 5-fluorouracil/calcium folinate treatment and calcium supplementation should be provided if calcium levels are low.

Calcium folinate/methotrexate

For specific details on reduction of methotrexate toxicity refer to the SPC of methotrexate.

Calcium folinate has no effect on non-haematological toxicities of methotrexate such as the nephrotoxicity resulting from methotrexate and/or metabolite precipitation in the kidney. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure and all toxicities associated with methotrexate (please refer to the SPC for methotrexate). The presence of preexisting- or methotrexate-induced renal insufficiency is potentially associated with delayed excretion of methotrexate and may increase the need for higher doses or more prolonged use of calcium folinate.

Excessive calcium folinate doses must be avoided since this might impair the antitumour activity of methotrexate, especially in CNS tumours where calcium folinate accumulates after repeated courses.

Resistance to methotrexate as a result of decreased membrane transport implies also resistance to folinic acid rescue as both medicinal products share the same transport system.

An accidental overdose with a folate antagonist, such as methotrexate, should be treated as a medical emergency. As the time interval between methotrexate administration and calcium folinate rescue increases, calcium folinate effectiveness in counteracting toxicity decreases.

The possibility that the patient is taking other medications that interact with methotrexate (eg, medications which may interfere with methotrexate elimination or binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicities are observed.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

When calcium folinate is given in conjunction with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may either be reduced or completely neutralised.

Calcium folinate may diminish the effect of anti-epileptic substances: phenobarbital, primidone, phenytoin and succinimides, and may increase the frequency of seizures (a decrease of plasma levels of enzymatic inductor anticonvulsant drugs may be observed because the hepatic metabolism is increased as folates are one of the cofactors) (see also sections 4.4 and 4.8).

Concomitant administration of calcium folinate with 5-fluorouracil has been shown to enhance the efficacy and toxicity of 5-fluorouracil (see sections 4.2, 4.4 and 4.8).

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women. No formal animal reproductive toxicity studies with calcium folinate have been conducted. There are no indications that folic acid induces harmful effects if administered during pregnancy. During pregnancy, methotrexate should only be administered on strict indications, where the benefits of the drug to the mother should be weighed against possible hazards to the foetus. Should treatment with methotrexate or other folate antagonists take place despite pregnancy or lactation, there are no limitations as to the use of calcium folinate to diminish toxicity or counteract the effects.

5-fluorouracil use is generally contraindicated during pregnancy and contraindicated during breastfeeding; this applies also to the combined use of calcium folinate with 5-fluorouracil.

Please refer also to the summaries of product characteristics for methotrexate-, other folate antagonists and 5-fluorouracil- containing medicinal products.

Lactation

It is not known whether calcium folinate is excreted into human breast milk. Calcium folinate can be used during breast feeding when considered necessary according to the therapeutic indications.

4.7 Effects On Ability To Drive And Use Machines

There is no evidence that calcium folinate has an effect on the ability to drive or use machines.

4.8 Undesirable Effects

Immune system disorders

Very rare (<0.01%): allergic reactions, including anaphylactoid reactions and urticaria.

Psychiatric disorders

Rare (0.01-0.1%): insomnia, agitation and depression after high doses.

Gastrointestinal disorders

Rare (0.01-0.1%): gastrointestinal disorders after high doses.

Neurological disorders

Rare (0.01-0.1%): increase in the frequency of attacks in epileptics (see also section 4.5 Interactions...).

General disorders and administration site conditions

Uncommon (0.1-1%): fever has been observed after administration of calcium folinate as solution for injection.

Combination therapy with 5-fluorouracil:

Generally, the safety profile depends on the applied regimen of 5-fluorouracil due to enhancement of the 5-fluorouracil induced toxicities:

Monthly regimen:

Gastrointestinal disorders

Very common (>10%): vomiting and nausea

General disorders and administration site conditions

Very common (>10%): (severe) mucosal toxicity.

No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity).

Weekly regimen:

Gastrointestinal disorders

Very common (>10%): diarrhoea with higher grades of toxicity, and dehydration, resulting in hospital admission for treatment and even death.

4.9 Overdose

There have been no reported sequelae in patients who have received significantly more calcium folinate than the recommended dosage. However, excessive amounts of calcium folinate may nullify the chemotherapeutic effect of folic acid antagonists.

Should overdosage of the combination of 5-fluorouracil and calcium folinate occur, the overdosage instructions for 5-FU should be followed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment; ATC code: V03AF03

Calcium folinate is the calcium salt of 5-formyl tetrahydrofolic acid. It is an active metabolite of folinic acid and an essential coenzyme for nucleic acid synthesis in cytotoxic therapy.

Calcium folinate is frequently used to diminish the toxicity and counteract the action of folate antagonists, such as methotrexate. Calcium folinate and folate antagonists share the same membrane transport carrier and compete for transport into cells, stimulating folate antagonist efflux. It also protects cells from the effects of folate antagonist by repletion of the reduce folate pool. Calcium folinate serves as a pre-reduced source of H4 folate; it can therefore bypass folate antagonist blockage and provide a source for the various coenzyme forms of folic acid.

Calcium folinate is also frequently used in the biochemical modulation of fluoropyridine (5-FU) to enhance its cytotoxic activity. 5-FU inhibits thymidylate synthase (TS), a key enzyme involved in pyrimidine biosynthesis, and calcium folinate enhances TS inhibition by increasing the intracellular folate pool, thus stabilising the 5FU-TS complex and increasing activity.

Finally intravenous calcium folinate can be administered for the prevention and treatment of folate deficiency when it cannot be prevented or corrected by the administration of folic acid by the oral route. This may be the case during total parenteral nutrition and severe malabsorption disorders. It is also indicated for the treatment of megaloblastic anaemia due to folic acid deficiency, when oral administration is not feasible.

5.2 Pharmacokinetic Properties

Absorption

Following intramuscular administration of the aqueous solution, systemic availability is comparable to an intravenous administration. However, lower peak serum levels (Cmax) are achieved.

Metabolism

Calcium folinate is a racemate where the L-form (L-5-formyl-tetrahydrofolate, L-5-formyl-THF), is the active enantiomer. The major metabolic product of folinic acid is 5-methyl-tetrahydrofolic acid (5-methyl-THF) which is predominantly produced in the liver and intestinal mucosa.

Distribution

The distribution volume of folinic acid is not known.

Peak serum levels of the parent substance (D/L-5-formyl-tetrahydrofolic acid, folinic acid) are reached 10 minutes after i.v. administration.

AUC for L-5-formyl-THF and 5-methyl-THF were 28.4±3.5 mg.min/l and 129±112 mg.min/l after a dose of 25 mg. The inactive D-isomer is present in higher concentration than L-5-formyltetrahydrofolate.

