ONKOLOGY

1. MAXTREX (100 tab/10 mg of methotrexate in tablet)

2. XANTRON (10 ml/2 mg of mitoxantrone hydrochloride in ml)

3. CAELYX (10 ml/2 mg of doxorubicin hydrochloride in ml)

4. BUSILVEX (10 ml/6 mg of busulfan in ml)

5. VINCRIS (10ml/1 mg of vincristine sulphate in ml)

MAXTREX (100 tab/10 mg of methotrexate in tablet)

 Therapeutic indications

Methotrexate is a folic acid antagonist and is classified as an antimetabolite cytotoxic agent.

Methotrexate has been used to produce regression in a wide range of neoplastic conditions including acute leukaemias, non-Hodgkin's lymphoma, soft-tissue and osteogenic sarcomas, and solid tumours particularly breast, lung, head and neck, bladder, cervical, ovarian, and testicular carcinoma.

Methotrexate has also been used in the treatment of severe, uncontrolled psoriasis which is not responsive to other therapy.

 Posology and method of administration

Method of Administration: Oral.

Dosage for cancer treatment:

A test dose of 5 - 10 mg parenterally is recommended, one week prior to therapy to detect idiosyncratic adverse events. Single doses, not exceeding 30 mg/m2, on not more than 5 consecutive days. A rest period of at least two weeks is recommended between treatments, in order to allow the bone marrow to return to normal.

Doses in excess of 100 mg are usually given parenterally, when the injectable preparation should be used. Doses in excess of 70 mg/m2 should not be administered without leucovorin rescue (folinic acid rescue) or assay of serum methotrexate levels 24 - 48 hours after dosing.

If methotrexate is administered in combination chemotherapy regimens, the dosage should be reduced, taking into consideration any overlapping toxicity of the other drug components.

Dosage for psoriasis:

For the treatment of severe psoriasis 10 - 25 mg orally, once a week is recommended. Dosage should be adjusted according to the patient's response and the haematological toxicity. The prescriber may specify the day of intake on the prescription.

Contraindications

Methotrexate is contra-indicated in the presence of severe/significant renal or significant hepatic impairment, liver disease including fibrosis, cirrhosis, recent or active hepatitis; active infectious disease; and overt or laboratory evidence of immunodeficiency syndrome(s) and serious anaemia, leucopenia or thrombocytopenia. Maxtrex should not be used concomitantly with drugs with antifolate properties (see section 4.5, Interactions with other Medicinal Products and other forms of Interaction). Methotrexate is teratogenic and should not be given during pregnancy or to mothers who are breast feeding (see Section 4.6., Pregnancy and Lactation).

Following administration to a man or woman conception should be avoided by using an effective contraceptive method for at least 3 months after using Maxtrex Tablets 10mg (see Section 4.4, Special Warnings and Special Precautions for Use).

Patients with a known allergic hypersensitivity to methotrexate or any of the excipients should not receive methotrexate.

 Special warnings and precautions for use

• The prescriber may specify the day of intake on the prescription.

• Patients should be aware of importance of adhering to the once weekly intakes.

Methotrexate should be used with extreme caution in patients with haematological depression, renal impairment, diarrhoea, ulcerative disorders of the GI tract and psychiatric disorders. Hepatic toxicity has been observed, usually associated with chronic hepatic disease. The administration of low doses of methotrexate for prolonged periods may give rise, in particular, to hepatic toxicity. Liver function should be closely monitored. If hepatic function abnormalities develop, methotrexate dosing should be suspended for at least two weeks. It is only appropriate to restart methotrexate provided the abnormalities return to normal and the re-exposure is deemed appropriate.

Particular care and possible cessation of treatment are indicated if stomatitis or GI toxicity occurs as haemorrhagic enteritis and intestinal perforation may result.

Reversible eosinophilic pulmonary reactions and treatment-resistant, interstitial fibrosis may occur, particularly after long-term treatment.

Renal lesions may develop if the urinary flow is impeded and urinary pH is low, especially if large doses have been administered.

Renal function should be closely monitored before, during and after treatment. Reduce dose of methotrexate in patients with renal impairment. High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5 – 7 by oral or intravenous administration of sodium bicarbonate (5x625mg tablets every three hours) is recommended as a preventative measure.

Haematopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white cell or platelet count develops, methotrexate therapy should be withdrawn immediately and appropriate supportive therapy given (see section 4.8, Undesirable Effects). Patients should be advised to report all symptoms or signs suggestive of infection.

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy.

Methotrexate has been shown to be teratogenic; it has been reported to cause foetal death and/or congenital abnormalities. Therefore, it is not recommended in women of childbearing potential unless the benefits can be expected to outweigh the considered risks. If this drug is used during pregnancy for antineoplastic indications, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the foetus.

Following administration to a man or woman conception should be avoided by using an effective contraceptive method for at least 3 months after using Maxtrex Tablets 10mg (see section 4.3, Contraindications).

Methotrexate has some immunosuppressive activity and therefore the immunological response to concurrent vaccination may be decreased. In addition, concomitant use of a live vaccine could cause severe antigenic reaction.

Methotrexate should only be used by clinicians that are familiar with the various characteristics of the drug and its mode of action. Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, a chest x-ray, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests. This will include a routine examination of lymph nodes and patients should report any unusual swelling to the doctor.

Patients receiving low-dose methotrexate should:

• Have a full blood count and renal and liver function tests before starting treatment. These should be repeated weekly until therapy is stabilised, thereafter patients should be monitored every 2-3 months throughout treatment.

• Patients should report all symptoms and signs suggestive of infection, especially sore throat.

If acute methotrexate toxicity occurs, patients may require treatment with folinic acid.

The disappearance of methotrexate from plasma should be monitored, if possible. This is recommended in particular when high, or very high doses are administered in order to permit calculation of an adequate dose of leucovorin (folinic acid) rescue.

Patients with pleural effusions and ascites should be drained prior to initiation of methotrexate therapy. A chest x-ray is recommended prior to initiation of methotrexate therapy or treatment should be withdrawn.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Acute or chronic pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry productive cough) and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea.

Methotrexate should be withdrawn from patients with pulmonary symptoms, and a thorough investigation should be made to exclude infection. If methotrexate induced lung disease is suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.

Lung manifestations of RA and other connective tissue disorders are recognised to occur. In patients with RA, the physician should be specifically alerted to the potential for methotrexate induced adverse effects on the pulmonary system.

 Interaction with other medicinal products and other forms of interaction

Methotrexate is immunosuppressive and may therefore reduce immunological response to concurrent vaccination. Severe antigenic reactions may occur if a live vaccine is given concurrently.

Methotrexate is extensively protein bound and may displace, or be displaced by, other acidic drugs. The concurrent administration of agents such as p-aminobenzoic acid, chloramphenicol, penicillines, ciprofloxacin, diphenylhydantoins, phenytoin, acidic anti-inflammatory agents, salicylates, sulphonamides, tetracyclines, thiazide diuretics, probenicid, sulfinpyrazone or oral hypoglycaemics will decrease the methotrexate transport function of renal tubules, thereby reducing excretion and almost certainly increasing methotrexate toxicity. Methotrexate dosage should be monitored if concomitant treatment with aspirin, ibuprofen or indometacin (NSAIDs) is commenced, as concomitant use of NSAID's has been associated with fatal methotrexate toxicity. Concomitant administration of folate antagonists such as trimethoprim, co-trimoxazole and nitrous oxide should be avoided. Hepatic and nephrotoxic drugs should be avoided.

Acitretin (a treatment for psoriasis) is metabolised to eretinate. Methotrexate levels may be increased by eretinate and severe hepatitis has been reported following concomitant use.

Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate.

 Pregnancy and lactation

Methotrexate is contra-indicated in pregnancy. Methotrexate affects spermatogenesis and oogenesis and may therefore decrease fertility. This effect appears to be reversible after discontinuation of therapy. Patients and their partners should be advised to avoid pregnancy until 3 months after cessation of methotrexate therapy.

Patients should not breast feed whilst taking methotrexate.

Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible risks of effects on reproduction should be discussed with patients of child bearing potential (see section 4.4, Special Warnings and Special Precautions for Use and section 4.3, Contraindications).

