ZOLSKETIL PEGYLATED LIPOSOMAL 2mg / ml concentrate for perfusable dispersion medication leaflet

ZOLSKETIL pegylated liposomal 2 mg/mL concentrate for dispersion for infusion

One mL of ZOLSKETIL pegylated liposomal contains 2 mg doxorubicin hydrochloride in a pegylatedliposomal formulation.

ZOLSKETIL pegylated liposomal, a liposome formulation, is doxorubicin hydrochloride encapsulatedin liposomes with surface-bound methoxypolyethylene glycol (MPEG). This process is known aspegylation and protects liposomes from detection by the mononuclear phagocyte system (MPS), whichincreases blood circulation time.

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

For the full list of excipients, see section 6.1.

Concentrate for dispersion for infusion

A translucent red coloured dispersion filled in a clear glass vial. When examined under suitableconditions of visibility it should be practically free from particles.

ZOLSKETIL 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 unsuitable forbone 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.

ZOLSKETIL 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).

ZOLSKETIL pegylated liposomal is indicated in adults.

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

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

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

ZOLSKETIL pegylated liposomal is administered at 30 mg/m2 on day 4 of the bortezomib 3 weekregimen as a 1 hour infusion administered immediately after the bortezomib infusion. The bortezomibregimen consists of 1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks. The dose should be repeated aslong as patients respond satisfactorily and tolerate treatment. Day 4 dosing of both medicinal productsmay be delayed up to 48 hours as medically necessary. Doses of bortezomib should be at least 72hours apart.

ZOLSKETIL pegylated liposomal is administered intravenously at 20 mg/m2 every two-to-threeweeks. Avoid intervals shorter than 10 days as medicinal product accumulation and increased toxicitycannot be ruled out. Treatment of patients for two-to-three months is recommended to achieve atherapeutic response. 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.

To manage adverse reaction such as palmar-plantar erythrodysesthesia (PPE), stomatitis orhaematological toxicity, the dose may be reduced or delayed. Guidelines for ZOLSKETIL 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 Doxorubicin pegylated liposomal dose

Toxicity grade at current Week 4 Week 5 Week 6assessment

Grade 1 Redose unless Redose unless Decrease dose by(mild erythema, swelling, patient has patient has 25%; return to 4or desquamation not experienced a experienced a week intervalinterfering with daily previous grade 3 or previous grade 3 or 4activities) 4 skin toxicity, in skin toxicity, in whichwhich case wait an case wait anadditional week additional week

Grade 2 Wait an additional Wait an additional Decrease dose by(erythema, desquamation, week week 25%; return to 4or swelling interfering week intervalwith, but not precludingnormal physical activities;small blisters orulcerations less than 2 cmin diameter)

Grade 3 Wait an additional Wait an additional Withdraw patient(blistering, ulceration, or week weekswelling interfering withwalking or normal dailyactivities; cannot wearregular 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 Doxorubicin 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 to 4erythema, or mild experienced a previous experienced a previous 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 to 4oedema, or ulcers, but 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 dose reduction.

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

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

Grade 4 < 500 < 25,000 Wait until ANC ≥ 1,500 and platelets ≥ 75,000;decrease dose by 25% or continue full dose withgrowth factor support.

For multiple myeloma patients treated with doxorubicin pegylated liposomal in combination withbortezomib who experience PPE or stomatitis, the doxorubicin 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 doxorubicin pegylated liposomal and bortezomib combination therapy. For moredetailed information on bortezomib dosing and dosage adjustments, see the SmPC for bortezomib.

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

Patient status Doxorubicin pegylated liposomal Bortezomib

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

On any day of medicine Do not dose this cycle if before day 4; Do not dose; if 2 or moreadministration after day 1 if after day 4 reduce next dose by 25% doses are not given in aof each cycle: in the following cycles if bortezomib is cycle, reduce dose by 25%

Platelet count reduced for haematologic toxicity.* in following cycles.< 25,000/mm3

Haemoglobin < 8 g/dl

ANC < 500/mm3

Grade 3 or 4 non- Do not dose until recovered to grade Do not dose until recoveredhaematologic medicine < 2 and reduce dose by 25% for all to grade < 2 and reducerelated toxicity subsequent doses. dose by 25% for allsubsequent doses.

