CAELYX PEGYLATED LIPOSOMAL 2mg / ml perfusive solution concentrate medication leaflet

Caelyx pegylated liposomal 2 mg/ml concentrate for solution for infusion

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

Caelyx pegylated liposomal is doxorubicin hydrochloride encapsulated in liposomes withsurface-bound methoxypolyethylene glycol (MPEG). This process is known as pegylation and protectsliposomes from detection by the mononuclear phagocyte system (MPS), which increases bloodcirculation time.

Contains fully hydrogenated soy phosphatidylcholine (from soyabean) - see section 4.3.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate)

The dispersion is sterile, translucent and red.

Caelyx pegylated liposomal is indicated:

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

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

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

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

Caelyx pegylated liposomal may be used as first-line systemic chemotherapy, or as second linechemotherapy 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 vincaalkaloid, bleomycin and standard doxorubicin (or other anthracycline).

Caelyx pegylated liposomal should only be administered under the supervision of a qualifiedoncologist specialised in the administration of cytotoxic agents.

Caelyx pegylated liposomal exhibits unique pharmacokinetic properties and must not be usedinterchangeably with other formulations of doxorubicin hydrochloride.

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

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

Caelyx pegylated liposomal is administered intravenously at 20 mg/m2 every two-to-three weeks.

Avoid intervals shorter than 10 days as medicinal product accumulation and increased toxicity cannotbe ruled out. Treatment of patients for two-to-three months is recommended to achieve a therapeuticresponse. Continue treatment as needed to maintain a therapeutic response.

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

Guidelines for Caelyx pegylated liposomal dose modification

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

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

The table for haematological toxicity (Table 3) provides the schedule followed for dose modificationin clinical trials in the treatment of patients with breast or ovarian cancer only. Dose modification inpatients with AIDS-KS is provided following Table 4.

Table 1. Palmar-Plantar erythrodysesthesia

Week after prior Caelyx pegylated liposomal dose

Toxicity grade at Week 4 Week 5 Week 6current assessment

Grade 1 Redose unless Redose unless Decrease dose by(mild erythema, patient has patient has 25%; return toswelling, or experienced a previous experienced a previous 4 week intervaldesquamation not grade 3 or 4 skin grade 3 or 4 skininterfering with daily toxicity, in which case toxicity, in which caseactivities) wait an additional wait an additionalweek week

Grade 2 Wait an additional Wait an additional Decrease dose by(erythema, week week 25%; return todesquamation, or 4 week intervalswelling interferingwith, but not precludingnormal physicalactivities; small blistersor ulcerations less than2 cm in diameter)

Grade 3 Wait an additional Wait an additional Withdraw patient(blistering, ulceration, week weekor swelling interferingwith walking or normaldaily activities; cannotwear regular clothing)

Grade 4 Wait an additional Wait an additional Withdraw patient(diffuse or local process week weekcausing infectiouscomplications, or abedridden state orhospitalisation)

Table 2. Stomatitis

Week after prior Caelyx pegylated liposomal dose

Toxicity grade at Week 4 Week 5 Week 6current assessment

Grade 1 Redose unless Redose unless Decrease dose by(painless ulcers, patient has patient has 25%; return toerythema, or mild experienced a previous experienced a previous 4 week interval orsoreness) grade 3 or 4 stomatitis grade 3 or 4 stomatitis withdraw patient perin which case wait an in which case wait an physician’s assessmentadditional week additional week

Grade 2 Wait an additional Wait an additional Decrease dose by(painful erythema, week week 25%; return tooedema, or ulcers, but 4 week interval orcan eat) withdraw patient perphysician’s assessment

Grade 3 Wait an additional Wait an additional Withdraw patient(painful erythema, week weekedema, or ulcers, butcannot eat)

Grade 4 Wait an additional Wait an additional Withdraw patient(requires parenteral or week weekenteral support)

Table 3. Haematological toxicity (ANC or platelets) - Management of patients with breast orovarian cancer

GRADE ANC PLATELETS MODIFICATION

Grade 1 1,500 - 1,900 75,000 - 150,000 Resume treatment with no dosereduction.

Grade 2 1,000 - < 1,500 50,000 - < 75,000 Wait until ANC ≥ 1,500 and platelets≥ 75,000; redose with no dosereduction.

Grade 3 500 - < 1,000 25,000 - < 50,000 Wait until ANC ≥ 1,500 and platelets≥ 75,000; redose with no dosereduction.

Grade 4 < 500 < 25,000 Wait until ANC ≥ 1,500 and platelets≥ 75,000; decrease dose by 25% orcontinue full dose with growth factorsupport.

For multiple myeloma patients treated with Caelyx pegylated liposomal in combination withbortezomib who experience PPE or stomatitis, the Caelyx pegylated liposomal dose should bemodified as described in Table 1 and 2 above respectively. Table 4, below provides the schedulefollowed for other dose modifications in the clinical trial in the treatment of patients with multiplemyeloma receiving Caelyx pegylated liposomal and bortezomib combination therapy. For moredetailed information on bortezomib dosing and dosage adjustments, see the SPC for bortezomib.

