ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 5

2 1. NAME OF THE MEDICINAL PRODUCT Caelyx 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 10 ml vial of Caelyx contains doxorubicin hydrochloride, 2mg/ml, concentrate for infusion. 3. PHARMACEUTICAL FORM 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. Caelyx is a concentrate for infusion presented as a sterile, translucent, red suspension in 10-ml glass vials for single-use intravenous infusion. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Caelyx is indicated for AIDS-related Kaposi's sarcoma (KS) in patients with low CD4 counts (< 200 CD4 lymphocytes/mm 3 ) 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 doxorubicin (or other anthracycline). 4.2 Posology and method of administration Dosage Caelyx should be administered intravenously at 20 mg/m 2 every two-to-three weeks. Intervals shorter than 10 days should be avoided as drug accumulation and increased toxicity cannot be ruled out. Patients should be treated for two-to-three months to achieve a therapeutic response. Treatment should be continued as needed to maintain a therapeutic response. Administration Caelyx, diluted in 250 ml 5% Glucose Intravenous Infusion, is administered by intravenous infusion over 30 minutes. DO NOT administer 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% Glucose Intravenous Infusion to achieve further dilution and minimise the risk of thrombosis and extravasation. Caelyx must not be given by the intramuscular or subcutaneous route. Patients with impaired hepatic function 6

3 In a small number of patients with impaired hepatic function (bilirubin values up to 4 mg/dl) administered 20 mg/m 2 of Caelyx, there appeared to be no change in the clearance and terminal half-life of Caelyx. However, until further experience is gained, the Caelyx dosage should be reduced in patients with impaired hepatic function, based on experience with conventional doxorubicin HCl. Prior to Caelyx administration, hepatic function should be evaluated using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase, and bilirubin. It is recommended that the Caelyx dosage be reduced if the bilirubin is elevated as follows: at serum bilirubin mg/dl, give 1/2 the normal dose; at >3 mg/dl, give 1/4 the normal dose. Patients with impaired renal function As doxorubicin is metabolised by the liver and excreted in the bile, dose modification should not be required with Caelyx. Patients with splenectomy As there is no experience with Caelyx in patients with splenectomy, treatment with Caelyx is not recommended. Paediatric patients The safety and effectiveness in patients less than 18 years of age have not been established. Elderly patients The safety and effectiveness in patients over 60 years of age have not been established. 4.3 Contra-indications Caelyx is contra-indicated in patients who have a history of hypersensitivity reactions to its components or to doxorubicin HCl. Caelyx should not be administered during pregnancy or while breast-feeding. Caelyx should not be used to treat AIDS-KS that may be effectively treated with local therapy or systemic alfa-interferon. 4.4 Special warnings and special precautions for use Special warnings Cardiac risk All patients receiving Caelyx should 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 7

4 most definitive test for anthracycline myocardial injury, i.e., endomyocardial biopsy, should 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 Multiple Gated Arteriography (MUGA). These methods should be applied routinely before the initiation of Caelyx therapy and should be repeated periodically during treatment. The evaluation of left ventricular function is considered to be mandatory before each additional administration of Caelyx which exceeds a cumulative dose of 450 mg/m 2. Whenever cardiomyopathy is suspected, i.e., the left ventricular ejection fraction has decreased relatively as compared to pre-treatment values and/or (at the same time) left ventricular ejection are lower than a prognostically relevant value (e.g. < 45%), endomyocardial biopsies should be performed and the benefit of continued therapy must be carefully evaluated against the risk of producing 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. The evaluation tests and methods mentioned above concerning the monitoring of cardiac performance during anthracycline therapy should 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. Patients with a history of cardiovascular disease should receive Caelyx only when the benefit outweighs the risk to the patient Caution should be exercised in patients with impaired cardiac function who receive Caelyx. Caution should be observed in patients who have received other anthracyclines. The total dose of doxorubicin HCl should also take into account any previous (or concomitant) therapy with cardiotoxic compounds such as other anthracyclines/anthraquinones or e.g. 5-FU. Myelosuppression Many AIDS-KS patients treated with Caelyx have baseline myelosuppression due to such factors as their HIV disease or numerous concomitant medications. In this population, myelosuppression appears to be the dose-limiting adverse event (see 4.8 Undesirable effects). Because of the potential for bone marrow suppression, periodic blood counts should 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 Infusion-associated reactions See Undesirable effects. Special precautions 8