 Effects on ability to drive and use machines

None known.

 Undesirable effects

In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions for the various systems are as follows:

Skin:

Stevens-Johnson Syndrome, epidermal necrolysis, erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques has been reported. The recall phenomenon has been reported in both radiation and solar damaged skin.

Haematopoietic:

Bone marrow depression is most frequently manifested by leucopenia, thrombocytopenia (which are usually reversible) and anaemia, or any combination may occur. Infection or hypogammaglobulinaemia has been reported.

Alimentary System:

Mucositis (most frequently stomatitis although gingivitis, pharyngitis and even enteritis, intestinal ulceration and bleeding) may occur. In rare cases the effect of Methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon. Nausea, anorexia and vomiting and/or diarrhoea may also occur.

Hepatic:

Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.

Urogenital System:

Renal failure and uraemia may follow methotrexate administration, particularly after high doses or prolonged administration. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported. Methotrexate can decrease fertility. This effect appears to be reversible after discontinuation of therapy (see section 4.6, Pregnancy and Lactation).

Pulmonary System:

Infrequently an acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.

In the treatment of rheumatoid arthritis, methotrexate induced lung disease is a potentially serious adverse drug reaction which may occur acutely at any time during therapy. It is not always fully reversible. Pulmonary symptoms (especially a dry, non productive cough) may require interruption of treatment and careful investigation.

Central Nervous System:

Headaches, drowsiness, ataxia and blurred vision have occurred following low doses of methotrexate, transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations have been reported occasionally. Aphasia, paresis, hemiparesis, and convulsions have also occurred following administration of higher doses.

There have been reports of leucoencephalopathy following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation.

Other reports include eye irritation, malaise, undue fatigue, vasculitis, sepsis, arthralgia/myalgia, chills and fever, dizziness, loss of libido/impotence and decreased resistance to infection. Also opportunistic infections such as herpes zoster. Osteoporosis, abnormal (usually "megaloblastic") red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death in relation to or attributed to the use of methotrexate.

Although very rare, anaphylactic reactions to methotrexate have been reported.

Acute or chronic interstitial pneumonitis, often associated with blood eosinophila, may occur and deaths have been reported (see Section 4.4, Special Warnings and Special Precautions for Use).

 Overdose

Leucovorin is a specific antidote for methotrexate and, following accidental overdosage, should be administered within one hour at a dosage equal to, or greater than, the methotrexate dose. It may be administered by i.v. bolus or infusion. Further doses may be required. The patient should be observed carefully and blood transfusions, renal dialysis and reverse barrier nursing may be necessary.

In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

Cases of overdose, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate have been reported. In these cases, symptoms that have been commonly reported are haematological and gastrointestinal reactions.

 Pharmacodynamic properties

Methotrexate is a folic acid antagonist and its major site of action is the enzyme dihydrofolate reductase. Its main effect is inhibition of DNA synthesis but it also acts directly both on RNA and protein synthesis. Methotrexate is a phase specific substance, the main effect being directed during the S-phase of cell division.

The inhibition of dihydrofolate reductase can be circumvented by the use of leucovorin (folinic acid; citrovorum factor) and protection of normal tissues can be carried out by properly timed administration of leucovorin calcium.

 Pharmacokinetic properties

When given in low doses, methotrexate is rapidly absorbed from the GI tract giving plasma concentrations equivalent to those achieved after i.v. administration. Higher doses are less well absorbed. About 50% has been shown to be protein bound. Biphasic and triphasic plasma clearance has been shown. The majority of the dose is excreted within 24 hours in the urine mainly as unchanged drug.

XANTRON (10 ml/2 mg of mitoxantrone hydrochloride in ml)

 Therapeutic indications

XANTRON is indicated in the treatment of metastatic breast cancer, non-Hodgkin's lymphoma and adult acute non-lymphocytic leukaemia.

XANTRON has also been used in the palliation of non-resectable primary hepatocellular carcinoma.

 Posology and method of administration

Posology

Metastatic breast cancer, Non-Hodgkin's lymphoma, Hepatoma:

Single Agent Dosage: The recommended initial dosage of  XANTRON as a single agent is 14 mg/m2 of body surface area, given as a single intravenous dose which may be repeated at 21-day intervals. A lower initial dosage (12 mg/m2 or less) is recommended for patients with inadequate bone marrow reserves e.g. due to prior chemotherapy or poor general condition.

Dosage modification and the timing of subsequent doses should be determined by clinical judgement depending on the degree and duration of myelosuppression. For subsequent courses the prior dose can usually be repeated if white blood cell and platelet counts have returned to normal levels after 21 days. The following table is suggested as a guide to dosage adjustment in the treatment of metastatic breast cancer, non-Hodgkin's lymphoma and hepatoma according to haematological nadir (which usually occurs about 10 days after dosing).

Combination Therapy: XANTRON  has been given as part of combination therapy. In metastatic breast cancer, combinations of XANTRON   with other cytotoxic agents including cyclophosphamide and 5-fluorouracil, or methotrexate and mitomycin C, have been shown to be effective. Reference should be made to the published literature for information on dosage modifications and administration. XANTRON  has also been used in various combinations for non-Hodgkin's lymphoma, however data are presently limited and specific regimens cannot be recommended.

As a guide, when  XANTRON is used in combination chemotherapy with another myelosuppressive agent, the initial dose of mitoxantrone should be reduced by 2-4 mg/m2 below the doses recommended for single agent use. Subsequent doses, as outlined in the table above, depend on the degree and duration of myelosuppression.

Adult acute non-lymphocytic leukaemia:

Single Agent Dosage in Relapse: The recommended dosage for remission induction is 12 mg/m2 of body surface area, given as a single intravenous dose daily for five consecutive days (total of 60 mg/m2). In clinical studies with a dosage of 12 mg/m2 daily for 5 days, patients who achieved a complete remission did so as a result of the first induction course.

Combination Therapy: XANTRON  has been used in combination regimens for the treatment of acute non-lymphocytic leukaemia (ANLL). Most clinical experience has been with XANTRON  combined with cytarabine. This combination has been used successfully for primary treatment of ANLL as well as in the treatment of relapse.

An effective regimen for induction in previously untreated patients has been   10-12 mg/m2 IV for 3 days combined with cytarabine 100 mg/m2 IV for 7 days (by continuous infusion). This is followed by second induction and consolidation courses as thought appropriate by the treating clinician. In clinical studies, duration of therapy in induction and consolidation courses with XANTRON  have been reduced to 2 days, and that of cytarabine to 5 days. However, modification to the above regimen should be carried out by the treating clinician depending on individual patient factors.

Efficacy has also been demonstrated with  XANTRON in combination with etoposide in patients who had relapsed or who were refractory to primary conventional chemotherapy. The use of  XANTRON in combination with etoposide, as with other cytotoxics, may result in greater myelosuppression than with XANTRON alone.

Reference should be made to the published literature for information on specific dosage regimens.  XANTRON should be used by clinicians experienced in the use of chemotherapy regimens. Dosage adjustments should be made by the treating clinician as appropriate, taking into account toxicity, response and individual patient characteristics. As with other cytotoxic drugs,  XANTRON should be used with caution in combination therapy until wider experience is available.

Paediatrics: The safety and efficacy of XANTRON  in paediatric patients have not been established.

 Special warnings and precautions for use

Special warnings

There may be an increased risk of leukaemia when XANTRON  is used as adjuvant treatment of non-metastatic breast cancer. In the absence of sufficient efficacy data, XANTRON   must not be used as adjuvant treatment of non-metastatic breast cancer.

XANTRON  should be used with caution in patients with myelosuppression or poor general condition.

Cases of functional cardiac changes, including congestive heart failure and decreases in left ventricular ejection fraction have been reported during  XANTRON therapy . These cardiac events have occurred most commonly in patients who have had prior treatment with anthracyclines, prior mediastinal/thoracic radiotherapy, or in patients with pre-existing heart disease. The concomitant administration of other cardiotoxic drugs may also increase the risk of cardiac toxicity. It is recommended that patients in these categories are treated with  XANTRON at full cytotoxic dosage and schedule. However, added caution is required in these patients and careful regular cardiac examinations are recommended from the initiation of treatment.