Table 4. Dosage adjustments for Caelyx pegylated liposomal + bortezomib combinationtherapy - patients with multiple myeloma

Patient status Caelyx pegylated liposomal Bortezomib

Fever ≥ 38○C and ANC Do not dose this cycle if before Reduce next dose by 25%.< 1,000/mm3 day 4; if after day 4, reducenext dose by 25%.

On any day of medicine Do not dose this cycle if before Do not dose; if 2 or more dosesadministration after day 1 of day 4; if after day 4 reduce next are not given in a cycle, reduceeach cycle: dose by 25% in the following dose by 25% in following

Platelet count < 25,000/mm3 cycles if bortezomib is reduced cycles.

Haemoglobin < 8 g/dl for haematologic toxicity.*

ANC < 500/mm3

Grade 3 or 4 non-haematologic Do not dose until recovered to Do not dose until recovered tomedicine related toxicity grade < 2 and reduce dose by grade < 2 and reduce dose by25% for all subsequent doses. 25% for all subsequent doses.

Neuropathic pain or peripheral No dosage adjustments. See the SPC for bortezomib.neuropathy

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

For AIDS-KS patients treated with Caelyx pegylated liposomal, haematological toxicity may requiredose reduction or suspension or delay of therapy. Temporarily suspend Caelyx pegylated liposomaltreatment in patients when the ANC count is < 1,000/mm3 and/or the platelet count is < 50,000/mm3.

G-CSF (or GM-CSF) may be given as concomitant therapy to support the blood count when the ANCcount is < 1,000/mm3 in subsequent cycles.

Hepatic Impairment

Caelyx pegylated liposomal pharmacokinetics determined in a small number of patients with elevatedtotal bilirubin levels do not differ from patients with normal total bilirubin; however, until furtherexperience is gained, the Caelyx pegylated liposomal dosage in patients with impaired hepaticfunction should be reduced based on the experience from the breast and ovarian clinical trial programsas follows: at initiation of therapy, if the bilirubin is between 1.2-3.0 mg/dl, the first dose is reduced by25%. If the bilirubin is > 3.0 mg/dl, the first dose is reduced by 50%. If the patient tolerates the firstdose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can be increased tothe next dose level, i.e., if reduced by 25% for the first dose, increase to full dose for cycle 2; ifreduced by 50% for the first dose, increase to 75% of full dose for cycle 2. The dosage can beincreased to full dose for subsequent cycles if tolerated. Caelyx pegylated liposomal can beadministered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymesup to 4 x the upper limit of the normal range. Prior to Caelyx pegylated liposomal administration,evaluate hepatic function using conventional clinical laboratory tests such as ALT/AST, alkalinephosphatase, and bilirubin.

Renal Impairment

As doxorubicin is metabolised by the liver and excreted in the bile, dose modification should not berequired. Population pharmacokinetic data (in the range of creatinine clearance tested of30-156 ml/min) demonstrate that Caelyx pegylated liposomal clearance is not influenced by renalfunction. No pharmacokinetic data are available in patients with creatinine clearance of less than30 ml/min.

As there is no experience with Caelyx pegylated liposomal in patients who have had splenectomy,treatment with Caelyx pegylated liposomal is not recommended.

The experience in children is limited. Caelyx pegylated liposomal is not recommended in patientsbelow 18 years of age.

Population based analysis demonstrates that age across the range tested (21-75 years) does notsignificantly alter the pharmacokinetics of Caelyx pegylated liposomal.

Caelyx pegylated liposomal is administered as an intravenous infusion. For further instructions onpreparation and special precautions for handling (see section 6.6).

Do not administer Caelyx pegylated liposomal as a bolus injection or undiluted dispersion. It isrecommended that the Caelyx pegylated liposomal infusion line be connected through the side port ofan intravenous infusion of 5% (50 mg/ml) glucose to achieve further dilution and minimise the risk ofthrombosis and extravasation. The infusion may be given through a peripheral vein. Do not use within-line filters. Caelyx pegylated liposomal must not be given by the intramuscular or subcutaneousroute (see section 6.6).

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

For doses ≥ 90 mg: dilute Caelyx pegylated liposomal in 500 ml 5% (50 mg/ml) glucose solution forinfusion.

To minimise the risk of infusion reactions, the initial dose is administered at a rate no greater than1 mg/minute. If no infusion reaction is observed, subsequent Caelyx pegylated liposomal infusionsmay be administered over a 60-minute period.

In those patients who experience an infusion reaction, the method of infusion should be modified asfollows:5% of the total dose should be infused slowly over the first 15 minutes. If tolerated without reaction,the infusion rate may then be doubled for the next 15 minutes. If tolerated, the infusion may then becompleted over the next hour for a total infusion time of 90 minutes.

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

Hypersensitivity to the active substance, peanut or soya, or to any of the excipients listed in section6.1.

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

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

It is recommended that all patients receiving Caelyx pegylated liposomal routinely undergo frequent

ECG monitoring. Transient ECG changes such as T-wave flattening, S-T segment depression andbenign arrhythmias are not considered mandatory indications for the suspension of Caelyx pegylatedliposomal therapy. However, reduction of the QRS complex is considered more indicative of cardiactoxicity. If this change occurs, the most definitive test for anthracycline myocardial injury, i.e.,endomyocardial biopsy, must be considered.

