4.1. Therapeutic indications

Doxorubicin Baxter pegylated liposomal is indicated:

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

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

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

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

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

4.2. Posology and method of administration

Doxorubicin Baxter pegylated liposomal should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents.

Doxorubicin Baxter pegylated liposomal exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride.

Posology

Breast cancer/Ovarian cancer

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

Multiple myeloma

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

AIDS‑related KS

Doxorubicin Baxter 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 cannot be ruled out. Treatment of patients for two‑to‑three months is recommended to achieve a therapeutic response. Continue treatment as needed to maintain a therapeutic response.

For all patients

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

Guidelines for Doxorubicin Baxter pegylated liposomal dose modification

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

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

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

Table 1. Palmar–Plantar erythrodysesthesia

Week after prior Doxorubicin Baxter pegylated liposomal dose

Toxicity grade at current assessment

Week 4

Week 5

Week 6

Grade 1

(mild erythema, swelling, or desquamation not interfering with daily activities)

Redose unless

patient has experienced a previous grade 3 or 4 skin toxicity, in which case wait an additional week

Redose unless

patient has experienced a previous grade 3 or 4 skin toxicity, in which case wait an additional week

Decrease dose by 25%; return to 4 week interval

Grade 2

(erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter)

Wait an additional week

Wait an additional week

Decrease dose by 25%; return to 4 week interval

Grade 3

(blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing)

Wait an additional week

Wait an additional week

Withdraw patient

Grade 4

(diffuse or local process causing infectious complications, or a bedridden state or hospitalisation)

Wait an additional week

Wait an additional week

Withdraw patient

Table 2. Stomatitis

Week after prior Doxorubicin Baxter pegylated liposomal dose

Toxicity grade at current assessment

Week 4

Week 5

Week 6

Grade 1

(painless ulcers, erythema, or mild soreness)

Redose unless

patient has experienced a previous grade 3 or 4 stomatitis in which case wait an additional week

Redose unless

patient has experienced a previous grade 3 or 4 stomatitis in which case wait an additional week

Decrease dose by 25%; return to 4 week interval or withdraw patient per physician's assessment

Grade 2

(painful erythema, oedema, or ulcers, but can eat)

Wait an additional week

Wait an additional week

Decrease dose by 25%; return to 4 week interval or withdraw patient per physician's assessment

Grade 3

(painful erythema, edema, or ulcers, but cannot eat)

Wait an additional week

Wait an additional week

Withdraw patient

Grade 4

(requires parenteral or enteral support)

Wait an additional week

Wait an additional week

Withdraw patient

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

GRADE

ANC

PLATELETS

MODIFICATION

Grade 1

1,500 – 1,900

75,000 – 150,000

Resume treatment with no dose reduction.

Grade 2

1,000 – < 1,500

50,000 – < 75,000

Wait until ANC ≥ 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 with growth factor support.

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

Table 4. Dosage adjustments for Doxorubicin Baxter pegylated liposomal + bortezomib combination therapy - patients with multiple myeloma

Patient status

Doxorubicin Baxter pegylated liposomal

Bortezomib

Fever ≥ 38○C and ANC < 1,000/mm3

Do not dose this cycle if before day 4; if after day 4, reduce next dose by 25%.

Reduce next dose by 25%.

On any day of medicine administration after day 1 of each cycle:

Platelet count < 25,000/mm3

Haemoglobin < 8 g/dl

ANC < 500/mm3

Do not dose this cycle if before day 4; if after day 4 reduce next dose by 25% in the following cycles if bortezomib is reduced for haematologic toxicity.*

Do not dose; if 2 or more doses are not given in a cycle, reduce dose by 25% in following cycles.

Grade 3 or 4 non‑haematologic medicine related toxicity

Do not dose until recovered to grade < 2 and reduce dose by 25% for all subsequent doses.

Do not dose until recovered to grade < 2 and reduce dose by 25% for all subsequent doses.