Neuropathic pain or No dosage adjustments. See the SmPC forperipheral neuropathy bortezomib.

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

For AIDS-KS patients treated with ZOLSKETIL pegylated liposomal, haematological toxicity mayrequire dose reduction or suspension or delay of therapy. Temporarily suspend ZOLSKETIL pegylatedliposomal treatment 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 countwhen the ANC count is < 1,000/mm3 in subsequent cycles.

Doxorubicin pegylated liposomal pharmacokinetics determined in a small number of patients withelevated total bilirubin levels do not differ from patients with normal total bilirubin; however, untilfurther experience is gained, the doxorubicin pegylated liposomal dosage in patients with impairedhepatic function should be reduced based on the experience from the breast and ovarian clinical trialprograms as follows: at initiation of therapy, if the bilirubin is between 1.2-3.0 mg/dl, the first dose isreduced by 25%. If the bilirubin is > 3.0 mg/dl, the first dose is reduced by 50%. If the patient toleratesthe first dose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can beincreased to the next dose level, i.e., if reduced by 25% for the first dose, increase to full dose for cycle2; if reduced 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. Doxorubicin 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 doxorubicin pegylated liposomal administration,evaluate hepatic function using conventional clinical laboratory tests such as ALT/AST, alkalinephosphatase, and bilirubin.

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 doxorubicin clearance is not influenced by renal function. Nopharmacokinetic data are available in patients with creatinine clearance of less than 30 mL/min.

As there is no experience with ZOLSKETIL pegylated liposomal in patients who have hadsplenectomy, treatment with ZOLSKETIL pegylated liposomal is not recommended.

The experience in children is limited ZOLSKETIL pegylated liposomal is not recommended inpatients below 18 years of age.

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

ZOLSKETIL pegylated liposomal is administered as an intravenous infusion. For further instructionson preparation and special precautions for handling (see section 6.6).

Doxorubicin pegylated liposomal must not be administered as a bolus injection or undiluted solution.

It is recommended that the doxorubicin pegylated liposomal infusion line be connected through theside port of an intravenous infusion of glucose 50 mg/mL (5%) solution to achieve further dilution andminimise the risk of thrombosis and extravasation. The infusion may be given through a peripheralvein. Do not use with in-line filters. Doxorubicin pegylated liposomal must not be given by theintramuscular or subcutaneous route (see section 6.6).

For doses < 90 mg: dilute doxorubicin pegylated liposomal in 250 mL glucose 50 mg/mL (5%)solution for infusion.

For doses ≥ 90 mg: dilute doxorubicin pegylated liposomal in 500 mL glucose 50 mg/mL (5%)solution for infusion.

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 doxorubicin pegylated liposomalinfusions may 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 doxorubicin pegylated liposomal is diluted in 250 mL glucose 50 mg/mL (5%) solutionfor infusion 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.

Doxorubicin pegylated liposomal must not be used to treat AIDS-KS that may be treated effectivelywith local therapy or systemic alfa-interferon.

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

It is recommended that all patients receiving doxorubicin pegylated liposomal routinely undergofrequent ECG monitoring. Transient ECG changes such as T-wave flattening, S-T segment depressionand benign arrhythmias are not considered mandatory indications for the suspension of doxorubicinpegylated liposomal therapy. However, reduction of the QRS complex is considered more indicativeof cardiac toxicity. If this change occurs, the most definitive test for anthracycline myocardial injury,i.e., endomyocardial biopsy, must be considered.

More specific methods for the evaluation and monitoring of cardiac functions as compared to ECG 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 doxorubicinpegylated liposomal therapy and repeated periodically during treatment. The evaluation of leftventricular function is considered to be mandatory before each additional administration ofdoxorubicin pegylated 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 doxorubicin pegylated liposomal therapy, the benefit ofcontinued therapy must be carefully weighed against the risk of myocardial injury.

In patients with cardiac disease requiring treatment, administer doxorubicin pegylated liposomal onlywhen the benefit outweighs the risk to the patient.