More specific methods for the evaluation and monitoring of cardiac functions as compared to ECG area measurement of left ventricular ejection fraction by echocardiography or preferably by Multigated

Angiography (MUGA). These methods must be applied routinely before the initiation of Caelyxpegylated liposomal therapy and repeated periodically during treatment. The evaluation of leftventricular function is considered to be mandatory before each additional administration of Caelyxpegylated liposomal that exceeds a lifetime cumulative anthracycline dose of 450 mg/m2.

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

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

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

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

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

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

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

Many patients treated with Caelyx pegylated liposomal have baseline myelosuppression due to suchfactors as their pre-existing HIV disease or numerous concomitant or previous medications, ortumours involving bone marrow. In the pivotal trial in patients with ovarian cancer treated at a dose of50 mg/m2, myelosuppression was generally mild to moderate, reversible, and was not associated withepisodes of neutropaenic infection or sepsis. Moreover, in a controlled clinical trial of Caelyxpegylated liposomal vs. topotecan, the incidence of treatment related sepsis was substantially less inthe Caelyx pegylated liposomal-treated ovarian cancer patients as compared to the topotecan treatmentgroup. A similar low incidence of myelosuppression was seen in patients with metastatic breast cancerreceiving Caelyx pegylated liposomal in a first-line clinical trial. In contrast to the experience inpatients with breast cancer or ovarian cancer, myelosuppression appears to be the dose-limitingadverse event in patients with AIDS-KS (see section 4.8). Because of the potential for bone marrowsuppression, periodic blood counts must be performed frequently during the course of Caelyxpegylated liposomal therapy, and at a minimum, prior to each dose of Caelyx pegylated liposomal.

Persistent severe myelosuppression, may result in superinfection or haemorrhage.

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

As with other DNA-damaging antineoplastic agents, secondary acute myeloid leukemias andmyelodysplasias have been reported in patients having received combined treatment with doxorubicin.

Therefore, any patient treated with doxorubicin should be kept under haematological supervision.

Very rare cases of secondary oral cancer have been reported in patients with long-term (more than oneyear) exposure to Caelyx pegylated liposomal or those receiving a cumulative Caelyx pegylatedliposomal dose greater than 720 mg/m2. Cases of secondary oral cancer were diagnosed both, duringtreatment with Caelyx pegylated liposomal, and up to 6 years after the last dose. Patients should beexamined at regular intervals for the presence of oral ulceration or any oral discomfort that may beindicative of secondary oral cancer.

Serious and sometimes life-threatening infusion reactions, which are characterised by allergic-like oranaphylactoid-like reactions, with symptoms including asthma, flushing, urticarial rash, chest pain,fever, hypertension, tachycardia, pruritus, sweating, shortness of breath, facial oedema, chills, backpain, tightness in the chest and throat and/or hypotension may occur within minutes of starting theinfusion of Caelyx pegylated liposomal. Very rarely, convulsions also have been observed in relationto infusion reactions. Temporarily stopping the infusion usually resolves these symptoms withoutfurther therapy. However, medications to treat these symptoms (e.g., antihistamines, corticosteroids,adrenaline, and anticonvulsants), as well as emergency equipment should be available for immediateuse. In most patients treatment can be resumed after all symptoms have resolved, without recurrence.

Infusion reactions rarely recur after the first treatment cycle. To minimise the risk of infusionreactions, the initial dose should be administered at a rate no greater than 1 mg/minute (see section4.2).

PPE is characterised by painful, macular reddening skin eruptions. In patients experiencing this event,it is generally seen after two or three cycles of treatment. Improvement usually occurs in 1-2 weeks,and in some cases, may take up to 4 weeks or longer for complete resolution. Pyridoxine at a dose of50-150 mg per day and corticosteroids have been used for the prophylaxis and treatment of PPE,however, these therapies have not been evaluated in phase III trials. Other strategies to prevent andtreat PPE include keeping hands and feet cool, by exposing them to cool water (soaks, baths, orswimming), avoiding excessive heat/hot water and keeping them unrestricted (no socks, gloves, orshoes that are tight fitting). PPE appears to be primarily related to the dose schedule and can bereduced by extending the dose interval 1- 2 weeks (see section 4.2). However, this reaction can besevere and debilitating in some patients and may require discontinuation of treatment (see section 4.8).

Although local necrosis following extravasation has been reported very rarely, Caelyx pegylatedliposomal is considered to be an irritant. Animal studies indicate that administration of doxorubicinhydrochloride as a liposomal formulation reduces the potential for extravasation injury. If any signs orsymptoms of extravasation occur (e.g., stinging, erythema) terminate the infusion immediately andrestart in another vein. The application of ice over the site of extravasation for approximately 30minutes may be helpful in alleviating the local reaction. Caelyx pegylated liposomal must not be givenby the intramuscular or subcutaneous route.

Please note that each vial of Caelyx pegylated liposomal contains sucrose and the dose is administeredin 5% (50 mg/ml) glucose solution for infusion.

This medicine contains less than 1 mmol sodium (23 mg) per dose and is essentially ‘sodium-free’.