Cardiac monitoring should also be performed in patients without identifiable risk factors during therapy exceeding 160 mg/m2 of XANTRON  , or during extended treatment.

Careful supervision is recommended when treating patients with hepatic insufficiency.

Topoisomerase II inhibitors, including XANTRON hydrochloride, when used concomitantly with other antineoplastic agents (particularly anthracyclines) and/or radiotherapy, have been associated with the development of Acute Myeloid Leukaemia (AML) or Myelodysplastic Syndrome (MDS). Treatment with XANTRON alone has also been associated with an increased risk of development of secondary acute myeloid leukaemia .

Sulphites can cause allergic-type reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma or allergy.

Immunisation may be ineffective when given during XANTRON therapy. Immunisation with live virus vaccines are generally not recommended.

There is no experience with the administration of XANTRON Sterile Concentrate other than by the intravenous route. Safety for intrathecal use has not been established.

Precautions for use

XANTRON is an active cytotoxic drug which should be used by clinicians who are familiar with the use of antineoplastic agents and have the facilities for regular monitoring of clinical, haematological and biochemical parameters during and after treatment.

Full blood counts should be undertaken serially during a course of treatment. Dosage adjustments may be necessary based on these counts (see Dosage section).

 Interaction with other medicinal products and other forms of interaction

Animal data suggest that if used in combination with other antineoplastic agents, additive myelosuppression may be expected. This has been supported by available clinical data on combination regimens. When used in combination regimens, the initial dose of XANTRON Sterile Concentrate should be reduced by 2-4 mg/m2 below the dose recommended for single agent usage. (see Posology and method of administration).

Combining XANTRON with potentially cardiotoxic drugs (anthracyclines) increases the risk of cardiac toxicity. The product must be used with caution in combination with immunosuppressive chemotherapy.

 Pregnancy and lactation

There are no adequate and well-controlled studies in pregnant women. XANTRON  should not normally be administered to patients who are pregnant. If the drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazard to the fetus. Women of childbearing potential and their partners should be advised to avoid becoming pregnant and use effective contraception during therapy and for at least six months after cessation of therapy.

XANTRON is excreted in human milk and significant concentrations (18 ng/ml) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from  XANTRON , breast-feeding should be discontinued before starting treatment.

 Effects on ability to drive and use machines

Not applicable.

 Undesirable effects

Serious or Life Threatening Reactions:

Blood and lymphatic system disorders: Some degree of leucopenia is to be expected following recommended doses of XANTRON. With the single dose every 21 days, suppression of WBC count below 1000/mm3 is infrequent. Leucopenia is usually transient reaching its nadir at about 10 days after dosing with recovery usually occurring by the 21st day. Thrombocytopenia and anaemia occur less frequently. Myelosuppression may be more severe and prolonged in patients who have had extensive prior chemotherapy or radiotherapy or in debilitated patients.

Cardiac disorders: Congestive heart failure may occur during therapy with XANTRON, or months to years after the end of treatment .. Some cases have been fatal. Treatment with digoxin and/or diuretics has been reported to be effective.

Other cardiovascular effects, which have been of clinical significance include decreased left ventricular ejection fraction, ECG changes and acute arrhythmia.

In patients with leukaemia an increase in the frequency of adverse cardiac events has been observed. The direct role of XANTRON in these cases is difficult to assess, since some patients had received prior therapy with anthracyclines and since the clinical course in leukaemic patients is frequently complicated by anaemia, fever, sepsis and intravenous fluid therapy. Cardiomyopathy has been reported in rare instances.

Other Undesirable Effects:

Hepato-biliary disorders and Renal and urinary disorders: XANTRON Sterile Concentrate may impart a blue-green colouration to the urine for 24 hours after administration, and patients should be advised to expect this during active therapy. Increased liver enzyme levels (with occasional reports of severe impairment of hepatic function in patients with leukaemia). Hyperuricaemia has also been reported. Elevated serum creatinine and blood urea nitrogen levels have been reported.

Skin and subcutaneous tissue disorders: Rash, onycholysis, blue discolouration of skin and nails and nail dystrophy has been reported occasionally. Alopecia may occur, but is most frequently of minimal severity and reversible on cessation of therapy

Eye Disorders: Reversible blue colouration of the sclerae has been reported. Conjunctivitis.

Respiratory disorders: Dyspnoea.

Gastrointestinal Disorders: Diarrhoea, anorexia, constipation, gastrointestinal bleeding, abdominal pain, stomatitis and mucositis. The most commonly encountered side effects are nausea and vomiting, although in the majority of cases these are mild and transient.

Neoplasms: Secondary acute myeloid leukaemia .

General disorders and administration site conditions: Fever, fatigue and weakness.

Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning and/or blue discolouration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of infusion.

Nervous system disorders: Altered taste. Non-specific neurological side effects such as somnolence and mild paraesthesia have been reported.

Metabolism and nutrition disorders: Tumour lysis syndrome (characterised by hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia) has been observed rarely during single-agent chemotherapy with XANTRON, as well as during combination chemotherapy.

Psychiatric disorders: Confusion, anxiety.

Reproductive system and breast disorders: Amenorrhoea.

In patients with leukaemia, the pattern of side-effects is generally similar, although there is an increase in both frequency and severity, particularly of stomatitis and mucositis. Nevertheless, overall, patients with leukaemia tolerate treatment with XANTRON well.

Immune system disorders: Allergic reaction.

Reporting of suspected adverse reactions

CAELYX (10 ml/2 mg of doxorubicin hydrochloride in ml)

 Therapeutic indications

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).

 Posology and method of administration

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  and stomatitis  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.

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, evaluate 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.

Method of administration

Caelyx is administered as an intravenous infusion.

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 ..

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.

 Contraindications

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

 Special warnings and precautions for use

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 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 Caelyx therapy and repeated periodically during treatment. The evaluation 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 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 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 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 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. 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. 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.

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.

 Interaction with other medicinal products and other forms of interaction

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.

 Fertility, pregnancy and lactation

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.

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 evaluated .

 Effects on ability to drive and use machines

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.

 Undesirable effects

Summary of the safety profile

The most common undesirable effect reported in breast/ovarian clinical trials (50 mg/m2 every 4 weeks) was palmar-plantar erythrodysesthesia (PPE). The overall incidence of PPE reported was 44.0%-46.1%. These effects were mostly mild, with severe (grade 3) cases reported in 17%-19.5%. The reported incidence of life-threatening (grade 4) cases was < 1%. PPE infrequently resulted in permanent treatment discontinuation (3.7%-7.0%). 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 one - two 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, which may be initiated for 4 to 7 days after treatment with Caelyx 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. However, this reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Stomatitis/mucositis and nausea were also commonly reported in breast/ovarian cancer patient populations, whereas the AIDS-KS Program (20 mg/m2 every 2 weeks), myelosuppression (mostly leukopaenia) was the most common side effect (see AIDS-KS). PPE was reported in 16% of multiple myeloma patients treated with Caelyx plus bortezomib combination therapy. Grade 3 PPE was reported in 5% of patients. No grade 4 PPE was reported. The most frequently reported (medicine-related treatment-emergent) adverse events in combination therapy (Caelyx + bortezomib) were nausea (40%), diarrhoea (35%), neutropaenia (33%), thrombocytopaenia (29%), vomiting (28%), fatigue (27%), and constipation (22%).

Breast cancer program

509 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with Caelyx (n=254) at a dose of 50 mg/m2 every 4 weeks, or doxorubicin (n=255) at a dose of 60 mg/m2 every 3 weeks, in a phase III clinical trial (I97-328). The following common adverse events were reported more often with doxorubicin than with Caelyx: nausea (53% vs. 37%; grade 3/4 5% vs. 3%), vomiting (31% vs. 19%; grade 3/4 4% vs. less than 1%), any alopecia (66% vs. 20%), pronounced alopecia (54% vs.7%), and neutropaenia (10% vs. 4%; grade 3/4 8% vs. 2%).