Exercise caution in patients with impaired cardiac function who receive doxorubicin pegylatedliposomal.

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 doxorubicin pegylated liposomal have baseline myelosuppression due tosuch factors as their pre-existing HIV disease or numerous concomitant or previous medicines, 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 doxorubicinpegylated liposomal vs. topotecan, the incidence of treatment related sepsis was substantially less inthe doxorubicin pegylated liposomal-treated ovarian cancer patients as compared to the topotecantreatment group. A similar low incidence of myelosuppression was seen in patients with metastaticbreast cancer receiving doxorubicin pegylated liposomal in a first-line clinical trial. In contrast to theexperience in patients with breast cancer or ovarian cancer, myelosuppression appears to be thedose-limiting adverse reaction in patients with AIDS-KS (see section 4.8). Because of the potential forbone marrow suppression, periodic blood counts must be performed frequently during the course ofdoxorubicin pegylated liposomal therapy, and at a minimum, prior to each dose of doxorubicinpegylated 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 doxorubicin 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 doxorubicinpegylated liposomal. Therefore, any patient treated with doxorubicin should be kept underhaematological supervision.

Very rare cases of secondary oral cancer have been reported in patients with long-term (more than oneyear) exposure to doxorubicin pegylated liposomal or those receiving a cumulative doxorubicinpegylated liposomal dose greater than 720 mg/m2. Cases of secondary oral cancer were diagnosedboth, during treatment with doxorubicin pegylated liposomal, and up to 6 years after the last dose.

Patients should be examined at regular intervals for the presence of oral ulceration or any oraldiscomfort that may be indicative 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 doxorubicin pegylated liposomal. Very rarely, convulsions also have been observed inrelation to infusion reactions (see section 4.8). Temporarily stopping the infusion usually resolvesthese symptoms without further therapy. However, medicines to treat these symptoms (e.g.,antihistamines, corticosteroids, adrenaline, and anticonvulsants), as well as emergency equipmentshould be available for immediate use. In most patients treatment can be resumed after all symptomshave resolved, without recurrence. Infusion reactions rarely recur after the first treatment cycle. Tominimise the risk of infusion reactions, the initial dose should be administered at a rate no greater than1 mg/minute (see section 4.2).

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).

Interstitial lung disease (ILD)

Interstitial lung disease (ILD), which may have an acute onset, has been observed in patients receivingpegylated liposomal doxorubicin, including fatal cases (see section 4.8). If patients experienceworsening of respiratory symptoms such as dyspnoea, dry cough, and fever, ZOLSKETIL pegylatedliposomal should be interrupted and the patient should be promptly investigated. If ILD is confirmed,

ZOLSKETIL pegylated liposomal should be discontinued and the patient treated appropriately.

Although local necrosis following extravasation has been reported very rarely, doxorubicin 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. Doxorubicin pegylated liposomal must not begiven by the intramuscular or subcutaneous route.

Doxorubicin pegylated liposomal contains sucrose and the dose is administered in glucose 50 mg/mL(5%) solution for infusion.

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

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

No formal medicinal product interaction studies have been performed with doxorubicin 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. Doxorubicin 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.

Women of child-bearing potential/contraception in men and women

Due to the genotoxic potential of doxorubicin hydrochloride (see section 5.3), women of child-bearingpotential should use effective contraceptive measures while being treated with doxorubicin pegylatedliposomal and for 8 months following completion of treatment.

Men are recommended to use effective contraceptive measures and to not father a child whilereceiving doxorubicin pegylated liposomal and for 6 months following completion of treatment.

Doxorubicin hydrochloride is suspected to cause serious birth defects when administered duringpregnancy. Therefore, doxorubicin pegylated liposomal should not be used during pregnancy unlessclearly necessary.

It is not known whether doxorubicin 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 doxorubicin pegylated liposomal treatment. Health experts recommend that HIV infectedwomen do 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).

