Cuprofen for Children

1. Name Of The Medicinal Product

Cuprofen for Children

2. Qualitative And Quantitative Composition

Ibuprofen 100mg / 5ml

For excipients, see 6.1

3. Pharmaceutical Form

Oral Suspension

White, opaque smooth suspension

4. Clinical Particulars

4.1 Therapeutic Indications

For reduction in fever (including post immunization fever); and relief of mild to moderate pain such as headache, sore throat, earache, teething pain and toothache, cold and flu symptoms, minor aches and sprains.

4.2 Posology And Method Of Administration

For oral administration and short term use only, as required:

• Children over 7 years: 10ml three times daily.

• Children 4 to 7 years: 7.5ml three times daily.

• Children 1 to 4 years: 5ml three times daily.

• Infants 6 months to 1 year: 2.5ml three to four times daily.

If the child's symptoms persist for more than 3 days, consult your doctor.

• Babies 3 to 6 months: 2.5ml three times daily.

Do not give to babies aged 3 to 6 months for more than 24 hours.

Doses should usually be given every 6-8 hours. Leave at least four hours between doses.

Not to be given to children under 3 months of age. Not recommended for children weighing less than 5kg.

For post immunisation fever: 2.5ml followed by one further 2.5ml 6 hours later, if necessary. No more than 2 doses (5ml) in 24 hours. If fever is not reduced, consult your doctor.

4.3 Contraindications

Hypersensitivity to ibuprofen or any of the excipients in the product.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs.

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Severe heart failure, renal failure or hepatic failure (see section 4.4 Special Warnings and Precautions for Use).

Last trimester of pregnancy (see section 4.6 Pregnancy and lactation).

4.4 Special Warnings And Precautions For Use

Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

The elderly have an increased frequency of adverse reactions to NSAID's especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory:

Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.

Other NSAIDs:

The use of Ibuprofen for children 100mg/5ml oral suspension with concomitant NSAIDs including cyclooxengenase-2-selective inhibitors should be avoided.

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease – increased risk of aseptic meningitis (see section 4.8 Undesirable effects).

Renal:

Renal impairment as renal function may further deteriorate (see section 4.3 Contraindications and section 4.8 Undesirable effects).

Hepatic:

Hepatic dysfunction (see section 4.3 Contraindications and section 4.8 Undesirable effects).

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.

Impaired female fertility:

There is limited evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) – as these conditions may be exacerbated (see section 4.8 Undesirable effects).

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3 Contraindications) and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as oral corticosteroids, or anticoagulants such as warfarin, selective serotonin reuptake inhibitors, or anti-platelet agents such as aspirin (see section 4.5 Interactions).

Where GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8 Undesirable Effects). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Ibuprofen for children 100mg/5ml oral suspension should be discontinued at the first appearance of skin rash mucosal lesions, or any other sign of hypersensitivity.

Information about some of the ingredients in this medicine:

Contains Liquid Maltitol (E965). Patients with rare hereditary problems of fructose intolerance should not take this medicine.

The label will include:

Please read the enclosed leaflet carefully before using this product.

Do not give this product if your child:

• has or has had a stomach ulcer, perforation or bleeding of the stomach

• is allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers

• is taking other NSAID painkillers, or aspirin with a daily dose above 75mg

Talk to a pharmacist or your doctor before giving this product if your child:

• has or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney, stomach or bowel problems

If you are an adult:

• if you are pregnant do not take this product and ask your doctor for advice

• consult your doctor or pharmacist before taking this product if you are elderly or if you are a smoker

Do not exceed the stated dose. Keep all medicines out of the reach and sight of children.

If your child's symptoms persist for more than 3 days, or if new symptoms occur, talk to your doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ibuprofen should not be used in combination with:

Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see section 4.3 Contraindications).

Other NSAIDs including cyclooxegenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.3 Contraindications).

Ibuprofen should be used with caution in combination with:

Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4 Special Warnings and Precautions for Use).

Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs. Diuretics can increase the risk of nephrotoxicity to NSAID's.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4 Special Warnings and Precautions for Use).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.

Cardiac Glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: There is evidence for potential increases in plasma levels of lithium.

Methotrexate: There is a potential for an increase in plasma methotrexate.

Cyclosporin: Increased risk of nephrotoxicity

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone. Administration of NSAID's can reduce the effect of mifepristone.

Tacrolimus: Possible risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological activity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Animal data indicate that NSAID's can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increase risk of developing convulsions.

Aspirin: Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dose concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use(see section 5.1).

4.6 Pregnancy And Lactation

Children under 9 years are unlikely to become pregnant or breast feed. However, whilst no teratogenic effects have been demonstrated in animal experiments, the use of the suspension should, if possible, be avoided during the first 6 months of pregnancy.

During the 3^rd trimester, there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see section 4.3 Contraindications).

In limited studies, ibuprofen appears in the breast milk in very low concentration and is unlikely to affect the breast-fed infant adversely.

See section 4.4 regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

None expected at recommended doses and duration of therapy.

4.8 Undesirable Effects

The following list of adverse effects relates to those experienced with ibuprofen at OTC doses, for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Blood and Lymphatic System Disorders:

Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Immune System Disorders:

Non-specific allergic reactions.

Respiratory tract reactivity (e.g. asthma, aggravated asthma and bronchospasm).

Various skin reactions including exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Uncommon: Hypersensitivity reactions with urticaria and pruritus.