Mucositis (23% vs. 13%; grade 3/4 4% vs. 2%), and stomatitis (22% vs. 15%; grade 3/4 5% vs. 2%) were reported more commonly with Caelyx than with doxorubicin. The average duration of the most common severe (grade 3/4) events for both groups was 30 days or less. See Table 5 for complete listing of undesirable effects reported in Caelyx-treated patients.

The incidence of life threatening (grade 4) haematologic effects was < 1.0% and sepsis was reported in 1% of patients. Growth factor support or transfusion support was necessary in 5.1% and 5.5% of patients, respectively (see section 4.2).

Clinically significant laboratory abnormalities (grades 3 and 4) in this group was low with elevated total bilirubin, AST and ALT reported in 2.4%, 1.6% and < 1% of patients respectively. No clinically significant increases in serum creatinine were reported.

Multiple myeloma program

Of 646 patients with multiple myeloma who have received at least 1 prior therapy, 318 patients were treated with combination therapy of Caelyx 30 mg/m2 as a one hour intravenous infusion administered on day 4 following bortezomib which is administered at 1.3 mg/m² on days 1, 4, 8, and 11, every three weeks or with bortezomib monotherapy in a phase III clinical trial. See Table 7 for adverse effects reported in ≥ 5% patients treated with combination therapy of Caelyx plus bortezomib.

Neutropaenia, thrombocytopaenia, and anaemia were the most frequently reported hematologic events reported with both combination therapy of Caelyx plus bortezomib and bortezomib monotherapy. The incidence of grade 3 and 4 neutropaenia was higher in the combination therapy group than in the monotherapy group (28% vs. 14%). The incidence of grade 3 and 4 thrombocytopaenia was higher in the combination therapy group than in the monotherapy group (22% vs. 14%). The incidence of anaemia was similar in both treatment groups (7% vs. 5%).

Stomatitis was reported more frequently in the combination therapy group (16%) than in the monotherapy group (3%), and most cases were grade 2 or less in severity. Grade 3 stomatitis was reported in 2% of patients in the combination therapy group. No grade 4 stomatitis was reported.

Nausea and vomiting were reported more frequently in the combination therapy group (40% and 28%) than in the monotherapy group (32% and 15%) and were mostly grade 1 and 2 in severity.

Treatment discontinuation of one or both agents due to adverse events was seen in 38% of patients. Common adverse events which led to treatment discontinuation of bortezomib and Caelyx included PPE, neuralgia, peripheral neuropathy, peripheral sensory neuropathy, thrombocytopaenia, decreased ejection fraction, and fatigue.

AIDS-related KS program

Clinical studies on AIDS-KS patients treated at 20 mg/m2 with Caelyx show that myelosuppression was the most frequent undesirable effect considered related to Caelyx occurring very commonly (in approximately one-half of the patients).

Leukopaenia is the most frequent undesirable effect experienced with Caelyx in this population; neutropaenia, anaemia and thrombocytopaenia have been observed. These effects may occur early on in treatment. Haematological toxicity may require dose reduction or suspension or delay of therapy. Temporarily suspend Caelyx 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. The haematological toxicity for ovarian cancer patients is less severe than in the AIDS-KS setting (see section for ovarian cancer patients above).

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

All patients

100 out of 929 patients (10.8%) with solid tumours were described as having an infusion-associated reaction during treatment with Caelyx as defined by the following Costart terms: allergic reaction, anaphylactoid reaction, asthma, face oedema, hypotension, vasodilatation, urticaria, back pain, chest pain, chills, fever, hypertension, tachycardia, dyspepsia, nausea, dizziness, dyspnoea, pharyngitis, rash, pruritus, sweating, injection site reaction and medicinal product interaction. Permanent treatment discontinuation was infrequently reported at 2%. A similar incidence of infusion reactions (12.4%) and treatment discontinuation (1.5%) was observed in the breast cancer program. In patients with multiple myeloma receiving Caelyx plus bortezomib, infusion-associated reactions have been reported at a rate of 3%. In patients with AIDS-KS, infusion-associated reactions, were characterised by flushing, shortness of breath, facial oedema, headache, chills, back pain, tightness in the chest and throat and/or hypotension and can be expected at the rate of 5% to 10%. Very rarely, convulsions have been observed in relation to infusion reactions. In all patients, infusion-associated reactions occurred primarily during the first infusion. Temporarily stopping the infusion usually resolves these symptoms without further therapy. In nearly all patients, Caelyx treatment can be resumed after all symptoms have resolved without recurrence. Infusion reactions rarely recur after the first treatment cycle with Caelyx (see section 4.2).

Myelosuppression associated with anaemia, thrombocytopaenia, leukopaenia, and rarely febrile neutropaenia, has been reported in Caelyx-treated patients.

Stomatitis has been reported in patients receiving continuous infusions of conventional doxorubicin hydrochloride and was frequently reported in patients receiving Caelyx. It did not interfere with patients completing therapy and no dosage adjustments are generally required, unless stomatitis is affecting a patient's ability to eat. In this case, the dose interval may be extended by 1-2 weeks or the dose reduced (see section 4.2).

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 Caelyx greater than 460 mg/m2 indicate no evidence of anthracycline-induced cardiomyopathy. The recommended dose of Caelyx 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 Caelyx 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 Caelyx 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 Caelyx 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 Caelyx 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.

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.

Although local necrosis following extravasation has been reported very rarely, Caelyx 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. Caelyx must not be given by the intramuscular or subcutaneous route.

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

Post-marketing experience

 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.

 Pharmacodynamic properties

Pharmacotherapeutic group: Cytotoxic agents (anthracyclines and related substances), ATC code: L01DB01.

Mechansim of action

The active ingredient of Caelyx is doxorubicin hydrochloride, a cytotoxic anthracycline antibiotic obtained from Streptomyces peucetius var. caesius. The exact mechanism of the antitumour activity of doxorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesis is responsible for the majority of the cytotoxic effects. This is probably the result of intercalation of the anthracycline between adjacent base pairs of the DNA double helix thus preventing their unwinding for replication.

Clinical efficacy and safety

A phase III randomised study of Caelyx versus doxorubicin in patients with metastatic breast cancer was completed in 509 patients. The protocol-specified objective of demonstrating non-inferiority between Caelyx and doxorubicin was met, the hazard ratio (HR) for progression-free survival (PFS) was 1.00 (95% 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 of cumulative anthracycline dose was significantly lower with Caelyx than with doxorubicin (HR=3.16, p < 0.001). At cumulative doses greater than 450 mg/m2 there were no cardiac events with Caelyx.

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

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

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

A phase III randomised, parallel-group, open-label, multicentre study comparing the safety and efficacy of Caelyx plus bortezomib combination therapy with bortezomib monotherapy in patients with multiple myeloma who have received at least 1 prior therapy and who did not progress while receiving anthracycline-based therapy, was conducted in 646 patients. There was a significant improvement in the primary endpoint of time to progression (TTP) for patients treated with combination therapy of Caelyx plus bortezomib compared to patients 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 bortezomib monotherapy patients compared with 8.9 months for the Caelyx plus bortezomib combination therapy patients. A protocol-defined interim analysis (based on 249 TTP events) triggered early study termination for efficacy. This interim analysis showed a TTP risk reduction of 45% (95% CI: 29-57%), p < 0.0001. The median TTP was 6.5 months for the bortezomib monotherapy patients compared with 9.3 months for the Caelyx plus bortezomib combination therapy patients. These results, though not mature, constituted the protocol defined final analysis. The final analysis for overall survival (OS) performed after a median follow-up of 8.6 years showed no significant difference in OS between the two treatment arms. The median OS was 30.8 months (95% CI; 25.2-36.5 months) for the bortezomib monotherapy patients and 33.0 months (95% CI; 28.9-37.1 months) for the Caelyx plus bortezomib combination therapy patients.

BUSILVEX (10 ml/6 mg of busulfan in ml)

 Therapeutic indications

Busilvex followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option.

Busilvex following fludarabine (FB) is indicated as conditioning treatment prior to haematopoietic progenitor cell transplantation (HPCT) in adult patients who are candidates for a reduced-intensity conditioning (RIC) regimen.

Busilvex followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation in paediatric patients.