5 Diabetic patients It should be noted that each vial of Caelyx contains sucrose and is administered in 5% Glucose Intravenous Infusion. 4.5 Interaction with other medicinal products and other forms of interaction No formal drug interaction studies have been conducted with Caelyx. Caution should be exercised in the concomitant use of drugs known to interact with doxorubicin HCl. Although not formally studied, Caelyx, like other doxorubicin HCl preparations, may potentiate the toxicity of other anti-cancer therapies. Exacerbation of cyclophosphamide-induced haemorrhage cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with doxorubicin HCl. Caution should be exercised when giving any other cytotoxic agents, especially myelotoxic agents, at the same time. 4.6 Use during pregnancy and lactation Pregnancy Caelyx is embryotoxic in rats and embryotoxic and abortifacient in rabbits. Teratogenicity cannot be ruled out. There is no experience in pregnant women with Caelyx. Caelyx therefore, should, not be administered to pregnant women. Women of child-bearing potential should 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 5.3 Preclinical safety data). Lactation It is not known whether this drug is excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Caelyx, mothers should discontinue nursing prior to taking this drug. 4.7 Effects on ability to drive and use machines Although Caelyx should not affect driving performance, in studies to date, dizziness and somnolence were associated infrequently (< 5%) with the administration of Caelyx. Patients who suffer from these effects should avoid driving and operating machinery. 4.8 Undesirable effects Open-label and controlled clinical studies on AIDS-KS patients treated with Caelyx show that myelosuppression was the most frequent side effect considered related to Caelyx occurring in approximately half of the patients. Leucopenia is the most frequent adverse event experienced with Caelyx in this population; and anaemia and thrombocytopenia can also be expected. These events may occur early on in treatment and are usually transient. In clinical trials patients rarely discontinued treatment due to 9

6 myelosuppression. Haematological toxicity may require dose reduction or suspension or delay of therapy. Caelyx treatment should be temporarily suspended in patients when the ANC count is < 1000/mm 3 and/or the platelet count is < 50,000/mm 3. G-CSF (or GM-CSF) may be given as concomitant therapy to support the blood count when the ANC count is < 1000/mm 3. Clinically significant laboratory abnormalities frequently ( 5%) occurred in clinical studies with Caelyx. These included increases in alkaline phosphatase; and increases in AST and bilirubin which are believed to be related to the underlying disease and not Caelyx. Reduction in haemoglobin and platelets were less frequently (<5%) reported. Sepsis related to leucopenia was rarely (<1%) observed. Some of these abnormalities may have been related to the underlying HIV infection and not Caelyx. Other frequently ( 5%) observed side effects were nausea, asthenia, alopecia, fever, diarrhoea, infusion-associated acute reactions, and stomatitis. Infusion-associated reactions are characterised by flushing, shortness of breath, facial oedema, headache, chills, back pain, tightness in the chest and throat and/or hypotension. In most cases, the side effect occurs during the first cycle of treatment. Temporarily stopping the infusion or slowing the rate of the infusion resolves these reactions over the course of several hours, regardless of whether any symptomatic treatment is used. Stomatitis has been reported in patients receiving continuous infusions of conventional doxorubicin HCl and was frequently reported in patients receiving Caelyx. It did not interfere with patients completing therapy and no dosage adjustments are generally required, unless stomatitis is affecting a patient s ability to eat. In this case, the dose interval may be extended by 1-2 weeks or the dose reduced. Respiratory side effects frequently ( 5%) occurred in clinical studies of Caelyx and may be related to opportunistic infections in the AIDS population. Opportunistic infections (OI's) are observed in KS patients after administration with Caelyx, and are frequently observed in patients with HIV-induced immunodeficiency. The most frequently observed OI's in clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis carinii pneumonia, and mycobacterium avium complex. Other less frequently (< 5%) observed side effects included palmar-plantar erythrodysesthesia, oral monoliasis, nausea and vomiting, vomiting, weight loss, rash, mouth ulceration, dyspnoea, abdominal pain, allergic reaction, vasodilatation, anorexia, glossitis, constipation, paresthesia and retinitis. Palmar-plantar erythrodysesthesia is characterised by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after six or more weeks of treatment. In most patients it clears in one or two weeks, with or without treatment with corticosteroids. It appears to be dose and schedule related and can be reduced by extending the dose interval 1-2 weeks or reducing the dose. This reaction can be severe and debilitating in some patients, however, and may require discontinuation of treatment. An increased incidence of congestive heart failure is associated with standard doxorubicin therapy. Although, endomyocardial biopsies on nine of ten AIDS-KS patients receiving cumulative doses of 10