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

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

Doxorubicin hydrochloride is suspected to cause serious birth defects when administered duringpregnancy. Therefore, Caelyx pegylated liposomal should not be used during pregnancy unless clearlynecessary.

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

It is not known whether Caelyx pegylated liposomal is excreted in human milk. Because manymedicinal products, including anthracyclines, are excreted in human milk, and because of the potentialfor serious adverse reactions in nursing infants, therefore mothers must discontinue nursing prior tobeginning Caelyx pegylated liposomal treatment. Health experts recommend that HIV infected womendo not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

The effect of doxorubicin hydrochloride on human fertility has not been evaluated (see section 5.3).

Caelyx pegylated liposomal has no or negligible influence on the ability to drive and use machines.

However, in clinical studies to date, dizziness and somnolence were associated infrequently (< 5%)with the administration of Caelyx pegylated liposomal. Patients who suffer from these effects mustavoid driving and operating machinery.

The most frequent adverse reactions (≥ 20%) were neutropaenia, nausea, leukopaenia, anaemia, andfatigue.

Severe adverse reactions (Grade 3/4 adverse reactions occurring in ≥ 2% of patients) wereneutropaenia, PPE, leukopaenia, lymphopaenia, anaemia, thrombocytopaenia, stomatitis, fatigue,diarrhoea, vomiting, nausea, pyrexia, dyspnoea, and pneumonia. Less frequently reported severeadverse reactions included Pneumocystis jirovecii pneumonia, abdominal pain, cytomegalovirusinfection including cytomegalovirus chorioretinitis, asthenia, cardiac arrest, cardiac failure, cardiacfailure congestive, pulmonary embolism, thrombophlebitis, venous thrombosis, anaphylactic reaction,anaphylactoid reaction, toxic epidermal necrolysis, and Stevens-Johnson syndrome.

Table 5 summarises the adverse drug reactions that occurred in patients receiving Caelyx pegylatedliposomal in 4,231 patients for the treatment of breast cancer, ovarian cancer, multiple myeloma, and

AIDS-related KS. Post-marketing adverse reactions are also included, as indicated by “b”. Frequenciesare defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100),rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (frequency cannot be estimatedfrom the available data). Within each frequency grouping, where relevant, adverse reactions arepresented in order of decreasing seriousness.

Table 5: Adverse reactions in patients treated with Caelyx pegylated liposomal

System Organ Frequency All Grades Adverse Drug Reaction

Class

Infections and Common Sepsisinfestations Pneumonia

Pneumocystis jirovecii pneumonia

Cytomegalovirus infection includingcytomegalovirus chorioretinitis

Mycobacterium avium complex infection

Candidiasis

Herpes zoster

Infection

Upper respiratory tract infection

Oral candidiasis

Folliculitis

Pharyngitis

Nasopharyngitis

Uncommon Herpes simplex

Fungal infection

Rare Opportunistic infection (including Aspergillus,

Histoplasma, Isospora, Legionella,

Microsporidium, Salmonella, Staphylococcus,

Toxoplasma, Tuberculosis)a

Neoplasms Not known Acute myeloid leukaemiabbenign, Myelodysplastic syndromebmalignant and Oral neoplasmbunspecified(including cystsand polyps)

Blood and Very common Leukopaenialymphatic system Neutropaeniadisorders Lymphopaenia

Anaemia (including hypochromic)

Common Thrombocytopaenia

Febrile neutropaenia

Uncommon Pancytopaenia

Thrombocytosis

Rare Bone marrow failure

Immune system Uncommon Hypersensitivitydisorders Anaphylactic reaction

Rare Anaphylactoid reaction

Metabolism and Very common Decreased appetitenutrition Common Cachexiadisorders Dehydration

Hyponatraemia

Uncommon Hyperkalaemia

Hypomagnesaemia

Psychiatric Common Confusional statedisorders Anxiety

Depression

Insomnia

Nervous system Common Neuropathy peripheraldisorders Peripheral sensory neuropathy

Neuralgia

Paraesthesia

Hypoaesthesia

Dysgeusia

Lethargy

Dizziness

Uncommon Polyneuropathy

Convulsion

Dysaesthesia

Somnolence

Eye disorders Common Conjunctivitis

Uncommon Vision blurred

Lacrimation increased

Rare Retinitis

Cardiac Common Tachycardiadisordersa Uncommon Palpitations

Cardiac arrest

Cardiac failure

Cardiac failure congestive

Cardiomyopathy

Rare Ventricular arrhythmia

Bundle branch block right

Conduction disorder

Atrioventricular block

Cyanosis

Vascular Common Hypertensiondisorders Hypotension

Flushing

Uncommon Pulmonary embolism

Infusion site necrosis (including soft tissuenecrosis and skin necrosis)

Phlebitis

Rare Thrombophlebitis

Venous thrombosis

Vasodilatation

Respiratory, Common Dyspnoeathoracic and Dyspnoea exertionalmediastinal Epistaxisdisorders Cough