Doxorubicin pegylated liposomal has no or negligible influence on the ability to drive and usemachines. However, in clinical studies to date, dizziness and somnolence were associated infrequently(< 5%) with the administration of doxorubicin pegylated liposomal. Patients who suffer from theseeffects must avoid 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 doxorubicinpegylated liposomal in 4,231 patients for the treatment of breast cancer, ovarian cancer, multiplemyeloma, and AIDS-related KS. Post-marketing adverse reactions are also included, as indicated by“b”. Frequencies are 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 (frequencycannot be estimated from the available data). Within each frequency grouping, where relevant, adversereactions are presented in order of decreasing seriousness

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

System Frequency all grades Adverse drug reaction

Organ

Infections Common Sepsisand Pneumoniainfestations 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

Not known Acute myeloid leukaemiab

Neoplasms Myelodysplastic syndromebbenign, Oral neoplasmbmalignant andunspecified(includingcysts and

Blol od )and Very common Leukopaenialymphatic Neutropaeniadisorders Lymphopaenia

Anaemia (including hypochromic)

Common Thrombocytopaenia

Febrile neutropaenia

Uncommon Pancytopaenia

Thrombocytosis

Rare Bone marrow failure

Immune Uncommon Hypersensitivitysystem Anaphylactic reactiondisorders Rare Anaphylactoid reaction

Metabolism Very common Decreased appetiteand nutrition Common Cachexiadisorders Dehydration

Hyponatraemia

Uncommon Hyperkalaemia

Hypomagnesaemia

Psychiatri Common Confusional statec Anxietydisorders Depression

Insomnia

Nervous Common Neuropathy peripheralsystem Peripheral sensory neuropathydisorders Neuralgia

Paraesthesia

Hypoaesthesia

Dysgeusia

Lethargy

Dizziness

Uncommon Polyneuropathy

Convulsion

Dysaesthesia

Somnolence

Eye disorders Common Conjunctivitis

Uncommon Vision blurred

Lacrimation increased

Rare Retinitis

Cardiac Common Tachycardiadisorders Uncommon Palpitationsa

Cardiac arrest

Cardiac failure

Cardiac failure congestive

Cardiomyopathy

Rare Ventricular arrhythmia

Bundle branch block right

Conduction disorder

Atrioventricular block

Cyanosis

Vascula Common Hypertensionr 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

Not Known Interstitial lung disease

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, andtissue disorders 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 musculoskeletal chestand connective 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 aminotransferase increased)

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 doxorubicin 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 doxorubicin pegylatedliposomal and may be related to opportunistic infections (OI’s) in the AIDS population. Opportunisticinfections are observed in KS patients after administration with doxorubicin pegylated liposomal, andare frequently observed in patients with HIV induced immunodeficiency. The most frequentlyobserved OI’s in clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystisjirovecii 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 patientswith cardiac risk factors.

Endomyocardial biopsies on nine of ten AIDS-KS patients receiving cumulative doses of doxorubicinpegylated liposomal greater than 460 mg/m2 indicate no evidence of anthracycline-inducedcardiomyopathy. The recommended dose of doxorubicin 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 ofdoxorubicin pegylated 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 withdoxorubicin pegylated liposomal at a dose of 50 mg/m2/every 4 weeks versus 48 treated withdoxorubicin at a dose of 60 mg/m2/every 3 weeks) met the protocol-defined criteria for cardiac toxicityduring treatment and/or follow-up. Cardiac toxicity was defined as a decrease of 20 points or greaterfrom baseline if the resting LVEF remained in the normal range or a decrease of 10 points or greater ifthe LVEF became abnormal (less than the lower limit for normal). None of the 10 doxorubicinpegylated liposomal subjects who had cardiac toxicity by LVEF criteria developed signs andsymptoms of CHF. In contrast, 10 of 48 doxorubicin subjects who had cardiac toxicity by LVEFcriteria also developed signs 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 withdoxorubicin pegylated liposomal 50 mg/m2/cycle, and having a baseline measurement of leftventricular ejection 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 doxorubicinpegylated liposomal 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 is doxorubicin hydrochloride, a cytotoxic anthracycline antibiotic obtainedfrom Streptomyces peucetius var. caesius. The exact mechanism of the antitumour activity ofdoxorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesisis responsible for the majority of the cytotoxic effects. This is probably the result of intercalation ofthe anthracycline between adjacent base pairs of the DNA double helix thus preventing theirunwinding for replication.