7 Caelyx greater than 460 mg/ m 2 indicate no evidence of anthracycline-induced cardiomyopathy, until further clinical data are available, the risk of developing cardiomyopathy is assumed to be similar to that of standard doxorubicin. The recommended dose of Caelyx for AIDS-KS patients is 20 mg/ m 2 every two-to-three weeks. The cumulative dose at which cardiotoxicity would become a concern (>400 mg/ m 2 ) would require more than 20 courses of Caelyx therapy over 40 to 60 weeks. Although no local necrosis following extravasation has been observed to date, Caelyx should be considered an irritant. Animal studies indicate that administration of doxorubicin HCl as a liposomal formulation reduces the potential for extravasation injury. If any signs or symptoms of extravasation occur (e.g., stinging, erythema) the infusion should be immediately terminated and restarted in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction. Caelyx must not be given by the intramuscular or subcutaneous route. Recall of skin reaction due to prior radiotherapy has rarely occurred with Caelyx administration. 4.9 Overdose Acute overdosage with doxorubicin HCl worsens the toxic effects of mucositis, leucopenia and thrombocytopenia. Treatment of acute overdosage of the severely myelosuppressed patient consists of hospitalisation, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmaco-therapeutic group : Cytotoxic agents (anthracyclines and related substances), ATC code L01DB. The active ingredient of Caelyx is doxorubicin HCl, a cytotoxic anthracycline antibiotic obtained from Streptomyces peucetius var. caesius. The exact mechanism of the antitumour activity of doxorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesis is responsible for the majority of the cytotoxic effects. This is probably the result of intercalation of the anthracycline between adjacent base pairs of the DNA double helix thus preventing their unwinding for replication. 5.2 Pharmacokinetic properties Caelyx is a long-circulating pegylated liposomal formulation of doxorubicin HCl that provides greater concentration of doxorubicin in KS tumours than in normal skin. Pegylated liposomes contains surface-grafted segments of the hydrophilic polymer methoxypolyethylene glycol (MPEG). These linear MPEG groups extend from the liposome surface creating a protective coating that reduces interactions between the lipid bilayer membrane and the plasma components. This allows the Caelyx liposomes to circulate for prolonged periods in the blood stream. Pegylated liposomes are small enough (average diameter of approximately 100 nm) to pass intact (extravasate) through defective blood vessels supplying tumours. Evidence of penetration of pegylated liposomes from blood vessels and their entry and accumulation in tumours has been 11

8 seen in mice with C-26 colon carcinoma tumours and in transgenic mice with KS-like lesions. The pegylated liposomes also have a low permeability lipid matrix and internal aqueous buffer system that combine to keep doxorubicin HCl encapsulated during liposome residence time in circulation. The plasma pharmacokinetics of Caelyx were evaluated in 23 patients with Kaposi's sarcoma who received single doses of 20 mg/m 2 administered by a 30-minute infusion. The pharmacokinetic parameters of Caelyx (primarily representing liposome-encapsulated doxorubicin HCl and low levels of unencapsulated doxorubicin HCl) observed after the 20 mg/m 2 doses are presented in the following table. Pharmacokinetic Parameters in Caelyx-Treated Patients Mean ± Standard Error Parameter 20 mg/m 2 (n=23) Maximum Plasma Concentration* (µg/ml) 8.34 ± 0.49 Plasma Clearance (L/h/m 2 ) ± Volume of Distribution (L/m 2 ) 2.72 ± AUC (µg/ml. h) 590 ± 58.7 λ1 half-live (hours) 5.2 ± 1.4 λ2 half-live (hours) 55.0 ± 4.8 * Measured at the end of a 30-minute infusion The plasma pharmacokinetics of Caelyx in humans differ significantly from those reported in the literature for standard doxorubicin HCl preparations. Caelyx displayed linear pharmacokinetics. Disposition occurred in two phases after Caelyx administration, with a relatively short first phase (~5 hours) and a prolonged second phase (~55 hours) that accounted for the majority of the area under the curve (AUC). Doxorubicin HCl displays extensive tissue distribution (volume of distribution, 700 to 1100 L/m 2 and a rapid elimination clearance (24 to 73 L/h/m 2 ). In contrast, the pharmacokinetic profile of Caelyx indicates that Caelyx is confined mostly to the vascular fluid volume and that the clearance of doxorubicin from the blood is dependent upon the liposomal carrier. Doxorubicin becomes available after the liposomes are extravasated and enter the tissue compartment. At equivalent doses, the plasma concentration and AUC values of Caelyx which represent mostly liposome-encapsulated doxorubicin HCl (containing 90% to 95% of the measured doxorubicin) are significantly higher than those achieved with standard doxorubicin HCl preparations. Kaposi's sarcoma lesion and normal skin biopsies were obtained 48 and 96 hours post-infusion. In patients receiving 20 mg/m 2 Caelyx the concentration of total (liposome encapsulated and unencapsulated) doxorubicin in the KS lesions was a median of 19 (range 3-53) times higher than in normal skin at 48 hours posttreatment. 12