Uncommon Asthma

Chest discomfort

Rare Throat tightness

Gastrointestinal Very common Stomatitisdisorders Nausea

Common Gastritis

Aphthous stomatitis

Mouth ulceration

Dyspepsia

Dysphagia

Oesophagitis

Abdominal pain

Abdominal pain upper

Oral pain

Dry mouth

Uncommon Flatulence

Gingivitis

Rare Glossitis

Lip ulceration

Skin and Very common Palmar plantar erythrodysaesthesia syndromeasubcutaneous Rash (including erythematous, maculo-papular,tissue disorders and papular)

Alopecia

Common Skin exfoliation

Dry skin

Erythema

Pruritus

Hyperhidrosis

Skin hyperpigmentation

Uncommon Dermatitis

Dermatitis exfoliative

Acne

Skin ulcer

Dermatitis allergic

Urticaria

Skin discolouration

Petechiae

Pigmentation disorder

Nail disorder

Rare Toxic epidermal necrolysis

Erythema multiforme

Dermatitis bullous

Lichenoid keratosis

Not known Stevens-Johnson syndromeb

Musculoskeletal Very common Musculoskeletal pain (including musculoskeletaland connective chest pain, back pain, pain in extremity)tissue disorders Common Muscle spasms

Myalgia

Arthralgia

Bone pain

Uncommon Muscular weakness

Renal and Common Dysuriaurinary disorders

Reproductive Uncommon Breast paindisorders Rare Vaginal infection

Scrotal erythema

General Very common Pyrexiadisorders and Fatigueadministration Common Infusion-related reactionsite conditions Pain

Chest pain

Influenza-like illness

Chills

Mucosal inflammation

Asthenia

Malaise

Oedema

Oedema peripheral

Uncommon Administration site extravasation

Injection site reaction

Face oedema

Hyperthermia

Rare Mucous membrane disorder

Investigations Common Weight decreased

Uncommon Ejection fraction decreased

Rare Liver function test abnormal (including Bloodbilirubin increased, Alanine aminotransferaseincreased and Aspartate aminotransferaseincreased)

Blood creatinine increased

Injury, poisoning Uncommon Radiation recall phenomenonaand proceduralcomplicationsa See Description of selected adverse reactionsb Post-marketing adverse reaction

The most common undesirable effect reported in breast/ovarian clinical trials was palmar-plantarerythrodysesthesia (PPE). The overall incidence of PPE reported was 41.3% and 51.1% in the ovarianand breast clinical trials, respectively. These effects were mostly mild, with severe (grade 3) casesreported in 16.3% and 19.6% of patients. The reported incidence of life-threatening (grade 4) caseswas < 1%. PPE infrequently resulted in permanent treatment discontinuation (1.9% and 10.8%). PPEwas reported in 16% of multiple myeloma patients treated with Caelyx pegylated liposomal plusbortezomib combination therapy. Grade 3 PPE was reported in 5% of patients. No grade 4 PPE wasreported. The rate of PPE was substantially lower in the AIDS-KS population (1.3% all grade, 0.4%grade 3 PPE, no grade 4 PPE). See section 4.4.

Respiratory undesirable effects commonly occurred in clinical studies of Caelyx pegylated liposomaland may be related to opportunistic infections (OI’s) in the AIDS population. Opportunistic infectionsare observed in KS patients after administration with Caelyx pegylated liposomal, and are frequentlyobserved in patients with HIV induced immunodeficiency. The most frequently observed OI’s inclinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis jirovecii pneumonia,and mycobacterium avium complex.

An increased incidence of congestive heart failure is associated with doxorubicin therapy atcumulative lifetime doses > 450 mg/m2 or at lower doses for patients with cardiac risk factors.

Endomyocardial biopsies on nine of ten AIDS-KS patients receiving cumulative doses of Caelyxpegylated liposomal greater than 460 mg/m2 indicate no evidence of anthracycline-inducedcardiomyopathy. The recommended dose of Caelyx pegylated liposomal for AIDS-KS patients is20 mg/m2 every two-to-three weeks. The cumulative dose at which cardiotoxicity would become aconcern for these AIDS-KS patients (> 400 mg/m2) would require more than 20 courses of Caelyxpegylated liposomal therapy over 40 to 60 weeks.

In addition, endomyocardial biopsies were performed in 8 solid tumour patients with cumulativeanthracycline doses of 509 mg/m2-1,680 mg/m2. The range of Billingham cardiotoxicity scores wasgrades 0-1.5. These grading scores are consistent with no or mild cardiac toxicity.

In the pivotal phase III trial versus doxorubicin, 58/509 (11.4%) randomised subjects (10 treated with

Caelyx pegylated liposomal at a dose of 50 mg/m2/every 4 weeks versus 48 treated with doxorubicinat a dose of 60 mg/m2/every 3 weeks) met the protocol-defined criteria for cardiac toxicity duringtreatment and/or follow-up. Cardiac toxicity was defined as a decrease of 20 points or greater frombaseline if the resting LVEF remained in the normal range or a decrease of 10 points or greater if the

LVEF became abnormal (less than the lower limit for normal). None of the 10 Caelyx pegylatedliposomal subjects who had cardiac toxicity by LVEF criteria developed signs and symptoms of CHF.

In contrast, 10 of 48 doxorubicin subjects who had cardiac toxicity by LVEF criteria also developedsigns and symptoms of CHF.