Very rare: Severe hypersensitivity reactions. Symptoms could include: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock).

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see section 4.4 Special Warnings and Precautions for Use).

Nervous System Disorders:

Uncommon: Headache.

Vary rare: Aseptic Meningitis – single cases have been reported very rarely.

Cardiac Disorders and Vascular Disorders:

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal Disorders:

The most commonly observed side effects of ibuprofen are gastrointestinal in nature.

Uncommon: Abdominal pain, nausea and dyspepsia.

Rare: Diarrhoea, flatulence, constipation and vomiting.

Very rare: Peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly, ulcerative stomatitis, gastritis.

Exacerbation of ulcerative colitis and Crohn's disease (see section 4.4 Special Warnings and Precautions for Use).

Hepatobiliary Disorders:

Very rare: Liver disorders.

Skin and Subcutaneous Tissue Disorders:

Uncommon: Various skin rashes.

Very rare: Severe forms of skin reactions such as bullous reactions, including Stevens Johnson syndrome, erythema multiforme and toxic epidermal necrolysis can occur.

Renal and Urinary Disorders:

Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.

4.9 Overdose

In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms

Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time / INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiinflammatory and antirheumatic products, non-steroids, propionic acid derivatives.

ATC code: M01A E01

Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swellings and fever, furthermore Ibuprofen reversibly inhibits platelet aggregation.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8h before or within 30min after immediate release aspirin dosing (81mg), a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

5.2 Pharmacokinetic Properties

Ibuprofen is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.

Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, high peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms.

The half life of ibuprofen is about 2 hours.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Methyl Parahydroxybenzoate (E219)

Sodium Propyl Parahydroxybenzoate (E217)

Citric Acid Anhydrous

Saccharin Sodium

Sodium Benzoate (E211)

Dispersible Cellulose

Juicy Orange Flavour

Polysorbate 80

Liquid Maltitol (E965)

Xanthan Gum

Purified Water.

6.2 Incompatibilities

None.

6.3 Shelf Life

Amber glass or PET bottles with PP closures: 2 years.

6.4 Special Precautions For Storage

Do not store above 25^oC. Store in the original container.

6.5 Nature And Contents Of Container

Amber glass or PET bottles with polypropylene child resistant screw closures, containing 100, 150 or 200ml enclosed in an outer carton. A measuring spoon is provided.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Galpharm Healthcare Ltd

Hugh House

Upper Cliffe Road

Dodworth Business Park

Dodworth

South Yorkshire

S75 3SP

8. Marketing Authorisation Number(S)

PL 16028/0075

9. Date Of First Authorisation/Renewal Of The Authorisation

10/02/2006

10. Date Of Revision Of The Text

03/11/2010

Cytarabine Injection Solution 20mg / ml

1. Name Of The Medicinal Product

Cytarabine 20 mg/ml Injection

2. Qualitative And Quantitative Composition

Each 1 ml contains 20 mg of cytarabine.

Presentations	100 mg/5 ml	500 mg/25 ml	1 g/50 ml
Amount cytarabine present	100 mg	500 mg	1 g

For excipients see 6.1.

3. Pharmaceutical Form

Solution for injection.

Clear, colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Cytarabine may be used alone or in combination with other antineoplastic agents. It is indicated alone or in combination for induction of remission and/or maintainance in patients with acute myeloid leukaemia, acute non-lymphoblastic leukaemias, acute lymphoblastic leukaemias, acute lymphocytic leukaemia, erythroleukaemia, blast crises of chronic myeloid leukaemia, diffuse histiocytic lymphomas (non-hodgkin's lymphomas of high malignancy), meningeal leukaemia and meningeal neoplasms. Clinicians should refer to the current literature on combination therapy before initiating treatment.

4.2 Posology And Method Of Administration

Cytarabine 20 mg/ml Injection is a ready to use solution and is suitable for intravenous, subcutaneous and intrathecal use.

Cytarabine 20 mg/ml Injection can be diluted with Sterilised Water for Injections BP, Glucose Intravenous Infusion BP or Sodium Chloride Intravenous Infusion BP. Prepared infusions, in the recommended diluents should be used immediately. Alternatively, the diluted infusion fluids may be stored at 2-8°C, protected from light, but portions remaining unused after 24 hours must be discarded.

Remission Induction: Adults

Continuous Dosing: The usual dose in leukaemia, is 2 mg/kg by rapid intravenous injection daily for ten days. If after ten days neither therapeutic response not toxicity has been observed, the dose may be increased to 4 mg/kg until a therapeutic response or toxicity is evident. Daily blood counts should be taken. Almost all patients can be carried to toxicity with these doses.

Alternatively, 0.5 to 1 mg/kg may be infused daily in 1-24 hours for ten days, and then at a rate of 2 mg/kg/day until toxicity is observed. Continue to toxicity or until remission occurs. Results from one hour infusions have been satisfactory in the majority of patients.

Intermittent dosing: Cytarabine may be given as intermittent intravenous doses of 3-5 mg/kg daily, for five consecutive days This course of treatment can be repeated after an interval of 2 to 9 days, and repeated until the therapeutic response or toxicity is exhibited.

Evidence of bone marrow inprovement has been reported to occur 7-64 days days after the beginning of therapy.

In general, if a patient shows neither remission or toxicity after a trial period, then cautiously administered higher doses can be administered. Generally patients tolerate higher doses given by rapid intravenous injection rather than slow infusion.