Neuropathic pain or peripheral neuropathy

No dosage adjustments.

See the SPC for bortezomib.

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

For AIDS-KS patients treated with Doxorubicin Baxter pegylated liposomal, haematological toxicity may require dose reduction or suspension or delay of therapy. Temporarily suspend Doxorubicin Baxter pegylated liposomal 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 count when the ANC count is < 1,000/mm3 in subsequent cycles.

Hepatic Impairment

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

Renal Impairment

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

AIDS‑related KS patients with splenectomy

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

Paediatric population

The experience in children is limited. Doxorubicin Baxter pegylated liposomal is not recommended in patients below 18 years of age.

Elderly

Population based analysis demonstrates that age across the range tested (21–75 years) does not significantly alter the pharmacokinetics of Doxorubicin Baxter pegylated liposomal.

Method of administration

Doxorubicin Baxter pegylated liposomal is administered as an intravenous infusion. For further instructions on preparation and special precautions for handling (see section 6.6).

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

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

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

Breast cancer/Ovarian cancer/Multiple myeloma

To minimise the risk of infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent Doxorubicin Baxter pegylated liposomal infusions may be administered over a 60‑minute period.

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

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

AIDS‑related KS

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

4.3. Contraindications

Hypersensitivity to the active substance, peanut or soya, or to any of the excipients listed in section 6.1.

Doxorubicin Baxter pegylated liposomal must not be used to treat AIDS‑KS that may be treated effectively with local therapy or systemic alfa‑interferon.

4.4. Special warnings and precautions for use

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

Cardiac toxicity

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

More specific methods for the evaluation and monitoring of cardiac functions as compared to ECG are a measurement of left ventricular ejection fraction by echocardiography or preferably by Multigated Angiography (MUGA). These methods must be applied routinely before the initiation of Doxorubicin Baxter pegylated liposomal therapy and repeated periodically during treatment. The evaluation of left ventricular function is considered to be mandatory before each additional administration of Doxorubicin Baxter 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 performance during anthracycline therapy are to be employed in the following order: ECG monitoring, measurement of left ventricular ejection fraction, endomyocardial biopsy. If a test result indicates possible cardiac injury associated with Doxorubicin Baxter pegylated liposomal therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury.

In patients with cardiac disease requiring treatment, administer Doxorubicin Baxter pegylated liposomal only when the benefit outweighs the risk to the patient.

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

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

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

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

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

Myelosuppression

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

Secondary haematological malignancies

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

Secondary oral neoplasms

Very rare cases of secondary oral cancer have been reported in patients with long‑term (more than one year) exposure to Doxorubicin Baxter pegylated liposomal or those receiving a cumulative Doxorubicin Baxter pegylated liposomal dose greater than 720 mg/m2. Cases of secondary oral cancer were diagnosed both, during treatment with Doxorubicin Baxter 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 oral discomfort that may be indicative of secondary oral cancer.

Infusion‑associated reactions

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

Palmar plantar erythrodysaesthesia syndrome (PPE)

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 of 50‑150 mg per day and corticosteroids have been used for the prophylaxis and treatment of PPE, however, these therapies have not been evaluated in phase III trials. Other strategies to prevent and treat PPE include keeping hands and feet cool, by exposing them to cool water (soaks, baths, or swimming), avoiding excessive heat/hot water and keeping them unrestricted (no socks, gloves, or shoes that are tight fitting). PPE appears to be primarily related to the dose schedule and can be reduced by extending the dose interval 1- 2 weeks (see section 4.2). However, this reaction can be severe and debilitating in some patients and may require discontinuation of treatment (see section 4.8).

Interstitial lung disease (ILD)

Interstitial lung disease (ILD), which may have an acute onset, has been observed in patients receiving pegylated liposomal doxorubicin, including fatal cases (see section 4.8). If patients experience worsening of respiratory symptoms such as dyspnoea, dry cough, and fever, doxorubicin baxter pegylated liposomal should be interrupted and the patient should be promptly investigated. If ILD is confirmed, Doxorubicin baxter pegylated liposomal should be discontinued and the patient treated appropriately.