 Posology and method of administration

Busilvex administration should be supervised by a physician experienced in conditioning treatment prior to haematopoietic progenitor cell transplantation.

Busilvex is administered prior to the haematopoietic progenitor cell transplantation (HPCT).

 Special warnings and precautions for use

The consequence of treatment with Busilvex at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia, or any combination thereof may develop. Frequent complete blood counts, including differential white blood cell counts, and platelet counts should be monitored during the treatment and until recovery is achieved.

Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period. Platelet and red blood cell support, as well as the use of growth factors such as granulocyte colony stimulating agent (G-CSF), should be employed as medically indicated.

In adults, absolute neutrophil counts < 0.5x109/l at a median of 4 days post transplant occurred in 100% of patients and recovered at median day 10 and 13 days following autologous and allogeneic transplant respectively (median neutropenic period of 6 and 9 days respectively). Thrombocytopenia (< 25x109/l or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients. Anaemia (haemoglobin< 8.0 g/dl) occurred in 69% of patients.

In paediatric population, absolute neutrophil counts < 0.5x109/l at a median of 3 days post transplant occurred in 100% of patients and lasted 5 and 18.5 days in autologous and allogeneic transplant respectively. In children, thrombocytopenia (< 25x109/l or requiring platelet transfusion) occurred in 100% of patients. Anaemia (haemoglobin< 8.0 g/dl) occurred in 100% of patients.

In children < 9 kg, a therapeutic drug monitoring may be justified on a case by case basis, in particular in extremely young children and neonates.

The Fanconi anaemia cells have hypersensitivity to cross-linking agents. There is limited clinical experience of the use of busulfan as a component of a conditioning regimen prior to HSCT in children with Fanconi's anaemia. Therefore Busilvex should be used with caution in this type of patients.

Hepatic impairment

Busilvex as well as busulfan has not been studied in patients with hepatic impairment. Since busulfan is mainly metabolized through the liver, caution should be observed when Busilvex is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment. It is recommended when treating these patients that serum transaminase, alkaline phosphatase, and bilirubin should be monitored regularly 28 days following transplant for early detection of hepatotoxicity.

Hepatic veno-occlusive disease is a major complication that can occur during treatment with Busilvex. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk.

Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with Busilvex due to a possible decrease in the metabolism of busulfan.

As documented in clinical studies, no treated patients experienced cardiac tamponade or other specific cardiac toxicities related to Busilvex. However cardiac function should be monitored regularly in patients receiving Busilvex.

Occurrence of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis was reported in Busilvex studies in one patient who died, although, no clear aetiology was identified. In addition, busulfan might induce pulmonary toxicity that may be additive to the effects produced by other cytotoxic agents. Therefore, attention should be paid to this pulmonary issue in patients with prior history of mediastinal or pulmonary radiation.

Periodic monitoring of renal function should be considered during therapy with Busilvex.

Seizures have been reported with high dose busulfan treatment. Special caution should be exercised when administering the recommended dose of Busilvex to patients with a history of seizures. Patients should receive adequate anticonvulsant prophylaxis. In adults and children studies, data with Busilvex were obtained when using concomitant administration of either phenytoin or benzodiazepines for seizure prophylaxis. The effect of those anticonvulsant agents on busulfan pharmacokinetics was investigated in a phase II study.

The increased risk of a second malignancy should be explained to the patient. On the basis of human data, busulfan has been classified by the International Agency for Research on Cancer (IARC) as a human carcinogen. The World Health Organisation has concluded that there is a causal relationship between busulfan exposure and cancer. Leukaemia patients treated with busulfan developed many different cytological abnormalities, and some developed carcinomas. Busulfan is thought to be leukemogenic.

Fertility

Busulfan can impair fertility. Therefore, men treated with Busilvex are advised not to father a child during and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Busilvex. Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in pre-menopausal patients. Busulfan treatment in a pre-adolescent girl prevented the onset of puberty due to ovarian failure. Impotence, sterility, azoospermia, and testicular atrophy have been reported in male patients. The solvent dimethylacetamide (DMA) may also impair fertility. DMA decreases fertility in male and female rodents.

 Interaction with other medicinal products and other forms of interaction

No specific clinical trial was carried out to assess drug-drug interaction between intravenous busulfan and itraconazole. From published studies in adults, administration of itraconazole to patients receiving high-dose busulfan may result in reduced busulfan clearance. Patients should be monitored for signs of busulfan toxicity when itraconazole is used as an antifungal prophylaxis with intravenous busulfan.

Published studies in adults described that ketobemidone (analgesic) might be associated with high levels of plasma busulfan. Therefore special care is recommended when combining these two compounds.

In adults, for the BuCy2 regimen it has been reported that the time interval between the last oral busulfan administration and the first cyclophosphamide administration may influence the development of toxicities. A reduced incidence of Hepatic Veno Occlusive Disease (HVOD) and other regimen-related toxicity have been observed in patients when the lag time between the last dose of oral busulfan and the first dose of cyclophosphamide is > 24hours.

There is no common metabolism pathway between busulfan and fludarabine.

In adults, for the FB regimen, published studies did not report any mutual drug-drug interaction between intravenous busulfan and fludarabine.

In paediatric population, for the BuMel regimen it has been reported that the administration of melphalan less than 24 hours after the last oral busulfan administration may influence the development of toxicities.

Paracetamol is described to decrease glutathione levels in blood and tissues, and may therefore decrease busulfan clearance when used in combination .

Either phenytoin or benzodiazepines were administered for seizure prophylaxis in patients participating to the clinical trials conducted with intravenous busulfan .

The concomitant systemic administration of phenytoin to patients receiving high-dose of oral busulfan has been reported to increase busulfan clearance, due to induction of glutathion-S-transferase whereas no interaction has been reported when benzodiazepines such as diazepam, clonazepam or lorazepam have been used to prevent seizures with high-dose busulfan.

No evidence of an induction effect of phenytoin has been seen on Busilvex data. A phase II clinical trial was performed to evaluate the influence of seizure prophylaxis treatment on intravenous busulfan pharmacokinetics. In this study, 24 adult patients received clonazepam (0.025-0.03 mg/kg/day as IV continuous infusions) as anticonvulsant therapy and the PK data of these patients were compared to historical data collected in patients treated with phenytoin. The analysis of data through a population pharmacokinetic method indicated no difference on intravenous busulfan clearance between phenytoin and clonazepam based therapy and therefore similar busulfan plasma exposures were achieved whatever the type of seizure prophylaxis.

No interaction was observed when busulfan was combined with fluconazole (antifungal agent) or 5 HT3 antiemetics such as ondansetron or granisetron.

 Fertility, pregnancy and lactation

Pregnancy

HPCT is contraindicated in pregnant women; therefore, Busilvex is contraindicated during pregnancy. Studies in animals have shown reproductive toxicity (embryo-fetal lethality and malformations). .

There are no or limited amount of data from the use of busulfan or DMA in pregnant women. A few cases of congenital abnormalities have been reported with low-dose oral busulfan, not necessarily attributable to the active substance, and third trimester exposure may be associated with impaired intrauterine growth.

Women of childbearing potential

Women of childbearing potential have to use effective contraception during and up to 6 months after treatment.

Breast-feeding

It is unknown whether busulfan and DMA are excreted in human milk. Because of the potential for tumorigenicity shown for busulfan in human and animal studies, breast-feeding should be discontinued during treatment with busulfan.

Fertility

Busulfan and DMA can impair fertility in man or woman. Therefore it is advised not to father child during the treatment and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to treatment because of the possibility of irreversible infertility .

 Effects on ability to drive and use machines

Not relevant

 Undesirable effects

Summary of the safety profile

Busilvex in combination with cyclophosphamide or melphalan

In adults

Adverse events information is derived from two clinical trials (n=103) of Busilvex.

Serious toxicities involving the haematologic, hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process. These include infection and Graft-versus host disease (GVHD) which although not directly related, were the major causes of morbidity and mortality, especially in allogeneic HPCT.

Blood and lymphatic system disorders:

Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioning regimen. Therefore all patients experienced profound cytopenia: leucopenia 96%, thrombocytopenia 94%, and anemia 88%. The median time to neutropenia was 4 days for both autologous and allogeneic patients. The median duration of neutropenia was 6 days and 9 days for autologous and allogeneic patients.