As a single agent for induction of remissions in patients with acute leukaemia, cytarabine has been given in doses of 200 mg/m² by continuous intravenous infusion for five days at approximately 2 week intervals.

Maintainance therapy: To maintain remission, doses of 1-1.5 mg/kg may be given intravenously or subcutaneously, once or twice weekly.

Leukaemic Meningitis: Therapy for established meningitis employs a wide variety of dose regimens but a recommended total daily dose not exceeding 100 mg, alternating with methotrexate (given either systemically or intrathecally) is recommended. Cytarabine has been given intrathecally at doses of 10-30 mg/m² three times a week until cerebro-spinal fluid findings return to normal.

Myelosuppression, anaemia and thrombocytopenia occur almost to all patients given daily infusions or injections. Myelosuppression is biphasic and nadirs at 7-9 and 15-24 days. Evidence of bone marrow improvement may be expected 7-64 (mean 28) days after the beginning of treatment.

Children: Children appear to tolerate higher doses of cytarabine than adults, and where the range of doses is given, children should receive the higher dose.

Elderly: No data is available to suggest that a change in dose is necessary in the elderly. However, the elderly patient is more susceptable to toxic reactions and therefore particular attention should be paid to drug induced leucopenia, thrombocytopenia and anaemia.

4.3 Contraindications

Cytarabine is contraindicated in patients with known hypersensitivity to the drug. Therapy with cytarabine should not be considered in patients with pre-existing drug-induced bone marrow suppression, unless in the opinion of the physician the potential benefits outweigh the hazards. Cytarabine should not be used in the management of non-malignant disease, except for immunosuppression.

4.4 Special Warnings And Precautions For Use

Cytarabine is a potent bone marrow suppressant. Patients receiving the drug should be kept under close medical supervision. Leucocyte and platelet counts should be performed frequently and daily during induction. One case of anaphylaxis that resulted in cardiopulmonary arrest and necessitated resuscitiation has been reported. This occurred immediately after intravenous cytarabine was administered.

Severe and at times fatal central nervous system (CNS), gastrointestinal (GI) and pulmonary toxicity (different from that seen with conventional therapy regimens of dosage schedules). These reactions include reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible; severe gastrointestinal ulceration including pneumatosis cysteroides intestinalis, leading to peritonitis; sepsis and liver abscess; and pulmonary oedema.

Central Nervous System: Rarely, neurological effects such as quadriplegia and paralysis have been reported with cytosine arabinoside and have been predominantly associated with intrathecal administration. Isolated cases have also been reported with high intravenous doses during combination chemotherapeutic regimens.

Cytarabine has been shown to be mutagenic and carcinogenic in animals.

Cytarabine should only be used under the constant supervision by physicians experienced in therapy with cytotoxic agents. Hyperuricaemia secondary to lysis of neoplastic cells may occur in patients receiving cytarabine; serum uric acid concentrations should be monitored.

Periodic determinations of renal and hepatic functions and bone marrow should also be performed and the drug should be used with caution in patients with impaired hepatic function.

However, dosage reduction does not appear to be necessary in patients with impaired renal function. The human liver apparently detoxifies a substantial fraction of the administered dose. The drug should be used with caution and at a reduced dose when liver function is poor. Frequent platelet and leucocyte counts are manditory. Therapy should be suspended or modified when drug-induced bone marrow depression results in a platelet count of less than 50,000 or a polymorphonuclear count of under 1000 per mm³. Counts may continue to fall after the therapy has been discontinued and may reach lowest values after five to seven days. Therapy may be restarted when the bone marrow appears to be recovering on successive bone marrow studies. Therapy should not wait until the normal blood values are obtained to be re-initiated.

When intravenous doses are given quickly, patients may become nauseated and may vomit for several hours afterwards. The problem tends to be less severe when infused.

When given intrathecally, as with any other intrathecal drug, care must be taken with radiotherapy given either during or after treatment; it is well recognised that this can exacerbate the toxicity of radiotherapy.

The safety of the drug has not been established in infants.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

i) Cardiac Glycosides

GI absorption of oral digoxin tablets may be substantially reduced in patients receiving combination chemotherapy regimens (including regimens containing cytarabine), possibly as a result of temporary damage to intestinal mucosa caused by the cytotoxic agents. Limited data suggest that the extent of GI absorption of digitoxin is not substantially affected by concomitant administration of combination chemotherapy regimens known to decrease absorption of digoxin.

ii) Anti-Infective Agents

One in vitro study indicates that cytarabine may antagonise the activity of gentamicin against Klebsiella pneumoniae. Limited data may suggest that cytarabine may antagonise the anti-infective activity of flucytosine, possibly by competitive inhibition of the anti-infective uptake by fungi.

4.6 Pregnancy And Lactation

Use in Pregnancy

Cytarabine is teratogenic in some animal species. It should not be used in pregnant women (especially during the first trimester) or in those who may become pregnant, unless the possible benefits outweigh the potential risks. Women who are, or become, pregnant during treatment with cytarabine should be informed of the risks.

Use in Lactation

It is not known if cytarabine or its metabolite is distributed into breast milk, and it should not be used.

4.7 Effects On Ability To Drive And Use Machines

No documented effect on ability to drive or operate machinery.

4.8 Undesirable Effects

Haematological Effects:

The major adverse effect of cytarabine is the haematological toxicity. Myelosuppression is manifested by megaloblastosis, reticulocytopenia, thrombocytopenia and anaemia.