Extravasation

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

Diabetic patients

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

Excipients

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.

4.5. Interaction with other medicinal products and other forms of interaction

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

4.6. Fertility, pregnancy and lactation

Pregnancy

Doxorubicin hydrochloride is suspected to cause serious birth defects when administered during pregnancy. Therefore, Doxorubicin Baxter pegylated liposomal should not be used during pregnancy unless clearly necessary.

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-bearing potential should use effective contraceptive measures while being treated with Doxorubicin Baxter pegylated liposomal and for 8 months following completion of treatment.

Men are recommended to use effective contraceptive measures and to not father a child while receiving Doxorubicin Baxter pegylated liposomal and for 6 months following completion of treatment

Breast‑feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

Doxorubicin Baxter 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 Doxorubicin Baxter pegylated liposomal. Patients who suffer from these effects must avoid driving and operating machinery.

4.8. Undesirable effects

Summary of the safety profile

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

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

Tabulated list of adverse reactions

Table 5 summarises the adverse drug reactions that occurred in patients receiving Doxorubicin Baxter pegylated liposomal 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”. 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 (frequency cannot be estimated from the available data). Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness.

Table 5: Adverse reactions in patients treated with Doxorubicin Baxter pegylated liposomal

System Organ Class

Frequency All Grades

Adverse Drug Reaction

Infections and infestations

Common

Sepsis

Pneumonia

Pneumocystis jirovecii pneumonia

Cytomegalovirus infection including cytomegalovirus chorioretinitis

Mycobacterium avium complex infection

Candidiasis

Herpes zoster

Urinary tract infection

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 benign, malignant and unspecified (including cysts and polyps)

Not known

Acute myeloid leukaemiab

Myelodysplastic syndromeb

Oral neoplasmb

Blood and lymphatic system disorders

Very common

Leukopaenia

Neutropaenia

Lymphopaenia

Anaemia (including hypochromic)

Common

Thrombocytopaenia

Febrile neutropaenia

Uncommon

Pancytopaenia

Thrombocytosis

Rare

Bone marrow failure

Immune system disorders

Uncommon

Hypersensitivity

Anaphylactic reaction

Rare

Anaphylactoid reaction

Metabolism and nutrition disorders

Very common

Decreased appetite

Common

Cachexia

Dehydration

Hypokalaemia

Hyponatraemia

Hypocalcaemia

Uncommon

Hyperkalaemia

Hypomagnesaemia

Psychiatric disorders

Common

Confusional state

Anxiety

Depression

Insomnia

Nervous system disorders

Common

Neuropathy peripheral

Peripheral sensory neuropathy

Neuralgia

Paraesthesia

Hypoaesthesia

Dysgeusia

Headache

Lethargy

Dizziness

Uncommon

Polyneuropathy

Convulsion

Syncope

Dysaesthesia

Somnolence

Eye disorders

Common

Conjunctivitis

Uncommon

Vision blurred

Lacrimation increased

Rare

Retinitis

Cardiac disordersa

Common

Tachycardia

Uncommon

Palpitations

Cardiac arrest

Cardiac failure

Cardiac failure congestive

Cardiomyopathy

Cardiotoxicity

Rare

Ventricular arrhythmia

Bundle branch block right

Conduction disorder

Atrioventricular block

Cyanosis

Vascular disorders

Common

Hypertension

Hypotension

Flushing

Uncommon

Pulmonary embolism

Infusion site necrosis (including soft tissue necrosis and skin necrosis)

Phlebitis

Orthostatic hypotension

Rare

Thrombophlebitis

Venous thrombosis

Vasodilatation

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea

Dyspnoea exertional

Epistaxis

Cough

Uncommon

Asthma

Chest discomfort

Rare

Throat tightness

Not Known

Interstitial lung disease

Gastrointestinal disorders

Very common

Stomatitis

Nausea

Vomiting

Diarrhoea

Constipation

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 subcutaneous tissue disorders