9 5.3 Preclinical safety data In repeat dose studies conducted in animals, the toxicity profile of Caelyx appears very similar to that reported in humans who receive long-term infusions of doxorubicin hydrochloride. With Caelyx, the encapsulation of doxorubicin hydrochloride in pegylated liposomes results in these effects having a differing strength, as follows: Cardiotoxicity Studies in rabbits have shown that the cardiotoxicity of Caelyx is reduced compared with conventional doxorubicin HCl preparations. Dermal toxicity In studies performed after the repeated administration of Caelyx to rats and dogs, serious dermal inflammations and ulcer formations were observed at clinically relevant dosages. In the study in dogs, the occurrence and severity of these lesions was reduced by lowering the dose or prolonging the intervals between doses. Similar dermal lesions, which are described as palmarplantar erythrodysesthesia were also observed in patients after long-term intravenous infusion (see section 4.8 Undesirable effects) Anaphylactoid Response During repeat dose toxicology studies in dogs, an acute response characterised by hypotension, pale mucous membranes, salivation, emesis and periods of hyperactivity followed by hypoactivity and lethargy was observed following administration of pegylated liposomes (placebo). A similar, but less severe response was also noted in dogs treated with Caelyx and doxorubicin. The hypotensive response was reduced in magnitude by pretreatment with antihistamines. However, the response was not life-threatening and the dogs recovered quickly upon discontinuation of treatment. Local toxicity Subcutaneous tolerance studies indicate that Caelyx, as against doxorubicin HCl, causes slighter local irritation or damage to the tissue after a possible extravasation. Mutagenicity and carcinogenicity Although no studies have been conducted with Caelyx, doxorubicin HCl, the pharmacologically active ingredient of Caelyx, is mutagenic and carcinogenic. Pegylated placebo liposomes are neither mutagenic or genotoxic. Reproductive Toxicity 13

10 Caelyx resulted in mild to moderate ovarian and testicular atrophy in mice after a single dose of 36 mg/kg. Decreased testicular weights and hypospermia were present in rats after repeat doses 0.25 mg/kg/day and diffuse degeneration of the semniferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (See Section 4.6 Use during pregnancy and lactation). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients The following excipients are contained in each vial of product: α-2(2-[1,2-distearoyl-sn-glycero(3)phosphooxy]ethylcarbamoyl)-ω-methoxypoly (oxyethylen)-40, sodium salt (MPEG-DSPE) Fully Hydrogenated Soy Phosphatidylcholine (HSPC) Cholesterol, NF Ammonium Sulphate, ACS Sucrose, Ph Eur Histidine, Ph Eur Water for Injections, Ph Eur Hydrochloric Acid, Ph Eur Sodium Hydroxide, Ph Eur 6.2 Incompatibilities Do not mix with other drugs. 6.3 Shelf-life Unopened vials of material have a shelf-life of 18 months and should be stored at 2 C to 8 C. After dilution with 5% Glucose Intravenous Infusion, the diluted Caelyx solution should be used immediately. Diluted product not for immediate use should be prepared under aseptic conditions and in line with good pharmaceutical practice should be stored at 2 C to 8 C for no longer than 24 hours. Partially used vials should be discarded. 6.4 Special precautions for storage Store at 2 C to 8 C. Avoid freezing. 6.5 Nature and content of container The container is a Type I glass vial, with a siliconised grey bromobutyl stopper, and an aluminium seal. Caelyx is supplied as a single pack or packs of ten. Each 10 ml vial of Caelyx contains doxorubicin hydrochloride 2mg/ml; concentrate for infusion. 6.6 Instructions for use and handling, and disposal (if appropriate) Do not use material that shows evidence of precipitation or any other particulate matter. 14