These appear to be more evident after high doses and continuous infusions; the severity depends on the dose of the drug and schedule of administration.

GI Effects:

Nausea and vomiting occur and are generally more frequent following rapid intravenous administration than with continuous intravenous infusion of the drug.

Diarrhoea, anorexia, oral and anal inflammation or ulceration and less frequently abdominal pain, sore throat, oesphagitis, oesophageal ulceration and gastrointestinal haemorrhage may also occur.

Other reported adverse effects of cytarabine include fever, rash, alopecia, skin ulceration, conjunctivitis, chest pain, urinary retention, dizziness, neuritis or neural toxicity and pain, cellulitis or thrombophlebitis at the site of injection. Cytarabine has also been associated with renal dysfunction, hepatic dysfunction and jaundice in some patients. It has also been associated with sepsis, irritation or sepsis at the injection site, neuritis or neurotoxicity rash, freckling, skin and mucosal bleeding, chest pain, joint pain and reduction in reticulocytes.

A cytarabine reaction is characterised by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and malaise. It usually occurs 6-12 hours after administration. Corticosteroids have been shown to be beneficial in treating or preventing this syndrome. If the symptoms of the syndrome are serious enough to warrant treatment, corticosteroids should be contemplated as well as continuation of cytarabine therapy.

4.9 Overdose

Cessation of therapy followed by management of ensuing bone marrow depression including whole blood or platelet transfusion and antibiotics as required.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Cytarabine (ARA-C) is metabolised in vivo to ARA-CTP phosphorylated compound. This competitively inhibits DNA polymerase and may also inhibit certain acid kinase enzymes. Primarily the drug acts as a false nucleoside and competes for enzymes involved in the conversion of cytidine nucleotide to deoxycytidine nucleotide and also incorporation into the DNA.

Cytarabine has no effect on non proliferating cells nor on proliferating cells unless in the S phase. It is a cell cycle specific antineoplastic drug.

5.2 Pharmacokinetic Properties

Oral administration is ineffective due to rapid deamination in the gut. Cytidine deaminase is concentrated in the liver and intravenous doses show biphasic elimination with half lifes of approximately 10 minutes and 1-3 hours.

After 24 hours 80% of a dose has been eliminated either as the inactive metabolite or as the unchanged cytarabine, mostly in urine but some in bile.

CSF levels of 50% of plasma levels are achieved with intravenous infusion. Intrathecal dosing results in slower elimination (T1/2 2-11 hours).

Cytarabine is rapidly and widely distributed into tissues, crosses the blood brain barrier and also the placenta.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Water for Injections

6.2 Incompatibilities

Solutions of cytarabine have been reported to be incompatible with various drugs, i.e. carbenicillin sodium, cephalothin sodium, fluorouracil, gentamicin sulphate, heparin sodium, hydrocortisone sodium succinate, insulin-regular, methylprednisolone sodium succinate, nafacillin sodium, oxacillin sodium, penicillin G sodium. However, the incompatibility depends on several factors (e.g. concentrations of the drug, specific diluents used, resulting pH, temperature). Specialised references should be consulted for specific compatibility information.

6.3 Shelf Life

Before use: 12 months.

In use: Chemical and physical in-use stability has been demonstrated for 7 days at room temperature.

From a microbiological 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 not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Do not store above 25°C. Keep container in the outer carton .

6.5 Nature And Contents Of Container

Clear Type I glass vials, rubber stopper.

Clear Type I Onco-Tain® Vials, rubber stopper.

Pack sizes 5's, 25's and 50's.

Not all presentations and pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Hospira UK Ltd

Queensway

Royal Leamington Spa

Warwickshire CV31 3RW

United Kingdom.

8. Marketing Authorisation Number(S)

PL 04515/0040

9. Date Of First Authorisation/Renewal Of The Authorisation

7^th July 1992/10^th October 2006

10. Date Of Revision Of The Text

08^th February 2010

Cubicin powder for concentrate for solution for injection or infusion

1. Name Of The Medicinal Product

2. Qualitative And Quantitative Composition

Cubicin 350 mg powder for solution for infusion or injection: Each vial contains 350 mg daptomycin.

One ml provides 50 mg of daptomycin after reconstitution with 7 ml of sodium chloride 9 mg/ml (0.9%) solution.

Cubicin 500 mg powder for solution for infusion or injection: Each vial contains 500 mg daptomycin.

One ml provides 50 mg of daptomycin after reconstitution with 10 ml of sodium chloride 9 mg/ml (0.9%) solution.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for injection or infusion

A pale yellow to light brown lyophilised powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Cubicin is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1).

- Complicated skin and soft-tissue infections (cSSTI).

- Right-sided infective endocarditis (RIE) due to Staphylococcus aureus. It is recommended that the decision to use daptomycin should take into account the antibacterial susceptibility of the organism and should be based on expert advice. See sections 4.4 and 5.1.

- Staphylococcus aureus bacteraemia (SAB) when associated with RIE or with cSSTI.

Daptomycin is active against Gram positive bacteria only (see section 5.1). In mixed infections where Gram negative and/or certain types of anaerobic bacteria are suspected, Cubicin should be co-administered with appropriate antibacterial agent(s).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

Clinical studies in patients employed infusion of daptomycin over 30 minutes. There is no clinical experience in patients with the administration of daptomycin as an injection over 2 minutes. This mode of administration was only studied in healthy subjects. However, when compared with the same doses given as intravenous infusions over 30 minutes there were no clinically important differences in the pharmacokinetics and safety profile of daptomycin (see also sections 4.8 and 5.2).