Elimination

The elimination half-life is 32 - 35 minutes for the active L-form and 352 - 485 minutes for the inactive D-form, respectively.

The total terminal half-life of the active metabolites is about 6 hours (after intravenous and intramuscular administration).

Excretion

80-90 % with the urine (5- and 10-formyl-tetrahydrofolates inactive metabolites), 5-8 % with the faeces.

5.3 Preclinical Safety Data

There are no preclinical data considered relevant to clinical safety beyond data included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Water for Injections

6.2 Incompatibilities

Incompatibilities have been reported between injectable forms of calcium folinate and injectable forms of droperidol, fluorouracil, foscarnet and methotrexate.

Droperidol

1. Droperidol 1.25 mg/0.5 ml with calcium folinate 5 mg/0.5 ml, immediate precipitation in direct admixture in syringe for 5 minutes at 25° C followed by 8 minutes of centrifugation.

2. Droperidol 2.5 mg/0.5 ml with calcium folinate 10 mg/0.5 ml, immediate precipitation when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections.

Fluorouracil

Calcium folinate must not be mixed in the same infusion as 5-fluorouracil because a precipitate may form. Fluorouracil 50 mg/ml with calcium folinate 20 mg/ml, with or without dextrose 5% in water, has been shown to be incompatible when mixed in different amounts and stored at 4°C, 23°C, or 32° C in polyvinyl chloride containers.

Foscarnet

Foscarnet 24 mg/ml with calcium folinate 20 mg/ml formation of a cloudy yellow solution reported.

6.3 Shelf Life

Product as packaged for sale: 24 months.

In use: From a microbial point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally mot be longer than 24 hours at 2 to 8°C.

6.4 Special Precautions For Storage

Store in a refrigerator (+2°C to +8°C)

Keep vial in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

5 mL Type I glass vials (50 mg/5 mL)

10 mL Type I glass vials (100 mg/10 mL)

30 mL Type I glass vials (300 mg/30 mL)

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Prior to administration, calcium folinate should be inspected visually. The solution for injection or infusion should be a clear and yellowish solution. If cloudy in appearance or particles are observed, the solution should be discarded. Calcium folinate solution for injection or infusion is intended only for single use. Any unused portion of the solution should be disposed of in accordance with the local requirements.

7. Marketing Authorisation Holder

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

UK

8. Marketing Authorisation Number(S)

PL 04515/0069

9. Date Of First Authorisation/Renewal Of The Authorisation

March 2003

10. Date Of Revision Of The Text

January 2008

Calcough Children's Soothing Syrup

1. Name Of The Medicinal Product

Glycerin and Blackcurrant Soothing Cough Syrup or Glycerin and Blackcurrant Linctus or Benylin Dry Coughs Blackcurrant or CalCough Children's Soothing Syrup or Benylin Children's Blackcurrant Flavour Cough Syrup

2. Qualitative And Quantitative Composition

Active Ingredient Glycerin Ph. Eur. Liquid sugar (Equivalent to sucrose B.P.

Quantity per 5ml 0.75ml 1.93ml 1.7g)

3. Pharmaceutical Form

Liquid

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of irritating, tickling dry coughs and sore throats.

4.2 Posology And Method Of Administration

Adults, elderly and children over 5 years: 10ml

Children 1 - 5 years: 5ml

The dose may be repeated three or four times a day.

Children under one year: Not to be given to children under 1 year.

For oral administration.

4.3 Contraindications

Hypersensitivity or intolerance to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Diabetics should take note of the carbohydrate content of this product.

Do not give to children under one year.

Keep all medicines out of the reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant interactions known.

4.6 Pregnancy And Lactation

The safety of this medicine during pregnancy and lactation has not been established, but is not considered to constitute a hazard during these periods.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

No adverse effects would be anticipated.

4.9 Overdose

Overdosage would not be expected to cause any problems and treatment would be merely symptomatic and supportive.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Glycerin and sucrose have demulcent properties and will soothe irritated sore throats and possibly block sensory cough receptors within the respiratory tract.

5.2 Pharmacokinetic Properties

Glycerin is readily absorbed from the gastrointestinal tract and undergoes extensive metabolism principally in the liver. It may be used in the synthesis of lipids, and is metabolised to glucose or glycogen or oxidised to carbon dioxide and water. It may also be excreted in the urine unchanged.

Sucrose is hydrolysed in the small intestine by the enzyme sucrase to glucose and fructose which are then absorbed.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Citric acid monohydrate gran

Sodium benzoate

Anthocyanin

Blackcurrant Flavour 1740.7107 IFF

Blackcurrant Juice 1740.1436 IFF

Liquid Glucose BPC 1963

Purified Water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

None stated.

6.5 Nature And Contents Of Container

125ml, 150ml or 200ml white flint glass, or amber glass bottle with an aluminium roll-on pilfer-proof cap with a flowed in liner, or a triseal (LDPE/EPE/LDPE) liner.

Alternative caps: A wadless polypropylene tamper evident cap, or a child resistant polypropylene cap with a LDPE liner.

A double ended measuring spoon of 2.5ml and 5.0ml capacity may optionally be provided with the product.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham NG2 3AA

Trading as: BCM

8. Marketing Authorisation Number(S)

PL 00014/0307

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of First Authorisation: Date of Last Renewal:

14 March 1984 25 July 2000

10. Date Of Revision Of The Text

April 2010

Cerezyme 400 U Powder for concentrate for solution for infusion

1. Name Of The Medicinal Product

Cerezyme 400 U Powder for concentrate for solution for infusion

2. Qualitative And Quantitative Composition

Each vial contains 400 units* of imiglucerase**.

After reconstitution, the solution contains 40 units (approximately 1.0 mg) of imiglucerase per ml (400 U/10 ml).

* An enzyme unit (U) is defined as the amount of enzyme that catalyses the hydrolysis of one micromole of the synthetic substrate para-nitrophenyl β-D-glucopyranoside (pNP-Glc) per minute at 37°C.

** Imiglucerase is a modified form of human acid β-glucosidase and is produced by recombinant DNA technology using a mammalian Chinese Hamster Ovary (CHO) cell culture, with mannose modification for targeting macrophages.

Excipients:

For a full list of excipients, see section 6.1.

This medicinal product contains sodium and is administered in 0.9% sodium chloride intravenous solution (see section 6.6). After reconstitution, the solution contains 1.24 mmol sodium (400 U/10 mL). To be taken into consideration by patients on a controlled sodium diet.

3. Pharmaceutical Form

Powder for concentrate for solution for infusion.