11 Determine the dose of Caelyx to be administered (based upon the recommended dose and the patient's surface area). Take the appropriate volume of Caelyx up into a sterile syringe. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in Caelyx. The appropriate dose of Caelyx must be diluted in 250 ml of 5% Glucose Intravenous prior to administration. The use of any diluent other than 5% Glucose Intravenous Infusion, or the presence of any bacteriostatic agent such as benzyl alcohol may cause precipitation of Caelyx. It is recommended that the Caelyx infusion line be connected through the side port of an intravenous infusion of 5% Glucose Intravenous Infusion. Caution should be exercised in handling Caelyx solution. The use of gloves is required. If Caelyx comes into contact with skin or mucosa, wash immediately and thoroughly with soap and water. Caelyx should be handled and disposed of in a manner consistent with that of other anti-cancer drugs. 7. MARKETING AUTHORISATION HOLDER SP Europe, Rue de Stalle, Brussels, Belgium 8. NUMBERS IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS EU/1/96/011/001 EU/1/96/011/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION June 21, DATE OF REVISION OF THE TEXT 15

12 ANNEX II THE MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR IMPORT AND BATCH RELEASE AND CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 16

13 A. HOLDER OF THE MANUFACTURING AUTHORISATION Manufacturer of the active substance : Meiji Seika Kaisha, Ltd, 4-16 Kyobashi 2 Chome, Chou-Ku, Tokyo 104, Japan Manufacturer of the medicinal product : Ben Venue Laboratories, Inc., 270 Northfield Road, PO Box 46568, Bedford, Ohio 44146, USA Manufacturer responsible for the importation of the medicinal product, packaging and batch release of the finished medicinal product in the European Economic Area : N.V. SP Labo, Industriepark 30, 2220, Heist-op-den-Berg, Belgium Manufacturing authorisation issued on 16 September 1994 by the Belgian Ministry of Public Health (Manufacturing authorisation No. 304) B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to non-renewable restricted medical prescription. C. SPECIFIC OBLIGATIONS OF THE MARKETING AUTHORISATION HOLDER The company, after having been consulted (letter dated on 13 February 1996) (CPMP/196/96) agreed to meet the commitment to submit to the EMEA the additional information set out below with the defined timeframe : Clinical aspects : 1. The company will submit on 31 May 1996 the final report of the study (A randomised comparison of Caelyx versus Bleomycin, Vincristine combination in the treatment of AIDS-related Kaposi s sarcoma) 2. The company will submit on 31 July 1996 the final report of the study (An open label study on patients with AIDS-related Kaposi s sarcoma). 17

14 ANNEX III LABELLING AND PACKAGE LEAFLET 18

15 A. LABELLING 19

16 Label vial Caelyx 10 ml 2 mg/ml (doxorubicin HCl [pegylated liposomal) 2 mg/ml Concentrate for infusion Single dose vial For intravenous use only SP Europe Rue de Stalle 73, 1180 Brussels, Belgium Lot/Exp: 20

17 Carton label: 1 vial Caelyx 10 ml 2 mg/ml (doxorubicin HCL [pegylated liposomal) 2 mg/ml Concentrate for infusion 1 single dose vial For intravenous use only, following dilution in 5% Glucose Intravenous Infusion. Keep out of reach of children Store at 2-8 C. Avoid freezing Partially used vials should be discarded. Caelyx should be handled and disposed of in a manner consistent with that of other cytotoxic drugs. Medicinal product subject to medical prescription. Each vial contains 20 mg doxorubicin HCl, α-2(2-[1,2-distearoyl-sn-glycero(3)phosphooxy)ethylcarbamoyl)- -methoxypoly(oxyethylen)-40, sodium salt, fully hydrogenated soy phosphatidylcholine, cholesterol, ammonium sulphate, sucrose, histidine, water for injections, hydrochloric acid and sodium hydroxide. MA Nr. EU/1/96/011/001 Marketing Authorisation Holder: SP Europe Rue de Stalle 73, 1180 Brussels, Belgium Lot/Exp: 21