A phase III randomised study of doxorubicin pegylated liposomal versus doxorubicin in patients withmetastatic breast cancer was completed in 509 patients. The protocol-specified objective ofdemonstrating non-inferiority between doxorubicin pegylated liposomal and doxorubicin was met, thehazard ratio (HR) for progression-free survival (PFS) was 1.00 (95% Confidence interval (CI) for

HR=0.82-1.22). The treatment HR for PFS when adjusted for prognostic variables was consistent with

PFS for the ITT population.

The primary analysis of cardiac toxicity showed the risk of developing a cardiac event as a function ofcumulative anthracycline dose was significantly lower with doxorubicin pegylated liposomal thanwith doxorubicin (HR=3.16, p < 0.001). At cumulative doses greater than 450 mg/m2 there were nocardiac events with doxorubicin pegylated liposomal.

A phase III comparative study of doxorubicin 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 doxorubicin 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 doxorubicin 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 doxorubicin 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 doxorubicin 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 doxorubicin 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 doxorubicin pegylated liposomal plus bortezomib compared topatients treated 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 doxorubicin pegylated liposomal plusbortezomib combination therapy patients. A protocol-defined interim analysis (based on 249 TTPevents) triggered early study termination for efficacy. This interim analysis showed a TTP riskreduction of 45% (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 doxorubicin pegylated liposomal plusbortezomib combination therapy patients. These results, though not mature, constituted the protocoldefined final analysis. The final analysis for overall survival (OS) performed after a median follow-upof 8.6 years showed no significant difference in OS between the two treatment arms. The median OSwas 30.8 months (95% CI; 25.2-36.5 months) for the bortezomib monotherapy patients and 33.0months (95% CI; 28.9-37.1 months) for the doxorubicin pegylated liposomal plus bortezomibcombination therapy patients.

Doxorubicin 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 doxorubicin pegylated liposomal liposomes to circulate forprolonged periods 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 doxorubicin pegylated liposomal in humans differ significantly fromthose reported in the literature for standard doxorubicin hydrochloride preparations. At lower doses(10 mg/m2-20 mg/m2) doxorubicin pegylated liposomal displayed linear pharmacokinetics. Over thedose range of 10 mg/m2-60 mg/m2 doxorubicin pegylated liposomal in displayed non-linearpharmacokinetics. Standard doxorubicin hydrochloride displays extensive tissue distribution (volumeof distribution: 700 to 1,100 l/m2) and a rapid elimination clearance (24 to 73 l/h/m2). In contrast, thepharmacokinetic profile of doxorubicin pegylated liposomal indicates that doxorubicin pegylatedliposomal is confined mostly to the vascular fluid volume and that the clearance of doxorubicin fromthe blood is dependent upon the liposomal carrier. Doxorubicin becomes available after the liposomesare extravasated and enter the tissue compartment.

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

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

The pharmacokinetics of doxorubicin pegylated liposomal was evaluated in 120 patients from 10different clinical trials using the population pharmacokinetic approach. The pharmacokinetics ofdoxorubicin pegylated liposomal over the dose range of 10 mg/m2 to 60 mg/m2 was best described bya two compartment non-linear model with zero order input and Michaelis-Menten elimination. Themean intrinsic clearance of doxorubicin pegylated liposomal was 0.030 l/h/m2 (range 0.008 to 0.152l/h/m2) and the mean central volume of distribution was 1.93 l/m2 (range 0.96-3.85 l/m2)approximating the plasma volume. The apparent half-life ranged from 24-231 hours, with a mean of73.9 hours.

The pharmacokinetics of doxorubicin pegylated liposomal determined in 18 patients with breastcarcinoma were similar to the pharmacokinetics determined in the larger population of 120 patientswith various cancers. The mean intrinsic clearance was 0.016 l/h/m2(range 0.008-0.027 l/h/m2), themean central volume of distribution was 1.46 l/m2 (range 1.10-1.64 l/m2). The mean apparent half-lifewas 71.5 hours (range 45.2-98.5 hours).