Immune system disorders:

The incidence of acute graft versus host disease (a-GVHD) data was collected in OMC-BUS-4 study (allogeneic)(n=61). A total of 11 patients (18%) experienced a-GVHD. The incidence of a-GVHD grades I-II was 13% (8/61), while the incidence of grade III-IV was 5% (3/61). Acute GVHD was rated as serious in 3 patients. Chronic GVHD (c-GVHD) was reported if serious or the cause of death, and was reported as the cause of death in 3 patients.

Infections and infestations:

39% of patients (40/103) experienced one or more episodes of infection, of which 83% (33/40) were rated as mild or moderate. Pneumonia was fatal in 1% (1/103) and life-threatening in 3% of patients. Other infections were considered severe in 3% of patients. Fever was reported in 87% of patients and graded as mild/moderate in 84% and severe in 3%. 47% of patients experienced chills which were mild/moderate in 46% and severe in 1%.

Hepato-biliary disorders:

15% of SAEs involved liver toxicity. HVOD is a recognized potential complication of conditioning therapy post-transplant. Six of 103 patients (6%) experienced HVOD. HVOD occurred in: 8.2% (5/61) allogeneic patients (fatal in 2 patients) and 2.5% (1/42) of autologous patients. Elevated bilirubin (n=3) and elevated AST (n=1) were also observed. Two of the above four patients with serious serum hepatotoxicity were among patients with diagnosed HVOD.

Respiratory, thoracic and mediastinal disorders:

One patient experienced a fatal case of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis in the Busilvex studies.

Paediatric population

Adverse events information are derived from the clinical study in paediatrics (n=55). Serious toxicities involving the hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process.

Immune system disorders:

The incidence of acute graft versus host disease (a-GVHD) data was collected in allogeneic patients (n=28). A total of 14 patients (50%) experienced a-GVHD. The incidence of a-GVHD grades I-II was 46.4% (13/28), while the incidence of grade III-IV was 3.6% (1/28). Chronic GVHD was reported only if it is the cause of death: one patient died 13 months post-transplant.

Infections and infestations:

Infections (documented and non documented febrile neutropenia) were experienced in 89% of patients (49/55). Mild/moderate fever was reported in 76% of patients.

Hepato-biliary disorders :

Grade 3 elevated transaminases were reported in 24% of patients.

Veno occlusive disease (VOD) was reported in 15% (4/27) and 7% (2/28) of the autologous and allogenic transplant respectively. VOD observed were neither fatal nor severe and resolved in all cases.

Busilvex in combination with fludarabine (FB)

In adults

The safety profile of Busilvex combined with fludarabine (FB) has been examined through a review of adverse events reported in published data from clinical trials in RIC regimen. In these studies, a total of 1574 patients received FB as a reduced intensity conditioning (RIC) regimen prior to haematopoietic progenitor cell transplantation.

Myelo-suppression and immuno-suppression were the desired therapeutic effects of the conditioning regimen and consequently were not considered undesirable effects.

Infections and infestations:

The occurrence of infectious episodes or reactivation of opportunistic infectious agents mainly reflects the immune status of the patient receiving a conditioning regimen.

The most frequent infectious adverse reactions were Cytomegalovirus (CMV) reactivation [range: 30.7% - 80.0%], Epstein-Barr Virus (EBV) reactivation [range: 2.3% - 61%], bacterial infections [range: 32.0% - 38.9%] and viral infections [range: 1.3% - 17.2%].

Gastrointestinal disorders:

The highest frequency of nausea and vomiting was 59.1% and the highest frequency of stomatitis was 11%.

Renal and urinary disorders:

It has been suggested that conditioning regimens containing fludarabine were associated with higher incidence of opportunistic infections after transplantation because of the immunosuppressive effect of fludarabine. Late haemorrhagic cystitis occurring 2 weeks post-transplant are likely related to viral infection / reactivation. Haemorrhagic cystitis including haemorrhagic cystitis induced by viral infection was reported in a range between 16% and 18.1%.

Hepato-biliary disorders:

VOD was reported with a range between 3.9% and 15.4%.

The treatment-related mortality/non-relapse mortality (TRM/NRM) reported until day+100 post-transplant has also been examined through a review of published data from clinical trials. It was considered as deaths that could be attributable to secondary side effects after HPCT and not related to the relapse/progression of the underlying haematological malignancies.

The most frequent causes of reported TRM/NRMs were infection/sepsis, GVHD, pulmonary disorders and organ failure.

Overdose

The principal toxic effect is profound myeloablation and pancytopenia but the central nervous system, liver, lungs, and gastrointestinal tract may also be affected.

There is no known antidote to Busilvex other than haematopoietic progenitor cell transplantation. In the absence of haematopoietic progenitor cell transplantation, the recommended dose of Busilvex would constitute an overdose of busulfan. The haematologic status should be closely monitored and vigorous supportive measures instituted as medically indicated.

There have been two reports that busulfan is dialyzable, thus dialysis should be considered in the case of an overdose. Since, busulfan is metabolized through conjugation with glutathione, administration of glutathione might be considered.

It must be considered that overdose of Busilvex will also increase exposure to DMA. In human the principal toxic effects were hepatotoxicity and central nervous system (CNS) effects. CNS changes precede any of the more severe side effects. No specific antidote for DMA overdose is known. In case of overdose, management would include general supportive care.

Pharmacodynamic properties

Pharmacotherapeutic group: Alkyl sulfonates, ATC code: L01AB01.

Mechanism of action

Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent. In aqueous media, release of the methanesulphonate groups produces carbonium ions which can alkylate DNA, thought to be an important biological mechanism for its cytotoxic effect.

Clinical efficacy and safety

Busilvex in combination with cyclophosphamide

In adults

Documentation on the safety and efficacy of Busilvex in combination with cyclophosphamide in the BuCy2 regimen prior to conventional allogeneic and/or autologous HPCT derives from two clinical trials (OMC-BUS-4 and OMC-BUS-3).

Two prospective, single arm, open-label, uncontrolled phase II studies were conducted in patients with haematological disease, the majority of whom had advanced disease.

Diseases included were acute leukaemia past first remission, in first or subsequent relapse, in first remission (high risk), or induction failures; chronic melogenous leukaemia in chronic or advanced phase; primary refractory or resistant relapsed Hodgkin's disease or non-Hodgkin's lymphoma, and myelodysplastic syndrome.

Patients received doses of 0.8 mg/kg busulfan every 6 hours infusion for a total 16 doses followed by cyclophosphamide at 60 mg/kg once per day for two days (BuCy2 regimen).

The primary efficacy parameters in these studies were myeloablation, engraftment, relapse, and survival.

In both studies, all patients received a 16/16 dose regimen of Busilvex. No patients were discontinued from treatment due to adverse reactions related to Busilvex.

All patients experienced a profound myelosuppression. The time to Absolute Neutrophil Count (ANC) greater than 0.5x109 /l was 13 days (range 9-29 days) in allogenic patients (OMC-BUS 4), and 10 days (range 8-19 days) in autologous patients (OMC-BUS 3). All evaluable patients engrafted. There is no primary or secondary graft rejection. Overall mortality and non- relapse mortality at more than 100 days post-transplant was (8/61) 13% and (6/61) 10% in allotransplanted patients, respectively. During the same period there was no death in autologous recipients.

Paediatric population

Documentation of the safety and efficacy of Busilvex in combination with cyclophosphamide in the BuCy4 or with melphalan in the BuMel regimen prior to conventional allogeneic and/or autologous HPCT derives from clinical trial F60002 IN 101 G0.

The patients received the dosing mentioned in section 4.2.

All patients experienced a profound myelosuppression. The time to Absolute Neutrophil Count (ANC) greater than 0.5x109/l was 21 days (range 12-47 days) in allogenic patients, and 11 days (range 10-15 days) in autologous patients. All children engrafted. There is no primary or secondary graft rejection. 93% of allogeneic patients showed complete chimerism. There was no regimen-related death through the first 100-day post-transplant and up to one year post-transplant.