Posology

- cSSTI without concurrent Staphylococcus aureus bacteraemia: Cubicin 4 mg/kg is administered once every 24 hours for 7

- cSSTI with concurrent Staphylococcus aureus bacteraemia: Cubicin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The duration of therapy may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient.

- Known or suspected right-sided infective endocarditis due to Staphylococcus aureus: Cubicin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The duration of therapy should be in accordance with available official recommendations.

Cubicin is administered intravenously in 0.9% sodium chloride (see section 6.6). Cubicin should not be used more frequently than once a day.

Renal impairment

Daptomycin is eliminated primarily by the kidney.

Due to limited clinical experience (see table and footnotes below) Cubicin should only be used in patients with any degree of renal impairment (CrCl < 80 ml/min) when it is considered that the expected clinical benefit outweighs the potential risk. The response to treatment, renal function and creatine phosphokinase (CPK) levels should be closely monitored in all patients with any degree of renal impairment (see also sections 4.4 and 5.2).

Dose adjustments in patients with renal impairment by indication and creatinine clearance

Indication for use	Creatinine clearance	Dose recommendation	Comments
cSSTI without S. aureus bacteraemia		4 mg/kg once daily	See section 5.1
	< 30 ml/min	4 mg/kg every 48 hours	(1, 2)
RIE or cSSTI associated with S. aureus bacteraemia		6 mg/kg once daily	See section 5.1
	< 30 ml/min	6 mg/kg every 48 hours	(1, 2)

(1) The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is based on pharmacokinetic studies and modelling results (see sections 4.4 and 5.2).

(2) The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK modelling results, are recommended for patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered following the completion of dialysis on dialysis days (see section 5.2).

Hepatic impairment

No dose adjustment is necessary when administering Cubicin to patients with mild or moderate hepatic impairment (Child-Pugh Class B) (see section 5.2). No data are available in patients with severe hepatic impairment (Child-Pugh Class C). Therefore caution should be exercised if Cubicin is given to such patients.

Elderly patients

The recommended doses should be used in elderly patients except those with severe renal impairment (see above and section 4.4). However, there are limited data on the safety and efficacy of daptomycin in patients aged> 65 years and caution should be exercised if Cubicin is given to such patients.

Paediatric population

The safety and efficacy of Cubicin in children and adolescents below the age of 18 have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Method of administration

Cubicin is given by intravenous infusion (see section 6.6) and administered over a 30-minute period or by intravenous injection (see section 6.6) and administered over a 2-minute period.

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

General

If a focus of infection other than cSSTI or RIE is identified after initiation of Cubicin therapy consideration should be given to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of the specific type of infection(s) present.

Anaphylaxis/hypersensitivity reactions

Anaphylaxis/hypersensitivity reactions have been reported with Cubicin. If an allergic reaction to Cubicin occurs, discontinue use and institute appropriate therapy.

Pneumonia

It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of pneumonia. Cubicin is therefore not indicated for the treatment of pneumonia.

RIE due to Staphylococcus aureus

Clinical data on the use of Cubicin to treat RIE due to Staphylococcus aureus are limited to 19 patients (see “Information from clinical trials” in section 5.1).

The efficacy of Cubicin in patients with prosthetic valve infections or with left-sided infective endocarditis due to Staphylococcus aureus has not been demonstrated.

Deep-seated infections

Patients with deep-seated infections should receive any required surgical interventions (e.g. debridement, removal of prosthetic devices, valve replacement surgery) without delay.

Enterococcal infections

There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Cubicin against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose regimens of daptomycin that might be appropriate for the treatment of enterococcal infections, with or without bacteraemia, have not been identified. Failures with daptomycin in the treatment of enterococcal infections that were mostly accompanied by bacteraemia have been reported. In some instances treatment failure has been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).

Non-susceptible organisms

The use of antibiotics may promote the overgrowth of non-susceptible micro-organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Clostridium difficile -associated diarrhoea

Clostridium difficile-associated diarrhoea (CDAD) has been reported with Cubicin (see section 4.8). If CDAD is suspected or confirmed, Cubicin may need to be discontinued and appropriate treatment instituted as clinically indicated.

Drug/laboratory test interactions

False prolongation of prothrombin time (PT) and elevation of international normalised ratio (INR) have been observed when certain recombinant thromboplastin reagents are utilised for the assay (see also section 4.5).

Creatine phosphokinase and myopathy

Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular pains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported during therapy with Cubicin (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked increases in plasma CPK to> 5x Upper Limit of Normal (ULN) without muscle symptoms occurred more commonly in Cubicin-treated patients (1.9%) than in those that received comparators (0.5%). Therefore, it is recommended that:

• Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) during therapy in all patients.

• CPK should be measured more frequently (e.g. every 2

• It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at baseline may be at increased risk of further increases during daptomycin therapy. This should be taken into account when initiating daptomycin therapy and, if daptomycin is given, these patients should be monitored more frequently than once weekly.

• Cubicin should not be administered to patients who are taking other medicinal products associated with myopathy unless it is considered that the benefit to the patient outweighs the risk.

• Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy.

• Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. Cubicin should be discontinued in the presence of unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of normal.

Peripheral neuropathy

Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy with Cubicin should be investigated and consideration should be given to discontinuation of daptomycin (see sections 4.8 and 5.3).