Cerezyme is a white to off-white powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Cerezyme (imiglucerase) is indicated for use as long-term enzyme replacement therapy in patients with a confirmed diagnosis of non-neuronopathic (Type 1) or chronic neuronopathic (Type 3) Gaucher disease who exhibit clinically significant non-neurological manifestations of the disease.

The non-neurological manifestations of Gaucher disease include one or more of the following conditions:

• anaemia after exclusion of other causes, such as iron deficiency

• thrombocytopenia

• bone disease after exclusion of other causes such as Vitamin D deficiency

• hepatomegaly or splenomegaly

4.2 Posology And Method Of Administration

Disease management should be directed by physicians knowledgeable in the treatment of Gaucher disease.

Posology

Due to the heterogeneity and the multi-systemic nature of Gaucher disease, dosage should be individualised for each patient based on a comprehensive evaluation of all clinical manifestations of the disease. Once individual patient response for all relevant clinical manifestations is well-established, dosages and frequency of administration may be adjusted with the goal to either maintain already reached optimal parameters for all clinical manifestations or further improve those clinical parameters which have not yet been normalised.

A range of dosage regimens has proven effective towards some or all of the non-neurological manifestations of the disease. Initial doses of 60 U/kg of body weight once every 2 weeks have shown improvement in haematological and visceral parameters within 6 months of therapy and continued use has either stopped progression of or improved bone disease. Administration of doses as low as 15 U/kg of body weight once every 2 weeks has been shown to improve haematological parameters and organomegaly, but not bone parameters. The usual frequency of infusion is once every 2 weeks; this is the frequency of infusion for which the most data are available.

Paediatric population

No dose adjustment is necessary for the paediatric population.

The efficacy of Cerezyme on neurological symptoms of chronic neuronopathic Gaucher patients has not been established and no special dosage regimen can be recommended for these manifestations (see section 5.1).

Method of Administration

After reconstitution and dilution, the preparation is administered by intravenous infusion. At initial infusions, Cerezyme should be administered at a rate not exceeding 0.5 unit per kg body weight per minute. At subsequent administrations, infusion rate may be increased but should not exceed 1 unit per kg body weight per minute. Infusion rate increases should occur under supervision of a health care professional.

Infusion of Cerezyme at home may be considered for patients who are tolerating their infusions well for several months. Decision to have patient move to home infusion should be made after evaluation and recommendation by the treating physician. Infusion of Cerezyme by the patient or caregiver at home requires training by a health care professional in a clinical setting. The patient or caregiver will be instructed in infusion technique and the keeping of a treatment diary. Patients experiencing adverse events during the infusion need to immediately stop the infusion process and seek the attention of a healthcare professional. Subsequent infusions may need to occur in a clinical setting. Dose and infusion rate should remain constant while at home, and not be changed without supervision of a health care professional.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Medical or healthcare professionals are encouraged to register Gaucher patients, including those with chronic neuronopathic manifestations of the disease, in the “ICGG Gaucher Registry” (see section 5.1).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see section 4.4).

4.4 Special Warnings And Precautions For Use

Hypersensitivity

Current data using a screening ELISA followed by a confirmatory radioimmunoprecipitation assay, suggest that, during the first year of therapy, IgG antibodies to imiglucerase are formed in approximately 15% of the treated patients. It appears that patients who will develop IgG antibody are most likely to do so within 6 months of treatment and will rarely develop antibodies to Cerezyme after 12 months of therapy. It is suggested that patients suspected of a decreased response to the treatment be monitored periodically for IgG antibody formation to imiglucerase.

Patients with antibody to imiglucerase have a higher risk of hypersensitivity reactions (see section 4.8). If a patient experiences a reaction suggestive of hypersensitivity, subsequent testing for imiglucerase antibodies is advised. As with any intravenous protein product, severe allergic-type hypersensitivity reactions are possible, but occur uncommonly. If these reactions occur, immediate discontinuation of the Cerezyme infusion is recommended and appropriate medical treatment should be initiated. The current medical standards for emergency treatment are to be observed.

Patients who have developed antibodies or symptoms of hypersensitivity to Ceredase (alglucerase) should be treated with caution when administering Cerezyme (imiglucerase).

Excipients

This medicinal product contains sodium and is administered in 0.9% sodium chloride intravenous solution (see section 6.6). To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

Limited experience from 150 pregnancy outcomes (primarily based on spontaneous reporting and literature review) is available suggesting that use of Cerezyme is beneficial to control the underlying Gaucher disease in pregnancy. Furthermore, these data indicate no malformative toxicity for the foetus by Cerezyme, although the statistical evidence is low. Foetal demise has been reported rarely, although it is not clear whether this related to the use of Cerezyme or to the underlying Gaucher disease.

No animal studies have been carried out with respect to assessing the effects of Cerezyme on pregnancy, embryonal/foetal development, parturition and postnatal development. It is not known whether Cerezyme passes via the placenta to the developing foetus.

In pregnant Gaucher patients and those intending to become pregnant, a risk-benefit treatment assessment is required for each pregnancy. Patients who have Gaucher disease and become pregnant may experience a period of increased disease activity during pregnancy and the puerperium. This includes an increased risk of skeletal manifestations, exacerbation of cytopenia, haemorrhage, and an increased need for transfusion. Both pregnancy and lactation are known to stress maternal calcium homeostasis and to accelerate bone turnover. This may contribute to skeletal disease burden in Gaucher disease.

Treatment naïve women should be advised to consider commencing therapy prior to conception in order to attain optimal health. In women receiving Cerezyme treatment continuation throughout pregnancy should be considered. Close monitoring of the pregnancy and clinical manifestations of Gaucher disease is necessary for the individualization of dose according to the patient's needs and therapeutic response.

It is not known whether this active substance is excreted in human milk, however, the enzyme is likely to be digested in the child's gastrointestinal tract

4.7 Effects On Ability To Drive And Use Machines

Cerezyme has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Adverse drug reactions are listed by system organ class and frequency (common (

Nervous system disorders
	Uncommon:	Dizziness, headache, paraesthesia*
Cardiac disorders
	Uncommon:	Tachycardia*, cyanosis*
Vascular disorders
	Uncommon:	Flushing*, hypotension*
Respiratory, thoracic and mediastinal disorders
	Common:	Dyspnoea*, coughing*
Gastrointestinal disorders
	Uncommon:	Vomiting, nausea, abdominal cramping, diarrhoea
Immune system disorders	Common: Rare :	Hypersensitivity reactions Anaphylactoid reactions
Skin and subcutaneous tissue disorders
	Common:	Urticaria/angioedema*, pruritus*, rash*
Musculoskeletal and connective tissue disorders
	Uncommon:	Arthralgia, backache*
General disorders and administration site conditions
	Uncommon:	Infusion site discomfort, infusion site burning, infusion site swelling, injection site sterile abscess, chest discomfort*, fever, rigors, fatigue

Symptoms suggestive of hypersensitivity (* marked in the table above) have been noted, overall in approximately 3% of the patients. Onset of such symptoms has occurred during or shortly after infusions. These symptoms generally respond to treatment with antihistamines and/or corticosteroids. Patients should be advised to discontinue infusion of the product and contact their physician if these symptoms occur.