Busilvex in combination with fludarabine (FB)

In adults

Documentation on the safety and efficacy of Busilvex in combination with fludarabine (FB) prior to allogeneic HPCT derives from the literature review of 7 published studies involving 731 patients with myeloid and lymphoid malignancies reporting the use of intravenous busulfan infused once daily instead of four doses per day.

Patients received a conditioning regimen based on the administration of fludarabine immediately followed by single daily dose of 3.2 mg/kg busulfan over 2 or 3 consecutive days. Total dose of busulfan per patient was between 6.4 mg/kg and 9.6 mg/kg.

The FB combination allowed sufficient myeloablation modulated by the intensity of conditioning regimen through the variation of number of days of busulfan infusion. Fast and complete engraftment rates in 80-100% of patients were reported in the majority of studies. A majority of publications reported a complete donor chimerism at day+30 for 90-100% of patients. The long-term outcomes confirmed that the efficacy was maintained without unexpected effects.

Data from a recently completed prospective multicentre phase 2 study including 80 patients, aged 18 to 65 years old, diagnosed with different hematologic malignancies who underwent allo-HCT with an FB (3 days of Busilvex) reduced intensity conditioning regimen became available. In this study, all, but one, patients engrafted, at a median of 15 (range, 10-23) days after allo-HCT. The cumulative incidence of neutrophil recovery at day 28 was 98.8% (95%CI, 85.7-99.9%). Platelet engraftment occurred at a median of 9 (range, 1-16) days after allo-HCT.

The 2-year OS rate was 61.9% (95%CI, 51.1-72.7%)]. At 2 years, the cumulative incidence of NRM was 11.3% (95%CI, 5.5-19.3%), and that of relapse or progression from allo-HCT was 43.8% (95CI, 31.1-55.7%). The Kaplan-Meier estimate of DFS at 2 years was 49.9% (95%CI, 32.6-72.7).

 Pharmacokinetic properties

The pharmacokinetics of Busilvex has been investigated. The information presented on biotransformation and elimination is based on oral busulfan.

Pharmacokinetics in adults

Absorption

The pharmacokinetics of intravenous busulfan was studied in 124 evaluable patients following a 2-hour intravenous infusion for a total of 16 doses over four days. Immediate and complete availability of the dose is obtained after intravenous infusion of busulfan. Similar blood exposure was observed when comparing plasma concentrations in adult patients receiving oral and intravenous busulfan at 1 mg/kg and 0.8 mg/kg respectively. Low inter (CV=21%) and intra (CV=12%) patient variability on busulfan exposure was demonstrated through a population pharmacokinetic analysis, performed on 102 patients.

Distribution

Terminal volume of distribution Vz ranged between 0.62 and 0.85 l/kg.

Busulfan concentrations in the cerebrospinal fluid are comparable to those in plasma although these concentrations are probably insufficient for anti-neoplastic activity.

Reversible binding to plasma proteins was around 7% while irreversible binding, primarily to albumin, was about 32%.

Biotransformation

Busulfan is metabolised mainly through conjugation with glutathione (spontaneous and glutathione-S-transferase mediated). The glutathione conjugate is then further metabolised in the liver by oxidation. None of the metabolites is thought to contribute significantly to either efficacy or toxicity.

Elimination

Total clearance in plasma ranged 2.25 - 2.74 ml/minute/kg. The terminal half-life ranged from 2.8 to 3.9 hours.

Approximately 30% of the administered dose is excreted into the urine over 48 hours with 1% as unchanged busulfan. Elimination in faeces is negligible. Irreversible protein binding may explain the incomplete recovery. Contribution of long-lasting metabolites is not excluded.

Linearity

The dose proportional increase of busulfan exposure was demonstrated following intravenous busulfan up to 1 mg/kg.

Compared to the four times a day regimen, the once-daily regimen is characterized by a higher peak concentration, no drug accumulation and a wash out period (without circulating busulfan concentration) between consecutive administrations. The review of the literature allows a comparison of PK series performed either within the same study or between studies and demonstrated unchanged dose-independent PK parameters regardless the dosage or the schedule of administration. It seems that the recommended intravenous busulfan dose administered either as an individual infusion (3.2 mg/kg) or into 4 divided infusions (0.8 mg/kg) provided equivalent daily plasma exposure with similar both inter-and intrapatient variability. As a result, the control of intravenous busulfan AUC within the therapeutic windows is not modified and a similar targeting performance between the two schedules was illustrated.

Pharmacokinetic/pharmacodynamic relationships

The literature on busulfan suggests a therapeutic AUC window between 900 and 1500 µmol/L.minute per administration (equivalent to a daily exposure between 3600 and 6000 µmol/L.minute). During clinical trials with intravenous busulfan administered as 0.80 mg/kg four-times daily, 90% of patients AUCs were below the upper AUC limit (1500 µmol/L.minute) and at least 80% were within the targeted therapeutic window (900-1500 µmol/L.minute). Similar targeting rate is achieved within the daily exposure of 3600 - 6000 µmol/L.minute following the administration of intravenous busulfan 3.2 mg/kg once daily.

Special populations

Hepatic or renal impairment

The effects of renal dysfunction on intravenous busulfan disposition have not been assessed.

The effects of hepatic dysfunction on intravenous busulfan disposition have not been assessed. Nevertheless the risk of liver toxicity may be increased in this population.

No age effect on busulfan clearance was evidenced from available intravenous busulfan data in patients over 60 years.

Paediatric population

A continuous variation of clearance ranging from 2.49 to 3.92 ml/minute/kg has been established in children from < 6 months up to 17 years old. The terminal half life ranged from 2.26 to 2.52 h.

Inter and intra patient variabilities in plasma exposure were lower than 20% and 10%, respectively.

A population pharmacokinetic analysis has been performed in a cohort of 205 children adequately distributed with respect to bodyweight (3.5 to 62.5 kg), biological and diseases (malignant and non-malignant) characteristics, thus representative of the high heterogeneity of children undergoing HPCT. This study demonstrated that bodyweight was the predominant covariate to explain the busulfan pharmacokinetic variability in children over body surface area or age.

The recommended posology for children as detailed in section 4.2 enabled over 70% up to 90% of children ≥ 9 kg in achieving the therapeutic window (900-1500 µmol/L.minute). However a higher variability was observed in children < 9 kg leading to 60% of children achieving the therapeutic window (900-1500 µmol/L.minute). For the 40% of children < 9 kg outside the target, the AUC was evenly distributed either below or above the targeted limits; i.e. 20% each < 900 and > 1500 µmol/L.min following 1 mg/kg. In this regard, for children < 9 kg, a monitoring of the plasma concentrations of busulfan (therapeutic drug monitoring) for dose-adjustment may improve the busulfan targeting performance, especially in extremely young children and neonates.

Pharmacokinetic/pharmacodynamic relationships:

The successful engraftment achieved in all patients during phase II trials suggests the appropriateness of the targeted AUCs. Occurrence of VOD was not related to overexposure. PK/PD relationship was observed between stomatitis and AUCs in autologous patients and between bilirubin increase and AUCs in a combined autologous and allogeneic patient analysis.

VINCRIS (10ml/1 mg of vincristine sulphate in ml)

 Therapeutic indications

Vincristine sulphate is used either alone or in conjunction with other oncolytic drugs for the treatment of:

1. Leukaemias, including acute lymphocytic leukaemia, chronic lymphocytic leukaemia, acute myelogenous leukaemia and blastic crisis of chronic myelogenous leukaemia.

2. Malignant lymphomas, including Hodgkin's disease and non-Hodgkin's lymphomas.

3. Multiple myeloma.

4. Solid tumours, including breast carcinoma, small cell bronchogenic carcinoma, head and neck carcinoma and soft tissue sarcomas.

5. Paediatric solid tumours, including Ewing's sarcoma, embryonal rhabdomyosarcoma, neuroblastoma, Wilms' tumour, retinoblastoma and medulloblastoma.