Eosinophilic pneumonia

Eosinophilic pneumonia has been reported in patients receiving Cubicin (see section 4.8). In most reported cases associated with Cubicin, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates. The majority of cases occurred after more than 2 weeks of treatment with Cubicin and improved when Cubicin was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving Cubicin should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes (e.g. bacterial infection, fungal infection, parasites, other medicinal products). Cubicin should be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.

Renal impairment

Renal impairment has been reported during treatment with Cubicin. Severe renal impairment may in itself also pre-dispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see above).

Dose adjustment is needed for patients whose creatinine clearance is < 30 ml/min (see sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Cubicin should only be used in such patients when it is considered that the expected clinical benefit outweighs the potential risk.

Caution is advised when administering Cubicin to patients who already have some degree of renal impairment (creatinine clearance < 80 ml/min) before commencing therapy with Cubicin. Regular monitoring of renal function is advised (see also section 5.2).

In addition, regular monitoring of renal function is advised during concomitant administration of potentially nephrotoxic agents, regardless of the patient's pre-existing renal function (see also section 4.5).

Obesity

In obese subjects with Body Mass Index (BMI) > 40 kg/m² but with creatinine clearance > 70 ml/min, the AUC_0- daptomycin was significantly increased (mean 42% higher) compared with non-obese matched controls. There is limited information on the safety and efficacy of daptomycin in the very obese and so caution is recommended. However, there is currently no evidence that a dose reduction is required (see section 5.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.

Interaction studies for Cubicin were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.

Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration using a Cubicin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of Cubicin is unknown. Caution is warranted when Cubicin is co-administered with tobramycin.

Experience with the concomitant administration of Cubicin and warfarin is limited. Studies of Cubicin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving Cubicin and warfarin should be monitored for the first several days after therapy with Cubicin is initiated.

There is limited experience regarding concomitant administration of daptomycin with other medicinal products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of marked rises in CPK levels and cases of rhabdomyolysis occurred in patients taking one of these medicinal products at the same time as Cubicin. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with Cubicin unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy. See sections 4.4, 4.8 and 5.3.

Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2 inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-administered with any other medicinal product known to reduce renal filtration.

During post–marketing surveillance, cases of interference between daptomycin and particular reagents used in some assays of prothrombin time/international normalised ratio (PT/INR) have been reported. This interference led to a false prolongation of PT and elevation of INR. If unexplained abnormalities of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin (see section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Cubicin should not be used during pregnancy unless clearly necessary i.e., only if the potential benefit outweighs the possible risk.

Breast-feeding

In a single case study, Cubicin was administered daily for 28 days to a nursing mother at a dose of 500 mg/day, and samples of the patient's breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 µg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feeding should be discontinued when Cubicin is administered to nursing women.

Fertility

No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

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.

On the basis of reported adverse drug reactions, Cubicin is presumed to be unlikely to produce an effect on the ability to drive or use machinery.

4.8 Undesirable Effects

In clinical studies, 2,011 subjects received Cubicin. Within these trials, 1,221 subjects received a daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported at similar frequencies for Cubicin and comparator regimens.

The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to very common (

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

Table 1 Adverse reactions from clinical studies and post-marketing reports

System organ class	Frequency	Adverse reactions
Infections and infestations	Common:	Fungal infections, urinary tract infection, candida infection
Uncommon:	Fungaemia
Not known*:	Clostridium difficile-associated diarrhoea**
Blood and lymphatic system disorders	Common:	Anaemia
Uncommon:	Thrombocythaemia, eosinophilia, international normalised ratio (INR) increased
Rare:	Prothrombin time (PT) prolonged
Immune system disorders	Not known*:	Hypersensitivity**, manifested by isolated spontaneous reports including, but not limited to pulmonary eosinophilia, vesicobullous rash with mucous membrane involvement and sensation of oropharyngeal swelling
Not known*:	Anaphylaxis**
Not known*:	Infusion reactions including the following symptoms: tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste
Metabolism and nutrition disorders	Uncommon:	Decreased appetite, hyperglycaemia, electrolyte imbalance
Psychiatric disorders	Common:	Anxiety, insomnia
Nervous system disorders	Common:	Dizziness, headache
Uncommon:	Paraesthesia, taste disorder, tremor
Not known*:	Peripheral neuropathy**
Ear and labyrinth disorders	Uncommon:	Vertigo
Cardiac disorders	Uncommon:	Supraventricular tachycardia, extrasystole
Vascular disorders	Common:	Hypertension, hypotension
Uncommon:	Flushes
Respiratory, thoracic and mediastinal disorders	Not known*:	Eosinophilic pneumonia1**
Gastrointestinal disorders	Common:	Gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension
Uncommon:	Dyspepsia, glossitis
Hepatobiliary disorders	Common:	Liver function tests abnormal2 (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP))
Rare:	Jaundice
Skin and subcutaneous tissue disorders	Common:	Rash, pruritus
Uncommon:	Urticaria
Musculoskeletal and connective tissue disorders	Common:	Limb pain, serum creatine phosphokinase (CPK)2 increased
Uncommon:	Myositis, increased myoglobin, muscular weakness, muscle pain, arthralgia, serum lactate dehydrogenase (LDH) increased
Not known*:	Rhabdomyolysis3 **
Renal and urinary disorders	Uncommon:	Renal impairment, including renal failure and renal insufficiency, serum creatinine increased
Reproductive system and breast disorders	Uncommon:	Vaginitis
General disorders and administration site conditions	Common:	Infusion site reactions, pyrexia, asthenia
Uncommon:	Fatigue, pain

* Based on post-marketing reports. Since these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to exposure to the medicinal product.