4.9 Overdose

No case of overdose has been reported. In patients dosages up to 240 U/kg body weight once every two weeks have been used.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Enzymes-Imiglucerase (recombinant macrophage targeted β-glucocerebrosidase), ATC code: A16AB02.

Gaucher disease is a rare recessively inherited metabolic disorder that results from a deficiency of the lysosomal enzyme acid β-glucosidase. This enzyme breaks down glucosylceramide, a key component of the lipid structure of cell membranes, into glucose and ceramide. In individuals with Gaucher disease, glucosylceramide degradation is insufficient, leading to accumulation of large quantities of this substrate within the lysosomes of macrophages (termed 'Gaucher cells'), leading to widespread secondary pathology.

Gaucher cells are typically found in liver, spleen and bone marrow and occasionally in lung, kidney and intestine. Clinically, Gaucher disease is a heterogeneous phenotypic spectrum. The most frequent disease manifestations are hepatosplenomegaly, thrombocytopenia, anaemia, and skeletal pathology, The skeletal abnormalities are frequently the most debilitating and disabling features of Gaucher disease. These skeletal manifestations include bone marrow infiltration, osteonecrosis, bone pain and bone crises, osteopenia and osteoporosis, pathological fractures, and growth impairment. Gaucher disease is associated with increased glucose production and increased resting energy expenditure rate, which may contribute to fatigue and cachexia. Patients with Gaucher disease may also have a low grade inflammatory profile. In addition, Gaucher disease has been associated with an increased risk of immunoglobulin abnormalities such as hyperimmunoglobulinemia, polyclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. The natural history of Gaucher disease usually shows progression, with the risk of irreversible complications arising in various organs over time. The clinical manifestations of Gaucher disease can adversely affect quality of life. Gaucher disease is associated with increased morbidity and early mortality.

Signs and symptoms presenting in childhood typically represent more severe Gaucher disease. In children, Gaucher disease can lead to growth retardation and delayed puberty.

Pulmonary hypertension is a known complication of Gaucher disease. Patients who have undergone a splenectomy have an increased risk of pulmonary hypertension. Cerezyme therapy reduces the requirement for splenectomy in most cases and early treatment with Cerezyme has been associated with a reduced risk of pulmonary hypertension. Routine evaluation to detect the presence of pulmonary hypertension after diagnosis of Gaucher disease and over time is recommended. Patients diagnosed with pulmonary hypertension, in particular, should receive adequate doses of Cerezyme to ensure control of underlying Gaucher disease as well as be evaluated for the need of additional pulmonary hypertension specific treatments.

Imiglucerase (recombinant macrophage targeted acid ß

The rate and extent of response to Cerezyme treatment is dose-dependent. Generally, improvements in organ systems with a faster turnover rate, such as the haematological, can be noted far more rapidly than in those with a slower turnover, such as the bone.

In an ICGG Gaucher Registry analysis of a large cohort of patients (n=528) with Gaucher disease type 1, a time- and dose-dependent effect for Cerezyme was observed for haematological and visceral parameters (platelet count, haemoglobin concentration, spleen and liver volume) within the dose range of 15, 30 and 60 U/kg body weight once every 2 weeks. Patients treated with 60 U/kg body weight every 2 weeks showed a faster improvement and a greater maximum treatment effect as compared to patients receiving the lower doses.

Similarly, in an ICGG Gaucher Registry analysis of bone mineral density using dual-energy X-ray absorptiometry (DXA) in 342 patients, after 8 years of treatment normal bone mineral density was achieved with a Cerezyme dose of 60 U/kg body weight once every 2 weeks, but not with lower doses of 15 and 30 U/kg body weight once every 2 weeks (Wenstrup et al, 2007).

In a study investigating 2 cohorts of patients treated with a median dose of 80 U/kg body weight every 4 weeks and a median dose of 30 U/kg body weight every 4 weeks, among the patients with bone marrow burden score

Treatment with Cerezyme at a dose of 60 U/kg body weight once every 2 weeks, showed improvement in bone pain as early as 3 months, decrease in bone crises within 12 months, and improvement in bone mineral density after 24 months of treatment (Sims et al, 2008).

The usual frequency of infusion is once every 2 weeks (see section 4.2). Maintenance therapy every 4 weeks (Q4) at the same cumulative dose as the bi-weekly (Q2) dose has been studied in adult patients with stable residual Gaucher disease type 1. Changes from baseline in hemoglobin, platelets, liver and spleen volumes, bone crisis, and bone disease comprised a predefined composite endpoint; achievement or maintenance of established Gaucher disease therapeutic goals for the hematologic and visceral parameters comprised an additional endpoint. Sixty-three percent of Q4- and 81% of Q2-treated patients met the composite endpoint at Month 24; the difference was not statistically significant based on the 95% CI (-0.357, 0.058). Eighty-nine percent of Q4- and 100% of Q2-treated patients met the therapeutic goals-based endpoint; the difference was not statistically significant based on the 95% CI (-0.231, 0.060). A Q4 infusion regimen may be a therapeutic option for some adult patients with stable residual Gaucher disease type 1, but clinical data are limited.

No controlled clinical studies have been conducted on the efficacy of Cerezyme on neurological manifestations of the disease. Therefore no conclusions on the effect of enzyme replacement therapy on the neurological manifestations of the disease can be drawn.

Medical or healthcare professionals are encouraged to register Gaucher patients, including those with chronic neuronopathic manifestations of the disease, in the “ICGG Gaucher Registry”. Patient data will be anonymously collected in this Registry. The objectives of the “ICGG Gaucher Registry” are to enhance the understanding of Gaucher disease and to evaluate the effectiveness of enzyme replacement therapy, ultimately leading to improvement in the safe and efficacious use of Cerezyme.

5.2 Pharmacokinetic Properties

During 1 hour intravenous infusions of 4 doses (7.5, 15, 30, 60 U/kg) of imiglucerase, steady-state enzymatic activity was achieved by 30 minutes. Following infusion, plasma enzymatic activity declined rapidly with a half-life ranging from 3.6 to 10.4 minutes. Plasma clearance ranged from 9.8 to 20.3 ml/min/kg, (mean ± S.D, 14.5 ± 4.0 ml/min/kg). The volume of distribution corrected for weight ranged from 0.09 to 0.15 l/kg (mean ± S.D 0.12 ± 0.02 l/kg). These variables do not appear to be influenced by dose or duration of infusion, however, only 1 or 2 patients were studied at each dose level and infusion rate.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, and genotoxicicty.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol, Sodium citrate (to adjust pH), Citric acid monohydrate (to adjust pH), Polysorbate 80

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Unopened vials:

2 years.