In patients with solid tumours, including a subset of patients with breast and ovarian cancers, treated ata dose of 50 mg/m2/cycle with lifetime cumulative anthracycline doses up to 1,532 mg/m2, theincidence of clinically significant cardiac dysfunction was low. Of the 418 patients treated with

Caelyx pegylated liposomal 50 mg/m2/cycle, and having a baseline measurement of left ventricularejection fraction (LVEF) and at least one follow-up measurement assessed by MUGA scan,88 patients had a cumulative anthracycline dose of > 400 mg/m2, an exposure level associated with anincreased risk of cardiovascular toxicity with conventional doxorubicin. Only 13 of these 88 patients(15%) had at least one clinically significant change in their LVEF, defined as an LVEF value less than45% or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (cumulativeanthracycline dose of 944 mg/m2), discontinued study treatment because of clinical symptoms ofcongestive heart failure.

Radiation recall phenomenon

Recall of skin reaction due to prior radiotherapy has occurred uncommonly with Caelyx pegylatedliposomal administration.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Acute overdosing with doxorubicin hydrochloride worsens the toxic effects of mucositis, leukopaeniaand thrombocytopaenia. Treatment of acute overdose of the severely myelosuppressed patient consistsof hospitalisation, antibiotics, platelet and granulocyte transfusions and symptomatic treatment ofmucositis.

Pharmacotherapeutic group: Cytotoxic agents (anthracyclines and related substances), ATC code:

L01DB01.

The active ingredient of Caelyx pegylated liposomal is doxorubicin hydrochloride, a cytotoxicanthracycline antibiotic obtained from Streptomyces peucetius var. caesius. The exact mechanism ofthe 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 theresult of intercalation of the anthracycline between adjacent base pairs of the DNA double helix thuspreventing their unwinding for replication.

A phase III randomised study of Caelyx pegylated liposomal versus doxorubicin in patients withmetastatic breast cancer was completed in 509 patients. The protocol-specified objective ofdemonstrating non-inferiority between Caelyx pegylated liposomal and doxorubicin was met, thehazard ratio (HR) for progression-free survival (PFS) was 1.00 (95% CI for HR=0.82-1.22). Thetreatment HR for PFS when adjusted for prognostic variables was consistent with PFS for the ITTpopulation.

The primary analysis of cardiac toxicity showed the risk of developing a cardiac event as a function ofcumulative anthracycline dose was significantly lower with Caelyx pegylated liposomal than withdoxorubicin (HR=3.16, p < 0.001). At cumulative doses greater than 450 mg/m2 there were no cardiacevents with Caelyx pegylated liposomal.

A phase III comparative study of Caelyx pegylated liposomal versus topotecan in patients withepithelial ovarian cancer following the failure of first-line, platinum-based chemotherapy wascompleted in 474 patients. There was a benefit in overall survival (OS) for Caelyx pegylatedliposomal-treated patients over topotecan-treated patients as indicated by a hazard ratio (HR) of 1.216(95% CI: 1.000; 1.478), p=0.050. The survival rates at 1, 2 and 3 years were 56.3%, 34.7% and 20.2%respectively on Caelyx pegylated liposomal, compared to 54.0%, 23.6% and 13.2% on topotecan.

For the sub-group of patients with platinum-sensitive disease the difference was greater: HR of 1.432(95% CI: 1.066; 1.923), p=0.017. The survival rates at 1, 2 and 3 years were 74.1%, 51.2% and 28.4%respectively on Caelyx pegylated liposomal, compared to 66.2%, 31.0% and 17.5% on topotecan.

The treatments were similar in the sub-group of patients with platinum-refractory disease: HR of 1.069(95% CI: 0.823; 1.387), p=0.618. The survival rates at 1, 2 and 3 years were 41.5%, 21.1% and 13.8%respectively on Caelyx pegylated liposomal, compared to 43.2%, 17.2% and 9.5% on topotecan.

A phase III randomised, parallel-group, open-label, multicentre study comparing the safety andefficacy of Caelyx pegylated liposomal plus bortezomib combination therapy with bortezomibmonotherapy in patients with multiple myeloma who have received at least 1 prior therapy and whodid not progress while receiving anthracycline-based therapy, was conducted in 646 patients. Therewas a significant improvement in the primary endpoint of time to progression (TTP) for patientstreated with combination therapy of Caelyx pegylated liposomal plus bortezomib compared to patientstreated with bortezomib monotherapy as indicated by a risk reduction (RR) of 35% (95% CI: 21-47%),p < 0.0001, based on 407 TTP events. The median TTP was 6.9 months for the bortezomibmonotherapy patients compared with 8.9 months for the Caelyx pegylated liposomal plus bortezomibcombination therapy patients. A protocol-defined interim analysis (based on 249 TTP events)triggered early study termination for efficacy. This interim analysis showed a TTP risk reduction of45% (95% CI: 29-57%), p < 0.0001. The median TTP was 6.5 months for the bortezomibmonotherapy patients compared with 9.3 months for the Caelyx pegylated liposomal plus bortezomibcombination therapy patients. These results, though not mature, constituted the protocol defined finalanalysis. The final analysis for overall survival (OS) performed after a median follow-up of 8.6 yearsshowed no significant difference in OS between the two treatment arms. The median OS was30.8 months (95% CI; 25.2-36.5 months) for the bortezomib monotherapy patients and 33.0 months(95% CI; 28.9-37.1 months) for the Caelyx pegylated liposomal plus bortezomib combination therapypatients.