** See section 4.4.

¹ While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown, to date the reporting rate of spontaneous reports is very low (< 1/10,000).

² In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1

³ When clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with pre-existing renal impairment, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.

The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.

4.9 Overdose

In the event of overdose, supportive care is advised. Daptomycin is slowly cleared from the body by haemodialysis (approximately 15% of the administered dose is removed over 4 hours) or by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code: J01XX09

Mechanism of action

Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only.

The mechanism of action involves binding (in the presence of calcium ions) to bacterial membranes of both growing and stationary phase cells causing depolarisation and leading to a rapid inhibition of protein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis.

PK/PD relationship

Daptomycin exhibits rapid, concentration dependent bactericidal activity against Gram positive organisms in vitro and in in vivo animal models. In animal models AUC/MIC and C_max/MIC correlate with efficacy and predicted bacterial kill in vivo at single doses equivalent to human doses of 4 mg/kg and 6 mg/kg once daily.

Mechanisms of resistance

Strains with decreased susceptibility to daptomycin have been reported especially during the treatment of patients with difficult-to-treat infections and/or following administration for prolonged periods. In particular, there have been reports of treatment failures in patients infected with Staphylococcus aureus, Enterococcus faecalis or Enterococcus faecium, including bacteraemic patients, that have been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin during therapy.

The mechanism(s) of daptomycin resistance is (are) not fully understood.

Breakpoints

Minimum inhibitory concentration (MIC) breakpoint established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except S. pneumoniae) are Susceptible

Susceptibility

The prevalence of resistance may vary geographically and over time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly Susceptible Species

Staphylococcus aureus *

Staphylococcus haemolyticus

Coagulase negative staphylococci

Streptococcus agalactiae*

Streptococcus dysgalactiae subsp equisimilis*

Streptococcus pyogenes*

Group G streptococci

Clostridium perfringens

Peptostreptococcus spp

Inherently resistant organisms

Gram negative organisms

* denotes species against which it is considered that activity has been satisfactorily demonstrated in clinical studies.

Information from clinical trials

In two clinical trials in complicated skin and soft tissues infections, 36% of patients treated with Cubicin met the criteria for systemic inflammatory response syndrome (SIRS). The most common type of infection treated was wound infection (38% of patients), while 21% had major abscesses. These limitations of the patients population treated should be taken into account when deciding to use Cubicin.

In a randomised controlled open-label study in 235 patients with Staphylococcus aureus bacteraemia (i.e, at least one positive blood culture of Staphylococcus aureus prior to receiving the first dose) 19 of 120 patients treated with Cubicin met the criteria for RIE. Of these 19 patients 11 were infected with methicillin-susceptible and 8 with methicillin-resistant Staphylococcus aureus. The success rates in RIE patients are shown in the table below.

Population	Daptomycin	Comparator	Differences in Success
	n/N (%)	n/N (%)	Rates (95% CI)
ITT (intention to treat) Population
RIE	8/19 (42.1%)	7/16 (43.8%)	-1.6% (-34.6, 31.3)
PP (per protocol) Population
RIE	6/12 (50.0%)	4/8 (50.0%)	0.0% (-44.7, 44.7)

Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was observed in 19/120 (15.8%) patients treated with Cubicin, 9/53 (16.7%) patients treated with vancomycin and 2/62 (3.2%) patients treated with an anti-staphylococcal semi-synthetic penicillin. Among these failures six patients treated with Cubicin and one patient treated with vancomycin were infected with Staphylococcus aureus that developed increasing MICs of daptomycin on or following therapy (see “Mechanisms of resistance” above). Most patients who failed due to persisting or relapsing Staphylococcus aureus infection had deep-seated infection and did not receive necessary surgical intervention.

5.2 Pharmacokinetic Properties

Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kg administered as a single daily dose by 30-minute intravenous infusion for up to 14 days in healthy volunteers. Steady

Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUC and C_max) was demonstrated in healthy subjects following administration of daptomycin as a 30-minute intravenous infusion or as a 2-minute intravenous injection.

Animal studies showed that daptomycin is not absorbed to any significant extent after oral administration.

Distribution

The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately 0.1 l/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycin appears to only minimally penetrate the blood

Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In healthy volunteers and patients treated with daptomycin, protein binding averaged about 90% including subjects with renal impairment.

Metabolism

In in vitro studies, daptomycin was not metabolised by human liver microsomes. In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.

After infusion of 14C-daptomycin, the plasma radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma, and minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.

Elimination

Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid and daptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no active tubular secretion of daptomycin.

Following intravenous administration, plasma clearance of daptomycin is approximately 7 to 9 ml/h/kg and its renal clearance is 4 to 7 ml/h/kg.

In a mass balance study using radiolabelled material, 78% of the administered dose was recovered from the urine based on total radioactivity, whilst urinary recovery of unchanged daptomycin was approximately 50% of the dose. About 5% of the administered radiolabel was excreted in the faeces.

Special populations

Elderly

Following administration of a single 4 mg/kg intravenous dose of Cubicin, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC_0- was approximately 58% higher in elderly subjects (_max. The differences noted are most likely due to the normal reduction in renal function observed in the geriatric population.

No dose adjustment is necessary based on age alone. However, renal function should be assessed and the dose should be reduced if there is evidence of severe renal impairment.

