Caelyx 2 mg/ml concentrate for solution for infusion

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

Caelyx, a liposome formulation, is doxorubicin hydrochloride encapsulated in liposomes with surface-bound methoxypolyethylene glycol (MPEG). This process is known as pegylation and protects liposomes from detection by the mononuclear phagocyte system (MPS), which increases blood circulation time.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion

The suspension is sterile, translucent and red.

 

Caelyx 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.

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

Caelyx should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents.

Caelyx exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride.

Posology

Breast cancer/Ovarian cancer

Caelyx 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

Caelyx 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

Caelyx 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 Caelyx 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 Caelyx 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 addressed in section 4.8.

Table 1. Palmar-Plantar erythrodysesthesia

	Week after prior Caelyx 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 Caelyx 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 Caelyx in combination with bortezomib who experience PPE or stomatitis, the Caelyx 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 Caelyx and bortezomib combination therapy. For more detailed information on bortezomib dosing and dosage adjustments, see the SPC for bortezomib.

Table 4. Dosage adjustments for Caelyx + bortezomib combination therapy - patients with multiple myeloma

Patient status	Caelyx	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 Hemoglobin < 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 hematologic 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-hematologic 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

Patients with impaired hepatic function

Caelyx 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 Caelyx 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. Caelyx 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 Caelyx administration, eva luate hepatic function using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase, and bilirubin.

Patients with impaired renal function

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 Caelyx 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 Caelyx in patients who have had splenectomy, treatment with Caelyx is not recommended.

Paediatric patients

The experience in children is limited. Caelyx is not recommended in patients below 18 years of age.

Older people

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

Method of administration

Caelyx is administered as an intravenous infusion. For further instructions on preparation and special precautions for handling see section 6.6.

Do not administer Caelyx as a bolus injection or undiluted solution. It is recommended that the Caelyx infusion line be connected through the side port of an intravenous infusion of 5% (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. Caelyx must not be given by the intramuscular or subcutaneous route (see section 6.6).

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

For doses ≥ 90 mg: dilute Caelyx 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 Caelyx 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 Caelyx is diluted in 250 ml 5% (50 mg/ml) glucose solution for infusion and administered by intravenous infusion over 30 minutes.

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

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

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

Cardiac toxicity

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

More specific methods for the eva luation 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 Caelyx therapy and repeated periodically during treatment. The eva luation of left ventricular function is considered to be mandatory before each additional administration of Caelyx that exceeds a lifetime cumulative anthracycline dose of 450 mg/m².

The eva luation 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 Caelyx therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury.

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

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

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 eva luated 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 Caelyx 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 Caelyx vs. topotecan, the incidence of treatment related sepsis was substantially less in the Caelyx-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 Caelyx 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 Caelyx therapy, and at a minimum, prior to each dose of Caelyx.

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. 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 Caelyx or those receiving a cumulative Caelyx dose greater than 720 mg/m². Cases of secondary oral cancer were diagnosed both, during treatment with Caelyx, 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 Caelyx. Very rarely, convulsions also have been observed in relation to infusion reactions (see section 4.8). 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).

Diabetic patients

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

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, 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. Caelyx, 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.

Pregnancy

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

Women of child-bearing potential

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

Breast-feeding

It is not known whether Caelyx 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 Caelyx 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 eva luated (see section 5.3).

Caelyx 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. Patients who suffer from these effects must avoid driving and operating machinery.