Diluted solution:

From a microbiological safety point of view, the product should be used immediately. If not used immediately, in-use storage and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C - 8°C under protection from light.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C).

For storage conditions of the diluted medicinal product, see section 6.3

6.5 Nature And Contents Of Container

Cerezyme is supplied in type I borosilicate (clear) glass 20 ml vials. The closure consists of a siliconised butyl stopper with a tamper proof flip-off cap.

To provide sufficient volume to allow accurate dispensing, each vial is formulated to contain an overfill of 0.6 ml.

Package sizes: 1, 5 or 25 vials per carton.

Not all package sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Each vial of Cerezyme is for single use only.

The powder for concentrate for solution for infusion has to be reconstituted with water for injections, diluted with 0.9% sodium chloride intravenous solution and then administered by intravenous infusion.

Determine the number of vials to be reconstituted based on the individual patient's dosage regimen and remove the vials from the refrigerator.

Occasionally, small dosage adjustments may be made to avoid discarding partially used vials. Dosages may be rounded to the nearest full vial, as long as the monthly administered dosage remains substantially unaltered.

Use Aseptic Technique

Reconstitution

Reconstitute each vial with 10.2 ml water for injections; avoid forceful impact of water for injections on the powder and, by mixing gently, avoid foaming of the solution. The reconstituted volume is

10.6 ml. The pH of the reconstituted solution is approximately 6.1.

After reconstitution it is a clear, colourless liquid, free from foreign matter. The reconstituted solution must be further diluted. Before further dilution, visually inspect the reconstituted solution in each vial for foreign particles and discoloration. Do not use vials exhibiting foreign particles or discoloration. After reconstitution, promptly dilute vials and do not store for subsequent use.

Dilution

The reconstituted solution contains 40 units imiglucerase per ml. The reconstituted volume allows accurate withdrawal of 10.0 ml (equal to 400 units) from each vial. Withdraw 10.0 ml reconstituted solution from each vial and combine the withdrawn volumes. Then dilute the combined volumes with 0.9% sodium chloride intravenous solution to a total volume of 100 to 200 ml. Mix the infusion solution gently.

It is recommended to administer the diluted solution through an in-line low protein-binding 0.2 µm filter to remove any protein particles. This will not lead to any loss of imiglucerase activity. It is recommended that the diluted solution be administered within 3 hours. The product diluted in 0.9% sodium chloride intravenous solution will retain chemical stability if stored up to 24 hours at 2°C and 8°C under protection from light; but microbiological safety will depend on the reconstitution and dilution having been performed aseptically.

Cerezyme contains no preservatives. Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands

8. Marketing Authorisation Number(S)

EU/1/97/053/003

EU/1/97/053/004

EU/1/97/053/005

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 17 November 1997

Date of latest renewal: 17 September 2007

10. Date Of Revision Of The Text

10/2010

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

Caelyx 2mg / ml concentrate for solution for infusion

1. Name Of The Medicinal Product

Caelyx 2 mg/ml concentrate for solution for infusion

2. Qualitative And Quantitative Composition

One ml of Caelyx contains 2 mg doxorubicin hydrochloride in a pegylated liposomal formulation.

Caelyx, a liposome formulation, is doxorubicin hydrochloride encapsulated in liposomes with surface-bound methoxypolyethylene glycol (MPEG). This process is known as pegylation and protects liposomes from detection by the mononuclear phagocyte system (MPS), which increases blood circulation time.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion

The suspension is sterile, translucent and red.

4. Clinical Particulars

4.1 Therapeutic Indications

Caelyx is indicated:

- As monotherapy for patients with metastatic breast cancer, where there is an increased cardiac risk.

- For treatment of advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen.

- In combination with bortezomib for the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplant.

- For treatment of AIDS-related Kaposi's sarcoma (KS) in patients with low CD₄ counts (< 200 CD₄ lymphocytes/mm³) and extensive mucocutaneous or visceral disease.

Caelyx may be used as first-line systemic chemotherapy, or as second line chemotherapy in AIDS-KS patients with disease that has progressed with, or in patients intolerant to, prior combination systemic chemotherapy comprising at least two of the following agents: a vinca alkaloid, bleomycin and standard doxorubicin (or other anthracycline).

4.2 Posology And Method Of Administration

Caelyx should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents.

Caelyx exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride.

Breast cancer/Ovarian cancer:

Caelyx is administered intravenously at a dose of 50 mg/m² once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment.

Multiple Myeloma: Caelyx is administered at 30 mg/m² on day 4 of the bortezomib 3 week regimen as a 1 hour infusion administered immediately after the bortezomib infusion. The bortezomib regimen consists of 1.3 mg/m² on days 1, 4, 8, and 11 every 3 weeks. The dose should be repeated as long as patients respond satisfactorily and tolerate treatment. Day 4 dosing of both medicinal products may be delayed up to 48 hours as medically necessary. Doses of bortezomib should be at least 72 hours apart.

For doses < 90 mg: dilute Caelyx in 250 ml 5 % (50 mg/ml) glucose solution for infusion.

For doses

To minimize the risk of infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent Caelyx infusions may be administered over a 60-minute period.

In those patients who experience an infusion reaction, the method of infusion should be modified as follows:

5 % of the total dose should be infused slowly over the first 15 minutes. If tolerated without reaction, the infusion rate may then be doubled for the next 15 minutes. If tolerated, the infusion may then be completed over the next hour for a total infusion time of 90 minutes.

AIDS-related KS:

Caelyx is administered intravenously at 20 mg/m² every two-to-three weeks. Avoid intervals shorter than 10 days as medicinal product accumulation and increased toxicity cannot be ruled out. Treatment of patients for two-to-three months is recommended to achieve a therapeutic response. Continue treatment as needed to maintain a therapeutic response.

The dose of Caelyx is diluted in 250 ml 5 % (50 mg/ml) glucose solution for infusion and administered by intravenous infusion over 30 minutes.

For all patients:

If the patient experiences early symptoms or signs of infusion reaction (see sections 4.4 and 4.8), immediately discontinue the infusion, give appropriate premedications (antihistamine and/or short acting corticosteroid) and restart at a slower rate.

Do not administer Caelyx as a bolus injection or undiluted solution. It is recommended that the Caelyx infusion line be connected through the side port of an intravenous infusion of 5 % (50 mg/ml) glucose to achieve further dilution and minimise the risk of thrombosis and extravasation. The infusion may be given through a peripheral vein. Do not use with in-line filters. Caelyx must not be given by the intramuscular or subcutaneous route (see section 6.6).