Caelyx pegylated liposomal is a long-circulating pegylated liposomal formulation of doxorubicinhydrochloride. Pegylated liposomes contain surface-grafted segments of the hydrophilic polymermethoxypolyethylene glycol (MPEG). These linear MPEG groups extend from the liposome surfacecreating a protective coating that reduces interactions between the lipid bilayer membrane and theplasma components. This allows the Caelyx pegylated liposomal liposomes to circulate for prolongedperiods in the blood stream. Pegylated liposomes are small enough (average diameter ofapproximately 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 accumulationin tumours has been 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 internalaqueous buffer system that combine to keep doxorubicin hydrochloride encapsulated during liposomeresidence time in circulation.

The plasma pharmacokinetics of Caelyx pegylated liposomal in humans differ significantly from thosereported in the literature for standard doxorubicin hydrochloride preparations. At lower doses(10 mg/m2-20 mg/m2) Caelyx pegylated liposomal displayed linear pharmacokinetics. Over the doserange of 10 mg/m2-60 mg/m2 Caelyx pegylated liposomal displayed non-linear pharmacokinetics.

Standard doxorubicin hydrochloride displays extensive tissue distribution (volume of distribution: 700to 1,100 l/m2) and a rapid elimination clearance (24 to 73 l/h/m2). In contrast, the pharmacokineticprofile of Caelyx pegylated liposomal indicates that Caelyx pegylated liposomal is confined mostly tothe vascular fluid volume and that the clearance of doxorubicin from the blood is dependent upon theliposomal carrier. Doxorubicin becomes available after the liposomes are extravasated and enter thetissue compartment.

At equivalent doses, the plasma concentration and AUC values of Caelyx pegylated liposomal whichrepresent mostly pegylated liposomal doxorubicin hydrochloride (containing 90% to 95% of themeasured doxorubicin) are significantly higher than those achieved with standard doxorubicinhydrochloride preparations.

Caelyx pegylated liposomal should not be used interchangeably with other formulations ofdoxorubicin hydrochloride.

The pharmacokinetics of Caelyx pegylated liposomal was evaluated in 120 patients from 10 differentclinical trials using the population pharmacokinetic approach. The pharmacokinetics of Caelyxpegylated liposomal over the dose range of 10 mg/m2 to 60 mg/m2 was best described by a twocompartment non-linear model with zero order input and Michaelis-Menten elimination. The meanintrinsic clearance of Caelyx pegylated liposomal was 0.030 l/h/m2 (range 0.008 to 0.152 l/h/m2) andthe mean central volume of distribution was 1.93 l/m2 (range 0.96-3.85 l/m2) approximating the plasmavolume. The apparent half-life ranged from 24-231 hours, with a mean of 73.9 hours.

The pharmacokinetics of Caelyx pegylated liposomal determined in 18 patients with breast carcinomawere similar to the pharmacokinetics determined in the larger population of 120 patients with variouscancers. The mean intrinsic clearance was 0.016 l/h/m2 (range 0.008-0.027 l/h/m2), the mean centralvolume of distribution was 1.46 l/m2 (range 1.10-1.64 l/m2). The mean apparent half-life was71.5 hours (range 45.2-98.5 hours).

The pharmacokinetics of Caelyx pegylated liposomal determined in 11 patients with ovariancarcinoma were similar to the pharmacokinetics determined in the larger population of 120 patientswith various cancers. The mean intrinsic clearance was 0.021 l/h/m2 (range 0.009-0.041 l/h/m2), themean central volume of distribution was 1.95 l/m2 (range 1.67-2.40 l/m2). The mean apparent half-lifewas 75.0 hours (range 36.1-125 hours).

The plasma pharmacokinetics of Caelyx pegylated liposomal were evaluated in 23 patients with KSwho received single doses of 20 mg/m2 administered by a 30-minute infusion. The pharmacokineticparameters of Caelyx pegylated liposomal (primarily representing pegylated liposomal doxorubicinhydrochloride and low levels of unencapsulated doxorubicin hydrochloride) observed after the20 mg/m2 doses are presented in Table 6.

Table 6. Pharmacokinetic parameters in Caelyx pegylated liposomal-treated AIDS-KSpatients

Mean + standard error

Parameter 20 mg/m2 (n=23)

Maximum plasma concentration* (µg/ml) 8.34 ± 0.49

Plasma clearance (l/h/m2) 0.041 ± 0.004

Volume of distribution (l/m2) 2.72 ± 0.120

AUC (µg/ml⋅h) 590.00 ± 58.7λ1 half-life (hours) 5.2 ± 1.4λ2 half-life (hours) 55.0 ± 4.8

* Measured at the end of a 30-minute infusion

In repeat dose studies conducted in animals, the toxicity profile of Caelyx pegylated liposomal appearsvery similar to that reported in humans who receive long-term infusions of standard doxorubicinhydrochloride. With Caelyx pegylated liposomal, the encapsulation of doxorubicin hydrochloride inpegylated liposomes results in these effects having a differing strength, as follows.