Children and adolescents (< 18 years of age)

The pharmacokinetics of daptomycin after a single 4 mg/kg dose of Cubicin were evaluated in three groups of paediatric patients with proven or suspected Gram-positive infection (2_max in adolescents. In the younger age groups (2_max) and elimination half-life. Efficacy was not assessed in this study.

A separate study was conducted to evaluate the pharmacokinetics of daptomycin after a single 8 mg/kg or 10 mg/kg dose of Cubicin as either a 1 or 2 hour infusion in paediatric subjects aged 2 to 6 years, inclusive, with proven or suspected Gram-positive infection who were receiving standard antibiotic therapy.

The mean exposure (AUC_0-) was approximately 429 and 550 μg*hr/ml after the administration of 8 and 10 mg/kg single doses, respectively, similar to the exposure seen in adults at the 4 mg/kg dose at steady state (495 μg*hr/ml). The pharmacokinetics of daptomycin appears to be linear in the dose range studied. The half life, clearance and volume of distribution were similar at both dose levels.

Obesity

Relative to non-obese subjects daptomycin systemic exposure measured by AUC was about 28% higher in moderately o

Cymalon Cranberry Liquid

Cymalon

Cranberry Liquid (potassium citrate)

Important information about Cymalon Cranberry liquid

• This medicine is used to relieve the symptoms of cystitis and other minor urinary tract infections.


• It can be taken by adults, the elderly and children over 6 years.

Talk to your doctor

• If you still have symptoms after 2 days.


• This medicine is not an antibiotic. If your symptoms persist the doctor may need to prescribe antibiotics aswell.

Now read the rest of the leaflet before you use this medicine. It includes other information which might be especially important for you.

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


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


• 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.

What the medicine is for

Cymalon Cranberry Liquid contains potassium citrate which makes the urine less acid. This helps relieve the symptoms of cystitis and other mild urinary tract infections.

Before you use this medicine

Do not use the medicine if you or your child have

• An allergy to potassium citrate or any of the ingredients listed in section 6.


• 
  High levels of potassium in your blood.
  


• 
  Kidney problems.
  


• 
  Irregular heart beat or heart problems.
  


• 
  Addison’s Disease (an adrenal gland problem).

Talk to your doctor if you or your child have

• Symptoms which carry on for more than 2 days after you start taking this medicine.


• Symptoms which keep recurring.


• Or are elderly, as elderly people can react differently to this medicine.

Talk to your doctor or pharmacist if you or your child are taking

• Nitrofurantoin or methenamine for a urinary or bladder infection.


• Cardiac glycosides (e.g. digoxin) for heart problems.


• Aspirin or other salicylates.


• Tetracycline (an antibiotic).


• Decongestants or drugs to help ease breathing (e.g. salbutamol, ephedrine, phenylephrine)


• Stimulant drugs (amphetamines).


• Barbiturates (e.g. phenobarbital).


• Other medicine containing potassium or medicine which may retain potassium in your body (e.g. drugs used for heart failure or cyclosporin) as these may be affected by taking this medicine.

Pregnant or breastfeeding

Ask your doctor or pharmacist for advice before using this medicine if you are pregnant, might be pregnant or are breastfeeding.

Cymalon Cranberry Liquid should not be used in pregnancy unless the doctor has told you to do so.

Important information about some of the ingredients

• This product contains small amounts of ethanol (alcohol), less than 100mg per 10ml dose.


• It also contains 2.2g sucrose per 10ml dose. This should be taken into account in people with diabetes. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

How to use this medicine

Take this medicine by mouth.

Adults, the elderly and children over 6 years:

• Shake the bottle thoroughly before use.


• Fill the dosing cup provided to the 10ml mark.


• Stir into a glass of water.


• Drink the diluted medicine 3 times a day after meals.

Children under 6 years

Do not give to children under 6 unless your doctor tells you to.

If you take too much

If you accidentally take too much, see a doctor straight away. Take the pack with you to show which medicine you have swallowed.

Possible side effects

Like all medicines, Cymalon Cranberry Liquid can have side effects, although these don’t affect everyone.

• Upset stomach.


• Nausea (feeling sick).


• Sickness.


• Abnormal heart rhythm due to high levels of potassium in the blood.

If you notice these or any other side effect not included above, stop use and tell your doctor or pharmacist. They will tell you what to do.

Storing this medicine

• Keep it out of the reach and sight of children.


• Store below 25°C.


• Keep the container tightly closed.


• Throw away any unused liquid 2 months after opening.


• Do not use after the expiry date shown on the carton. The expiry date refers to the last day of that month.


• Medicine should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of any unused medicine. These measures will help to protect the environment.

Further information

What is in this medicine

The active ingredient per 5ml is:

Potassium Citrate 1.5g.

The other ingredients are: citric acid monohydrate, quillaia tincture, cranberry flavour, ethanol, chloroform, purified water and syrup.

What the medicine looks like

Cymalon Cranberry Liquid is a cloudy, thick yellow/brown liquid.

It is supplied in 60ml bottles.

Marketing authorisation holder

Actavis Group PTC ehf

Reykjavikurvegi 76-78

220 Hafnarfjordur

Iceland

Manufacturer

Thornton and Ross Ltd.

Huddersfield

HD7 5QH

UK

This leaflet was revised in October 2008

Cymalon is a trade mark of Actavis Group PTC ehf.

THOPL007