To manage adverse events such as palmar-plantar erythrodysesthesia (PPE), stomatitis or haematological toxicity, the dose may be reduced or delayed. Guidelines for Caelyx dose modification secondary to these adverse effects are provided in the tables below. The toxicity grading in these tables is based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC).

The tables for PPE (Table 1) and stomatitis (Table 2) provide the schedule followed for dose modification in clinical trials in the treatment of breast or ovarian cancer (modification of the recommended 4 week treatment cycle): if these toxicities occur in patients with AIDS related KS, the recommended 2 to 3 week treatment cycle can be modified in a similar manner.

The table for haematological toxicity (Table 3) provides the schedule followed for dose modification in clinical trials in the treatment of patients with breast or ovarian cancer only. Dose modification in patients with AIDS-KS is addressed in 4.8.

Guidelines For Caelyx Dose Modification

Table 1. PALMAR – PLANTAR ERYTHRODYSESTHESIA
	Week After Prior Caelyx Dose
Toxicity Grade At Current Assessment	Week 4	Week 5	Week 6
Grade 1 (mild erythema, swelling, or desquamation not interfering with daily activities)	Redose unless patient has experienced a previous Grade 3 or 4 skin toxicity, in which case wait an additional week	Redose unless patient has experienced a previous Grade 3 or 4 skin toxicity, in which case wait an additional week	Decrease dose by 25 %; return to 4 week interval
Grade 2 (erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter)	Wait an additional week	Wait an additional week	Decrease dose by 25 %; return to 4 week interval
Grade 3 (blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing)	Wait an additional week	Wait an additional week	Withdraw patient
Grade 4 (diffuse or local process causing infectious complications, or a bedridden state or hospitalization)	Wait an additional week	Wait an additional week	Withdraw patient

Table 2. STOMATITIS
	Week after Prior Caelyx Dose
Toxicity Grade At Current Assessment	4	5	6
Grade 1 (painless ulcers, erythema, or mild soreness)	Redose unless patient has experienced a previous Grade 3 or 4 stomatitis in which case wait an additional week	Redose unless patient has experienced a previous Grade 3 or 4 stomatitis in which case wait an additional week	Decrease dose by 25 %; return to 4 week interval or withdraw patient per physician's assessment
Grade 2 (painful erythema, oedema, or ulcers, but can eat)	Wait an additional week	Wait an additional week	Decrease dose by 25 %; return to 4 week interval or withdraw patient per physician's assessment
Grade 3 (painful erythema, edema, or ulcers, but cannot eat)	Wait an additional week	Wait an additional week	Withdraw patient
Grade 4 (requires parenteral or enteral support)	Wait an additional week	Wait an additional week	Withdraw patient

Table 3. HAEMATOLOGICAL TOXICITY (ANC OR PLATELETS) – MANAGEMENT OF PATIENTS WITH BREAST OR OVARIAN CANCER
GRADE	ANC	PLATELETS	MODIFICATION
Grade 1	1,500 – 1,900	75,000 – 150,000	Resume treatment with no dose reduction.
Grade 2	1,000 – < 1,500	50,000 – < 75,000	Wait until ANC
Grade 3	500 – < 1,000	25,000 – < 50,000	Wait until ANC
Grade 4	< 500	< 25,000	Wait until ANC

For multiple myeloma patients treated with Caelyx in combination with bortezomib who experience PPE or stomatitis, the Caelyx dose should be modified as described in Table 1 and 2 above respectively. Table 4, below provides the schedule followed for other dose modifications in the clinical trial in the treatment of patients with multiple myeloma receiving Caelyx and bortezomib combination therapy. For more detailed information on bortezomib dosing and dosage adjustments, see the SPC for bortezomib.

Table 4. DOSAGE ADJUSTMENTS FOR CAELYX + BORTEZOMIB COMBINATION THERAPY - PATIENTS WITH MULTIPLE MYELOMA
Patient Status	Caelyx	Bortezomib
Fever 3	Do not dose this cycle if before Day 4; if after Day 4, reduce next dose by 25 %.	Reduce next dose by 25 %.
On any day of medicine administration after Day 1 of each cycle: Platelet count < 25,000/mm3 Hemoglobin < 8 g/dl ANC < 500/mm3	Do not dose this cycle if before Day 4; if after Day 4 reduce next dose by 25 % in the following cycles if bortezomib is reduced for hematologic toxicity.*	Do not dose; if 2 or more doses are not given in a cycle, reduce dose by 25 % in following cycles.
Grade 3 or 4 non-hematologic medicine related toxicity	Do not dose until recovered to Grade < 2 and reduce dose by 25 % for all subsequent doses.	Do not dose until recovered to Grade < 2 and reduce dose by 25 % for all subsequent doses.
Neuropathic pain or peripheral neuropathy	No dosage adjustments.	See the SPC for bortezomib.

*for more information on bortezomib dosing and dosage adjustment, see the SPC for bortezomib

Patients with impaired hepatic function: Caelyx pharmacokinetics determined in a small number of patients with elevated total bilirubin levels do not differ from patients with normal total bilirubin; however, until further experience is gained, the Caelyx dosage in patients with impaired hepatic function should be reduced based on the experience from the breast and ovarian clinical trial programs as follows: at initiation of therapy, if the bilirubin is between 1.2 - 3.0 mg/dl, the first dose is reduced by 25 %. If the bilirubin is> 3.0 mg/dl, the first dose is reduced by 50 %. If the patient tolerates the first dose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can be increased to the next dose level, i.e., if reduced by 25 % for the first dose, increase to full dose for cycle 2; if reduced by 50 % for the first dose, increase to 75 % of full dose for cycle 2. The dosage can be increased to full dose for subsequent cycles if tolerated. Caelyx can be administered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymes up to 4 x the upper limit of the normal range. Prior to Caelyx administration, evaluate hepatic function using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase, and bilirubin.

Patients with impaired renal function: As doxorubicin is metabolised by the liver and excreted in the bile, dose modification should not be required. Population pharmacokinetic data (in the range of creatinine clearance tested of 30 - 156 ml/min) demonstrate that Caelyx clearance is not influenced by renal function. No pharmacokinetic data are available in patients with creatinine clearance of less than 30 ml/min.

AIDS-KS patients with splenectomy: As there is no experience with Caelyx in patients who have had splenectomy, treatment with Caelyx is not recommended.

Paediatric patients: The experience in children is limited. Caelyx is not recommended in patients below 18 years of age.

Elderly patients: Population based analysis demonstrates that age across the range tested (21 – 75 years) does not significantly alter the pharmacokinetics of Caelyx.