Very common

Palmar plantar erythrodysaesthesia syndromea

Rash (including erythematous, maculo‑papular, and papular)

Alopecia

Common

Skin exfoliation

Blister

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 and connective tissue disorders

Very common

Musculoskeletal pain (including musculoskeletal chest pain, back pain, pain in extremity)

Common

Muscle spasms

Myalgia

Arthralgia

Bone pain

Uncommon

Muscular weakness

Renal and urinary disorders

Common

Dysuria

Not Known

Renal-limited thrombotic microangiopathy

Reproductive disorders

Uncommon

Breast pain

Rare

Vaginal infection

Scrotal erythema

General disorders and administration site conditions

Very common

Pyrexia

Fatigue

Common

Infusion-related reaction

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 Blood bilirubin increased, Alanine aminotransferase increased and Aspartate aminotransferase increased)

Blood creatinine increased

Injury, poisoning and procedural complications

Uncommon

Radiation recall phenomenona

a See Description of selected adverse reactions

b Post-marketing adverse reaction

Description of selected adverse reactions

Palmar plantar erythrodysaesthesia

The most common undesirable effect reported in breast/ovarian clinical trials was palmar-plantar erythrodysesthesia (PPE). The overall incidence of PPE reported was 41.3% and 51.1% in the ovarian and breast clinical trials, respectively. These effects were mostly mild, with severe (grade 3) cases reported in 16.3% and 19.6% of patients. The reported incidence of life-threatening (grade 4) cases was < 1%. PPE infrequently resulted in permanent treatment discontinuation (1.9% and 10.8%). PPE was reported in 16% of multiple myeloma patients treated with Doxorubicin Baxter pegylated liposomal plus bortezomib combination therapy. Grade 3 PPE was reported in 5% of patients. No grade 4 PPE was reported. 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.

Opportunistic infections

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

Cardiac toxicity

An increased incidence of congestive heart failure is associated with doxorubicin therapy at cumulative 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 Doxorubicin Baxter pegylated liposomal greater than 460 mg/m2 indicate no evidence of anthracycline‑induced cardiomyopathy. The recommended dose of Doxorubicin Baxter pegylated liposomal for AIDS‑KS patients is 20 mg/m2 every two‑to‑three weeks. The cumulative dose at which cardiotoxicity would become a concern for these AIDS‑KS patients (> 400 mg/m2) would require more than 20 courses of Doxorubicin Baxter pegylated liposomal therapy over 40 to 60 weeks.

In addition, endomyocardial biopsies were performed in 8 solid tumour patients with cumulative anthracycline doses of 509 mg/m2–1,680 mg/m2. The range of Billingham cardiotoxicity scores was grades 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 Doxorubicin Baxter pegylated liposomal at a dose of 50 mg/m2/every 4 weeks versus 48 treated with doxorubicin at a dose of 60 mg/m2/every 3 weeks) met the protocol‑defined criteria for cardiac toxicity during treatment and/or follow‑up. Cardiac toxicity was defined as a decrease of 20 points or greater from baseline 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 Doxorubicin Baxter pegylated liposomal 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 developed signs and symptoms of CHF.

In patients with solid tumours, including a subset of patients with breast and ovarian cancers, treated at a dose of 50 mg/m2/cycle with lifetime cumulative anthracycline doses up to 1,532 mg/m2, the incidence of clinically significant cardiac dysfunction was low. Of the 418 patients treated with Doxorubicin Baxter pegylated liposomal 50 mg/m2/cycle, and having a baseline measurement of left ventricular 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 an increased 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 than 45% or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (cumulative anthracycline dose of 944 mg/m2), discontinued study treatment because of clinical symptoms of congestive heart failure.

Radiation recall phenomenon

Recall of skin reaction due to prior radiotherapy has occurred uncommonly with Doxorubicin Baxter pegylated liposomal administration.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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