Studies in rabbits have shown that the cardiotoxicity of Caelyx pegylated liposomal is reducedcompared with conventional doxorubicin hydrochloride preparations.

In studies performed after the repeated administration of Caelyx pegylated liposomal to rats and dogs,serious dermal inflammations and ulcer formations were observed at clinically relevant dosages. In thestudy in dogs, the occurrence and severity of these lesions was reduced by lowering the dose orprolonging the intervals between doses. Similar dermal lesions, which are described as palmar-plantarerythrodysesthesia were also observed in patients after long-term intravenous infusion (see section4.8).

During repeat dose toxicology studies in dogs, an acute response characterised by hypotension, palemucous membranes, salivation, emesis and periods of hyperactivity followed by hypoactivity andlethargy was observed following administration of pegylated liposomes (placebo). A similar, but lesssevere response was also noted in dogs treated with Caelyx pegylated liposomal and standarddoxorubicin.

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 oftreatment.

Subcutaneous tolerance studies indicate that Caelyx pegylated liposomal, as against standarddoxorubicin hydrochloride, causes slighter local irritation or damage to the tissue after a possibleextravasation.

Although no studies have been conducted with Caelyx pegylated liposomal, doxorubicinhydrochloride, the pharmacologically active ingredient of Caelyx pegylated liposomal, is mutagenicand carcinogenic. Pegylated placebo liposomes are neither mutagenic nor genotoxic.

Caelyx pegylated liposomal resulted in mild to moderate ovarian and testicular atrophy in mice after asingle dose of 36 mg/kg. Decreased testicular weights and hypospermia were present in rats afterrepeat doses ≥ 0.25 mg/kg/day and diffuse degeneration of the seminiferous tubules and a markeddecrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (see section 4.6).

A study has shown that Caelyx pegylated liposomal at a single intravenous dose of over twice theclinical dose produces renal toxicity in monkeys. Renal toxicity has been observed with even lowersingle doses of doxorubicin HCl in rats and rabbits. Since an evaluation of the post-marketing safetydatabase for Caelyx pegylated liposomal in patients has not suggested a significant nephrotoxicityliability of Caelyx pegylated liposomal, these findings in monkeys may not have relevance to patientrisk assessment.

α-(2-[1,2-distearoyl-sn-glycero(3)phosphooxy]ethylcarbamoyl)-ω-methoxypoly(oxyethylen)-40sodium salt (MPEG-DSPE)fully hydrogenated soy phosphatidylcholine (HSPC)cholesterolammonium sulphatesucrosehistidinewater for injectionshydrochloric acid (for pH-adjustment)sodium hydroxide (for pH-adjustment)

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

20 months.

- Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C.

- From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the userand should not be longer than 24 hours at 2°C to 8°C.

- Partially used vials must be discarded.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

Type I glass vials, each with a siliconised grey bromobutyl stopper, and an aluminium seal, with adeliverable volume of 10 ml (20 mg) or 25 ml (50 mg).

Caelyx pegylated liposomal is supplied as a single pack or packs of ten vials.

Not all pack sizes may be marketed.

Do not use material that shows evidence of precipitation or any other particulate matter.

Caution must be exercised in handling Caelyx pegylated liposomal dispersion. The use of gloves isrequired. If Caelyx pegylated liposomal comes into contact with skin or mucosa, wash immediatelyand thoroughly with soap and water. Caelyx pegylated liposomal must be handled and disposed of in amanner consistent with that of other anticancer medicinal products in accordance with localrequirements.

Determine the dose of Caelyx pegylated liposomal to be administered (based upon the recommendeddose and the patient’s body surface area). Take the appropriate volume of Caelyx pegylated liposomalup into a sterile syringe. Aseptic technique must be strictly observed since no preservative orbacteriostatic agent is present in Caelyx pegylated liposomal. The appropriate dose of Caelyxpegylated liposomal must be diluted in 5% (50 mg/ml) glucose solution for infusion prior toadministration. For doses < 90 mg, dilute Caelyx pegylated liposomal in 250 ml, and for doses≥ 90 mg, dilute Caelyx pegylated liposomal in 500 ml. This can be infused over 60 or 90 minutes asdetailed in 4.2.

The use of any diluent other than 5% (50 mg/ml) glucose solution for infusion, or the presence of anybacteriostatic agent such as benzyl alcohol may cause precipitation of Caelyx pegylated liposomal.

It is recommended that the Caelyx pegylated liposomal infusion line be connected through the sideport of an intravenous infusion of 5% (50 mg/ml) glucose. Infusion may be given through a peripheralvein. Do not use with in-line filters.

Baxter Holding B.V.

Kobaltweg 49,3542 CE Utrecht,

Netherlands

EU/1/96/011/001

EU/1/96/011/002

EU/1/96/011/003

EU/1/96/011/004

Date of first authorisation: 21 June 1996

Date of lastest renewal: 19 May 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMEA) http://www.ema.europa.eu/.