4.3 Contraindications

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

Caelyx must not be used to treat AIDS-KS that may be treated effectively with local therapy or systemic alfa-interferon.

4.4 Special Warnings And Precautions For Use

Cardiac toxicity: It is recommended that all patients receiving Caelyx routinely undergo frequent ECG monitoring. Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias are not considered mandatory indications for the suspension of Caelyx therapy. However, reduction of the QRS complex is considered more indicative of cardiac toxicity. If this change occurs, the most definitive test for anthracycline myocardial injury, i.e., endomyocardial biopsy, must be considered.

More specific methods for the evaluation and monitoring of cardiac functions as compared to ECG are a measurement of left ventricular ejection fraction by echocardiography or preferably by Multigated Angiography (MUGA). These methods must be applied routinely before the initiation of Caelyx therapy and repeated periodically during treatment. The evaluation of left ventricular function is considered to be mandatory before each additional administration of Caelyx that exceeds a lifetime cumulative anthracycline dose of 450 mg/m².

The evaluation tests and methods mentioned above concerning the monitoring of cardiac performance during anthracycline therapy are to be employed in the following order: ECG monitoring, measurement of left ventricular ejection fraction, endomyocardial biopsy. If a test result indicates possible cardiac injury associated with Caelyx therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury.

In patients with cardiac disease requiring treatment, administer Caelyx only when the benefit outweighs the risk to the patient.

Exercise caution in patients with impaired cardiac function who receive Caelyx.

Whenever cardiomyopathy is suspected, i.e., the left ventricular ejection fraction has substantially decreased relative to pre-treatment values and/or left ventricular ejection fraction is lower than a prognostically relevant value (e.g. < 45 %), endomyocardial biopsy may be considered and the benefit of continued therapy must be carefully evaluated against the risk of developing irreversible cardiac damage.

Congestive heart failure due to cardiomyopathy may occur suddenly, without prior ECG changes and may also be encountered several weeks after discontinuation of therapy.

Caution must be observed in patients who have received other anthracyclines. The total dose of doxorubicin hydrochloride must also take into account any previous (or concomitant) therapy with cardiotoxic compounds such as other anthracyclines/anthraquinones or e.g. 5-fluorouracil. Cardiac toxicity also may occur at cumulative anthracycline doses lower than 450 mg/m² in patients with prior mediastinal irradiation or in those receiving concurrent cyclophosphamide therapy.

The cardiac safety profile for the dosing schedule recommended for both breast and ovarian cancer (50 mg/m²) is similar to the 20 mg/m² profile in patients with AIDS-KS (see section 4.8).

Myelosuppression: Many patients treated with Caelyx have baseline myelosuppression due to such factors as their pre-existing HIV disease or numerous concomitant or previous medications, or tumours involving bone marrow. In the pivotal trial in patients with ovarian cancer treated at a dose of 50 mg/m², myelosuppression was generally mild to moderate, reversible, and was not associated with episodes of neutropaenic infection or sepsis. Moreover, in a controlled clinical trial of Caelyx vs. topotecan, the incidence of treatment related sepsis was substantially less in the Caelyx-treated ovarian cancer patients as compared to the topotecan treatment group. A similar low incidence of myelosuppression was seen in patients with metastatic breast cancer receiving Caelyx in a first-line clinical trial. In contrast to the experience in patients with breast cancer or ovarian cancer, myelosuppression appears to be the dose-limiting adverse event in patients with AIDS-KS (see section 4.8). Because of the potential for bone marrow suppression, periodic blood counts must be performed frequently during the course of Caelyx therapy, and at a minimum, prior to each dose of Caelyx.

Persistent severe myelosuppression, may result in superinfection or haemorrhage.

In controlled clinical studies in patients with AIDS-KS against a bleomycin/vincristine regimen, opportunistic infections were apparently more frequent during treatment with Caelyx. Patients and doctors must be aware of this higher incidence and take action as appropriate.

As with other DNA-damaging antineoplastic agents, secondary acute myeloid leukemias and myelodysplasias have been reported in patients having received combined treatment with doxorubicin. Therefore, any patient treated with doxorubicin should be kept under haematological supervision.

Given the difference in pharmacokinetic profiles and dosing schedules, Caelyx should not be used interchangeably with other formulations of doxorubicin hydrochloride.

Infusion-associated reactions: Serious and sometimes life-threatening infusion reactions, which are characterised by allergic-like or anaphylactoid-like reactions, with symptoms including asthma, flushing, urticarial rash, chest pain, fever, hypertension, tachycardia, pruritus, sweating, shortness of breath, facial oedema, chills, back pain, tightness in the chest and throat and/or hypotension may occur within minutes of starting the infusion of Caelyx. Very rarely, convulsions also have been observed in relation to infusion reactions (see section 4.8). Temporarily stopping the infusion usually resolves these symptoms without further therapy. However, medications to treat these symptoms (e.g., antihistamines, corticosteroids, adrenaline, and anticonvulsants), as well as emergency equipment should be available for immediate use. In most patients treatment can be resumed after all symptoms have resolved, without recurrence. Infusion reactions rarely recur after the first treatment cycle. To minimise the risk of infusion reactions, the initial dose should be administered at a rate no greater than 1 mg/minute (see section 4.2).

Diabetic patients: Please note that each vial of Caelyx contains sucrose and the dose is administered in 5 % (50 mg/ml) glucose solution for infusion.

For common adverse events which required dose modification or discontinuation see section 4.8.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No formal medicinal product interaction studies have been performed with Caelyx, although phase II combination trials with conventional chemotherapy agents have been conducted in patients with gynaecological malignancies. Exercise caution in the concomitant use of medicinal products known to interact with standard doxorubicin hydrochloride. Caelyx, like other doxorubicin hydrochloride preparations, may potentiate the toxicity of other anti-cancer therapies. During clinical trials in patients with solid tumours (including breast and ovarian cancer) who have received concomitant cyclophosphamide or taxanes, no new additive toxicities were noted. In patients with AIDS, exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with standard doxorubicin hydrochloride. Caution must be exercised when giving any other cytotoxic agents, especially myelotoxic agents, at the same time.

4.6 Pregnancy And Lactation

Pregnancy: Doxorubicin hydrochloride is suspected to cause serious birth defects when administered during pregnancy. Therefore, Caelyx should not be used during pregnancy unless clearly necessary.

Women of child-bearing potential must be advised to avoid pregnancy while they or their male partner are receiving Caelyx and in the six months following discontinuation of Caelyx therapy (see section 5.3).