18 Carton label: 10 vials Caelyx 10 ml 2 mg/ml (doxorubicin HCl [pegylated liposomal) 2 mg/ml Concentrate for infusion 10 single dose vials For intravenous use only, following dilution in 5% Glucose Intravenous Infusion. Keep out of reach of children Store at 2-8 C. Avoid freezing Partially used vials should be discarded. Caelyx should be handled and disposed of in a manner consistent with that of other cytotoxic drugs. Medicinal product subject to medical prescription. Each vial contains 20 mg doxorubicin HCl, α-2(2-[1,2-distearoyl-sn-glycero(3)phosphooxy)ethylcarbamoyl)- -methoxypoly(oxyethylen)-40, sodium salt, fully hydrogenated soy phosphatidylcholine, cholesterol, ammonium sulphate, sucrose, histidine, water for injections, hydrochloric acid and sodium hydroxide. MA Nr. EU/1/96/011/002 Marketing Authorisation Holder: SP Europe Rue de Stalle 73, 1180 Brussels, Belgium Lot/Exp: 22

19 B. PACKAGE LEAFLET 23

20 Caelyx (doxorubicin HCl [pegylated liposomal]) 2 mg/ml, concentrate for infusion. Please read it carefully! This is important information you should know before you start taking Caelyx. If, after reading it, you have any more questions, please ask your doctor or hospital pharmacist. 1. WHAT YOUR MEDICINE IS MADE OF Your medicine is called Caelyx, a pegylated liposomal formulation of doxorubicin hydrochloride. The amount of doxorubicin hydrochloride in each 10ml vial is 20mg, which is 2mg per ml. The other ingredients are α-2(2-[1,2-distearoyl-sn-glycero(3)phosphooxy] ethylcarbamoyl)-ωmethoxypoly(oxyethylen)-40, sodium salt, fully hydrogenated soy phosphatidylcholine, cholesterol, ammonium sulphate, sucrose, histidine, water for injections, hydrochloric acid and sodium hydroxide. This medicine is a concentrate for infusion which means it must be diluted before use. Caelyx is supplied in single-use vials in one unit pack or as packs of ten. If you are allergic to any of these ingredients or want to know more about them, please talk to your doctor about it. 2. WHAT TYPE OF MEDICINE IS Caelyx Caelyx is a medicine containing a drug which is able to interact with cells in such a way as to selectively kill cancer cells. The doxorubicin hydrochloride in Caelyx is enclosed in tiny spheres called liposomes which help to deliver the drug from the blood stream to the cancerous tissue rather than healthy normal skin. 3. MARKETING AUTHORISATION HOLDER AND MANUFACTURER Marketing Authorisation Holder Manufacturer SP Europe, N.V. SP Labo Rue de Stalle, 73 Industriepark Brussels, Belgium 2220 Heist-op-den-Berg Belgium 4. WHAT YOUR MEDICINE IS USED FOR Your medicine is used to produce an improvement in your Kaposi s sarcoma including flattening, lightening and even shrinkage of the cancer. Other symptoms of Kaposi s sarcoma, such as swelling around the tumour, may also improve or disappear. Caelyx has not been used in patients less than 18 years of age or patients over 60 years of age. 5. WHAT TO DO BEFORE YOU START TAKING YOUR MEDICINE 24