The pharmacokinetics of doxorubicin 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 doxorubicin pegylated liposomal were evaluated in 23 patients with

KS who received single doses of 20 mg/m2administered by a 30-minute infusion. The pharmacokineticparameters of doxorubicin pegylated liposomal (primarily representing pegylated liposomaldoxorubicin hydrochloride and low levels of unencapsulated doxorubicin hydrochloride) observedafter the 20 mg/m2 doses are presented in Table 10.

Table 10. Pharmacokinetic parameters in doxorubicin 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 doxorubicin pegylated liposomalappears very similar to that reported in humans who receive long-term infusions of standarddoxorubicin hydrochloride. With doxorubicin pegylated liposomal, the encapsulation of doxorubicinhydrochloride in pegylated liposomes results in these effects having a differing strength, as follows.

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

In studies performed after the repeated administration of doxorubicin pegylated liposomal to rats anddogs, 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 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 doxorubicin pegylated liposomal and standarddoxorubicin. The hypotensive response was reduced in magnitude by pretreatment withantihistamines. However, the response was not life-threatening and the dogs recovered quickly upondiscontinuation of treatment.

Subcutaneous tolerance studies indicate that doxorubicin 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 doxorubicin pegylated liposomal, doxorubicinhydrochloride, the pharmacologically active ingredient of doxorubicin pegylated liposomal, ismutagenic and carcinogenic. Pegylated placebo liposomes are neither mutagenic nor genotoxic.

Doxorubicin pegylated liposomal resulted in mild to moderate ovarian and testicular atrophy in miceafter a single dose of 36 mg/kg. Decreased testicular weights and hypospermia were present in ratsafter repeat 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 doxorubicin 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 doxorubicin pegylated liposomal in patients has not suggested a significant nephrotoxicityliability of doxorubicin pegylated liposomal, these findings in monkeys may not have relevance topatient risk assessment.

N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl- sn-glycero-3-phosphoethanolamine,sodium salt (MPEG 2000-DSPE)

Hydrogenated soy phosphatidylcholine (HSPC)

Cholesterol

Ammonium sulphate (E 517)

Sucrose (E 473)

Histidine

Hydrochloric acid concentrated (E 507) (for pH adjustment)

Sodium hydroxide (E-524) (for pH adjustment)

Water for injections

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

Unopened vial18 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 vial with a siliconised grey bromobutyl stopper, and an aluminium seal, containing adeliverable volume of 10 mL (20 mg) or 25 mL (50 mg).

ZOLSKETIL 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 ZOLSKETIL pegylated liposomal dispersion. The use ofgloves is required. If ZOLSKETIL pegylated liposomal comes into contact with skin or mucosa, washimmediately and thoroughly with soap and water. ZOLSKETIL pegylated liposomal must be handledand disposed of in a manner consistent with that of other anticancer medicinal products in accordancewith local requirements.

Determine the dose of ZOLSKETIL pegylated liposomal to be administered (based upon therecommended dose and the patient's body surface area). Take the appropriate volume of ZOLSKETILpegylated liposomal up into a sterile syringe. Aseptic technique must be strictly observed since nopreservative or bacteriostatic agent is present in ZOLSKETIL pegylated liposomal. The appropriatedose of ZOLSKETIL Pegylated Liposomal must be diluted in glucose 50 mg/mL (5%) solution forinfusion prior to administration. For doses < 90 mg, dilute ZOLSKETIL pegylated liposomal in250 mL, and for doses ≥ 90 mg, dilute ZOLSKETIL pegylated liposomal in 500 mL. This can beinfused over 60 or 90 minutes as detailed in 4.2.

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

It is recommended that the ZOLSKETIL pegylated liposomal infusion line be connected through theside port of an intravenous infusion of glucose 50 mg/mL (5%). Infusion may be given through aperipheral vein. Do not use with in-line filters.

Accord Healthcare S.L.U.

World Trade Center,

Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039, Barcelona,

Spain

EU/1/22/1629/001

EU/1/22/1629/002

EU/1/22/1629/003

EU/1/22/1629/004

Date of first authorisation: 31 May 2022.

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

Agency http://www.ema.europa.eu