Lactation: It is not known whether Caelyx is excreted in human milk. Because many medicinal products, including anthracyclines, are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, therefore mothers must discontinue nursing prior to beginning Caelyx treatment. Health experts recommend that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

4.7 Effects On Ability To Drive And Use Machines

Caelyx has no or negligible influence on the ability to drive and use machines. However, in clinical studies to date, dizziness and somnolence were associated infrequently (< 5 %) with the administration of Caelyx. Patients who suffer from these effects must avoid driving and operating machinery.

4.8 Undesirable Effects

The most common undesirable effect reported in breast/ovarian clinical trials (50 mg/m² every 4 weeks) was palmar-plantar erythrodysesthesia (PPE). The overall incidence of PPE reported was 44.0 % - 46.1 %. These effects were mostly mild, with severe (Grade III) cases reported in 17 % - 19.5 %. The reported incidence of life-threatening (Grade IV) cases was < 1 %. PPE infrequently resulted in permanent treatment discontinuation (3.7 % - 7.0 %). PPE is characterised by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after two or three cycles of treatment. Improvement usually occurs in one - two weeks, and in some cases, may take up to 4 weeks or longer for complete resolution. Pyridoxine at a dose of 50 - 150 mg per day and corticosteroids have been used for the prophylaxis and treatment of PPE, however, these therapies have not been evaluated in phase III trials. Other strategies to prevent and treat PPE, which may be initiated for 4 to 7 days after treatment with Caelyx include keeping hands and feet cool, by exposing them to cool water (soaks, baths, or swimming), avoiding excessive heat/hot water and keeping them unrestricted (no socks, gloves, or shoes that are tight fitting). PPE appears to be primarily related to the dose schedule and can be reduced by extending the dose interval 1 - 2 weeks (see section 4.2). However, this reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Stomatitis/mucositis and nausea were also commonly reported in breast/ovarian cancer patient populations, whereas the AIDS-KS Program (20 mg/m² every 2 weeks), myelosuppression (mostly leukopaenia) was the most common side effect (see AIDS-KS). PPE was reported in 16 % of multiple myeloma patients treated with Caelyx plus bortezomib combination therapy. Grade 3 PPE was reported in 5 % of patients. No grade 4 PPE was reported. The most frequently reported (medicine-related treatment-emergent) adverse events in combination therapy (Caelyx + bortezomib) were nausea (40 %), diarrhoea (35 %), neutropaenia (33 %), thrombocytopaenia (29 %), vomiting (28 %), fatigue (27 %), and constipation (22 %).

Breast cancer program: 509 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with Caelyx (n=254) at a dose of 50 mg/m² every 4 weeks, or doxorubicin (n=255) at a dose of 60 mg/m² every 3 weeks, in a phase III clinical trial (I97-328). The following common adverse events were reported more often with doxorubicin than with Caelyx: nausea (53 % vs. 37 %; Grade III/IV 5 % vs. 3 %), vomiting (31 % vs. 19 %; Grade III/IV 4 % vs. less than 1 %), any alopecia (66 % vs. 20 %), pronounced alopecia (54 % vs.7 %), and neutropaenia (10 % vs. 4 %; Grade III/IV 8 % vs. 2 %).

Mucositis (23 % vs. 13 %; Grade III/IV 4 % vs. 2 %), and stomatitis (22 % vs. 15 %; Grade III/IV 5 % vs. 2 %) were reported more commonly with Caelyx than with doxorubicin. The average duration of the most common severe (Grade III/IV) events for both groups was 30 days or less. See Table 5 for complete listing of undesirable effects reported in Caelyx-treated patients.

The incidence of life threatening (Grade IV) haematologic effects was < 1.0 % and sepsis was reported in 1 % of patients. Growth factor support or transfusion support was necessary in 5.1 % and 5.5 % of patients, respectively (see section 4.2).

Clinically significant laboratory abnormalities (Grades III and IV) in this group was low with elevated total bilirubin, AST and ALT reported in 2.4 %, 1.6 % and < 1 % of patients respectively. No clinically significant increases in serum creatinine were reported.

Table 5. Treatment Related Undesirable Effects Reported in Breast Cancer Clinical Trials (50 mg/m2 every 4 weeks) (Caelyx-treated patients) by Severity, MedDRA System Organ Class and Preferred Term Very Common ( CIOMS III
AE by body system	Breast Cancer All Severities n=254 (	Breast Cancer Grades III/IV n=254 (	Breast Cancer n=404 (1-5 %) not previously reported in clinical trials
Infections and infestations
Common	Pharyngitis		Folliculitis, fungal infection, cold sores (non-herpetic), upper respiratory tract infection
Uncommon		Pharyngitis
Blood and lymphatic system disorders
Common	Leukopaenia, anaemia, neutropaenia, thrombocytopaenia	Leukopaenia, anaemia	Thrombocythemia
Uncommon		Neutropaenia
Metabolism and nutrition disorders
Very Common	Anorexia
Common		Anorexia
Nervous system disorders
Common	Paresthesia	Paresthesia	Peripheral neuropathy
Uncommon	Somnolence
Eye Disorders
Common			Lacrimation, blurred vision
Cardiac disorders
Common			Ventricular arrhythmia
Respiratory, thoracic and mediastinal disorders
Common			Epistaxis
Gastrointestinal disorders
Very Common	Nausea, stomatitis, vomiting
Common	Abdominal pain, constipation, diarrhoea, dyspepsia, mouth ulceration	Abdominal pain, diarrhoea, nausea, stomatitis	Oral pain
Uncommon		Mouth ulceration, constipation, Vomiting
Skin and subcutaneous tissue disorders
Very Common	PPE*, alopecia, rash	PPE*
Common	Dry skin, skin discolouration, pigmentation abnormal, erythema	Rash	Bullous eruption, dermatitis, erythematous rash, nail disorder, scaly skin
Uncommon		Pigmentation abnormal, erythema
Musculoskeletal and connective tissue disorders
Common			Leg cramps, bone pain, musculoskeletal pain
Reproductive system and breast disorders
Common			Breast pain
General disorders and administration site conditions
Very Common	Asthenia, fatigue, mucositis NOS
Common	Weakness, fever, pain	Asthenia, mucositis NOS	Oedema, leg oedema.
Uncommon		Fatigue, weakness, pain

* palmar-plantar erythrodysesthesia (Hand- foot syndrome).

Ovarian cancer program: 512 patients with ovarian cancer (a subset of 876 solid tumour patients) were treated with Caelyx at a dose of 50 mg/m² in clinical trials. See Table 6 for undesirable effects reported in Caelyx-treated patients.

Table 6 Treatment Related Undesirable Effects Reported in Ovarian Cancer Clinical Trials (50 mg/m2 every 4 weeks) (Caelyx-treated patients) by Severity, MedDRA System Organ Class and Preferred Term Very Common ( CIOMS III