21 If you are allergic to any of the ingredients of Caelyx, please tell your doctor. You should tell your doctor if you have any heart disease or liver disease or have had recent surgery to remove your spleen. If you are diabetic you should also make sure the doctor knows this because Caelyx contains sugar which may require an adjustment to the treatment of your diabetes. Caelyx may interact with other anti-cancer treatments so tell your doctor about any other treatments you are on or have been taking, as particular care needs to be taken with treatments which reduce the number of white blood cells. If you are unsure about what treatments you have received or any illnesses you have had, discuss these with your doctor. Because the active ingredient doxorubicin hydrochloride in Caelyx may cause birth defects or be harmful when nursing infants, you should also tell your doctor if you think you are pregnant or if you are breastfeeding. You should avoid becoming pregnant while you or your partner are taking Caelyx and in the six months following stopping Caelyx treatment. Caelyx causes some people to feel lightheaded or sleepy. You should not drive or use machines if you are affected in this way. 6. WHAT TO DO WHEN YOU TAKE YOUR MEDICINE Caelyx will be given to you by your doctor in a drip (called an infusion) over 30 minutes into a vein. The dose which you will be given is 20 mg per square metre of your body surface area. Your doctor will give you an infusion every 2 to 3 weeks for 2-3 months, then as often as necessary to maintain an improvement in your cancer. 7. CAN YOUR MEDICINE UPSET YOU As with other types of medicines Caelyx may upset some people. If your medicine starts to upset you or your symptoms become worse, you should contact your doctor. During the infusion of Caelyx, the following reactions may occur, flushing of the face, shortness of breath, headache, chills, back pain, tightness in the chest and/or throat, low blood pressure and possibly dizziness and puffing of the face. Stinging or swelling of the skin at the site of injection may also occur. If the drip stings or hurts whilst you are receiving a dose of Caelyx, tell your doctor immediately. Between infusions, the following may occur decrease in the number of white blood cells, which can increase the chances of infections. Anaemia (reduction in red blood cells) may cause tiredness, and decreased platelets in the blood may increase the risk of bleeding. In rare cases, having low white blood cells may lead to severe infection. The tests related to the function of the liver may either increase or decrease while on Caelyx. It is because of the potential changes in your blood cells that you will have regular blood tests. Some of these effects may be related to your disease and not Caelyx; 25

22 stomach pains, sickness (nausea or vomiting), diarrhoea, constipation, sores in mouth, oral thrush (a fungal infection in the mouth), loss of appetite, weight loss and tongue inflammation; general feeling of tiredness, sleepiness, inflammation of the retina, pins and needles; redness, swelling and sores on the palms of your hands and feet, hair loss and rash; heart problems, e.g, irregular heart beat, enlarged blood vessels; fever, increased temperature or any other sign of infection which may be related to your disease; respiratory problems, i.e., difficulty in breathing, which may be linked to infections you have caught as a result of your disease; if you have previously had skin reactions, i.e., pain, redness and dryness of skin, during treatment with radiotherapy, this may also happen with Caelyx. Contact your doctor immediately if you get reddening painful skin on your hands and feet, any heart problems or mouth sores or if you develop a temperature or any other sign of an infection. Also tell your doctor or hospital pharmacist if you notice any other unwanted effects not already mentioned. 8. LOOKING AFTER YOUR MEDICINE Unopened vials of Caelyx should be stored at 2 C to 8 C, i.e., in the refrigerator. Avoid freezing. The shelf-life under these conditions is 18 months. After dilution with 5% Glucose Intravenous Infusion, the diluted Caelyx solution should be used immediately. Diluted product not for immediate use should be prepared under aseptic conditions and in line with good pharmaceutical practice should be stored at 2 C to 8 C for no longer than 24 hours. Partially used vials should be discarded. 9. INSTRUCTIONS FOR USE AND HANDLING OF THIS MEDICINE DO NOT USE MATERIAL THAT SHOWS EVIDENCE OF PRECIPITATION OR ANY OTHER PARTICULATE MATTER. Caution should be exercised in handling Caelyx solution. The use of gloves is required. If Caelyx comes into contact with skin or mucosa, wash immediately and thoroughly with soap and water. Caelyx should be handled and disposed of in a manner consistent with that of other anti-cancer drugs. 26

23 Determine the dose of Caelyx to be administered (based upon the recommended dose and the patient's surface area). Take the appropriate volume of Caelyx up into a sterile syringe. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in Caelyx. The appropriate dose of Caelyx must be diluted in 250 ml of 5% Glucose Intravenous prior to administration. The use of any diluent other than 5% Glucose Intravenous Infusion, or the presence of any bacteriostatic agent such as benzyl alcohol may cause precipitation of Caelyx. It is recommended that the Caelyx infusion line be connected through the side port of an intravenous infusion of 5% Glucose Intravenous Infusion. 10. EXPIRY DATE This medicine should not be used after the expiry date printed on the carton. 11. MORE INFORMATION This leaflet is only a summary. If you want to know more about your medicine or your condition, ask your doctor or hospital pharmacist who will have more information. 12. DATE OF LAST REVISION 27