6. Idiopathic thrombocytopenic purpura. Patients with true ITP refractory to splenectomy and short-term treatment with adrenocortical steroids may respond to vincristine but the medicinal product is not recommended as primary treatment of this disorder. Recommended weekly doses of vincristine given for 3 to 4 weeks have produced permanent remissions in some patients. If patients fail to respond after 3 to 6 doses, it is unlikely that there will be any beneficial results with additional doses.

 Posology and method of administration

This preparation is for intravenous use only. It should only be administered by individuals experienced in vincristine administration.

FOR INTRAVENOUS USE ONLY

FATAL IF GIVEN BY ANY OTHER ROUTE

Vincristine sulphate is administered by intravenous infusion at weekly intervals.

Great care should be exercised in calculating and administering the dose, as overdosage may be extremely serious or even fatal. The dose should not be increased beyond the level which produces therapeutic benefit. Individual doses should not exceed 2 mg; and white cell counts should be carried out before and after giving each dose.

With the vial presentations, do not add extra fluid to the vial prior to removal of the dose. Withdraw the solution of Vincristine Sulphate into an accurate dry syringe, measuring the dose carefully. Do not add extra fluid to the vial in an attempt to empty it completely.

It is recommended to infuse vincristine sulphate over 5 to 10 minutes after dilution in a 50 ml infusion bag with Sodium Chloride 9 mg/ml (0.9%) Solution for Injection. After administration the vein must be flushed through thoroughly. Care should be taken to avoid extravasation as this may cause local ulceration.

Because of the narrow range between therapeutic and toxic levels and variations in response, the dosage must always be adjusted to the individual.

The following dosage regimens have been used:

Adults: The drug is administered intravenously at weekly intervals. The recommended dose is 1.4 to 1.5 mg/m2 up to a maximum weekly dose of 2 mg.

Children: The suggested dose is 1.4 to 2 mg/m2 given on a weekly basis with a maximum weekly dose of 2 mg. For children weighing 10 kg or less the starting dose should be 0.05 mg/kg administered as a weekly intravenous injection.

Elderly: The normal adult dose is still appropriate in the elderly.

Hepatic Impairment: Because of the hepatic metabolism and biliary excretion of vincristine, reduced doses are recommended in patients with obstructive jaundice or other hepatic impairment. Patients with liver disease sufficient to decrease biliary excretion may experience an increase in the severity of side-effects. A 50 per cent reduction in the dose of vincristine sulphate is recommended for patients having a direct serum bilirubin value above 3 mg/100 ml (51 micromol/l).

Caution: If leakage into surrounding tissue should occur during intravenous administration of vincristine, it may cause considerable irritation. The injection should be discontinued immediately and any remaining portion of the dose should then be introduced into another vein. Local injection of the hyaluronidase and the application of moderate heat to the area of leakage help to disperse the drug and are thought to minimise discomfort and the possibility of cellulitis.

 Contraindications

Intrathecal administration of vincristine sulphate is usually fatal.

Patients with the demyelinating form of Charcot-Marie-Tooth syndrome should not be given vincristine.

Vincristine Sulphate Injection should not be given to patients who have shown signs of hypersensitivity to vincristine or to any of the excipients.

Special warnings and precautions for use

Warnings

This preparation is for intravenous use only. It should be administered by physicians experienced in the administration of vincristine sulphate. Vincristine sulphate should not be given by intrathecal, intramuscular or subcutaneous injection. The intrathecal administration of vincristine sulphate usually results in death.

Syringes containing this product should be labelled 'VINCRISTINE FOR INTRAVENOUS USE ONLY. FATAL IF GIVEN BY OTHER ROUTES'.

After inadvertent intrathecal administration, immediate neurosurgical intervention is required in order to prevent ascending paralysis leading to death. In a very small number of patients, life-threatening paralysis and subsequent death was averted but resulted in devastating neurological sequelae, with limited recovery afterwards.

Based on the published management of these survival cases, if vincristine is mistakenly given by the intrathecal route, the following treatment should be initiated immediately after the injection:

1. Removal of as much CSF as is safely possible through the lumbar access.

2. Insertion of an epidural catheter into the subarachnoid space via the intervertebral space above initial lumbar access and CSF irrigation with lactated Ringer's solution. Fresh frozen plasma should be requested and, when available, 25 ml should be added to every 1 litre of lactated Ringer's solution.

3. Insertion of an intraventricular drain or catheter by a neurosurgeon and continuation of CSF irrigation with fluid removal through the lumbar access connected to a closed drainage system. Lactated Ringer's solution should be given by continuous infusion at 150 ml/h, or at a rate of 75 ml/h when fresh frozen plasma has been added as above.

The rate of infusion should be adjusted to maintain a spinal fluid protein level of 150 mg/dl.

The following measures have also been used in addition but may not be essential:

Folinic acid has been administered intravenously as a 100 mg bolus and then infused at a rate of 25 mg/h for 24 hours, then bolus doses of 25 mg 6-hourly for 1 week. Intravenous administration of glutamic acid 10 g over 24 hours, followed by 500 mg three times daily by mouth for one month. Pyridoxine has been given at a dose of 50 mg 8 hourly by intravenous infusion over 30 minutes. Their roles in the reduction of neurotoxicity are unclear.

Vincristine sulphate is a vesicant and may cause severe local reaction or extravasation, see Caution in Section 4.2, Posology and Method of Administration.

Precautions

Leucopenia is less likely following therapy with vincristine sulphate than is the case with other oncolytic agents. It is usually neuromuscular rather than bone marrow toxicity that limits dosage. However, because of the possibility of leucopenia, both physician and patient should remain alert for signs of any complicating infection. If leucopenia or a complicating infection is present, then administration of the next dose of vincristine sulphate warrants careful consideration. On occasions, these infections may prove fatal.

Acute uric acid nephropathy, which may occur after administration of oncolytic agents, has also been reported with vincristine sulphate.

As vincristine sulphate penetrates the blood-brain barrier poorly, additional agents and routes of administration may be required for central nervous system leukaemias.

The neurotoxic effect of vincristine sulphate may be additive with other neurotoxic agents or increased by spinal cord irradiation and neurological disease. Elderly patients may be more susceptible to the neurotoxic effects of vincristine sulphate.

Both in vivo and in vitro laboratory tests have failed to demonstrate conclusively that this product is mutagenic. Fertility following treatment with vincristine alone for malignant disease has not been studied in humans. Clinical reports of both male and female patients who received multiple-agent chemotherapy that included vincristine indicate that azoospermia and amenorrhoea can occur in postpubertal patients. Recovery occurred many months after completion of chemotherapy in some but not all patients. When the same treatment is administered to prepubertal patients, it is much less likely to cause permanent azoospermia and amenorrhoea.

Patients who received vincristine chemotherapy in combination with anticancer drugs known to be carcinogenic have developed second malignancies. The contributing role of vincristine in this development has not been determined. No evidence of carcinogenicity was found following intraperitoneal administration in rats and mice, although this study was limited.

Care should be exercised to avoid accidental contamination of the eyes as vincristine sulphate is highly irritant and can cause corneal ulceration. The eye should be washed immediately and thoroughly.

Vincristine can cause foetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving vincristine

 Interaction with other medicinal products and other forms of interaction

The neurotoxicity of vincristine sulphate may be additive with that of isoniazid and other drugs acting on the nervous system.

Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids. These reactions have been encountered most frequently when the vinca alkaloid was used in combination with mitomycin-C and may be serious when there is pre-existing pulmonary dysfunction. The onset may be within minutes or several hours after the vinca is injected and may occur up to 2 weeks following the dose of mitomycin. Progressive dyspnoea, requiring chronic therapy, may occur. Vincristine should not be re-administered.

The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations, that included vincristine sulphate, have been reported to reduce blood levels of the anticonvulsant and to increase seizure activity. Although the contribution of the vinca alkaloids has not been established, dosage adjustment of phenytoin, based on serial blood level monitoring, may need to be made when it is used in combination with vincristine.

Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vincristine sulphate with itraconazole (a known inhibitor of the metabolic pathway) has been reported to cause an earlier onset and/or an increased severity of neuromuscular side-effects (see Section 4.8 Undesirable effects). This interaction is presumed to be related to inhibition of the metabolism of vincristine.

When vincristine sulphate is used in combination with L-asparaginase, it should be given 12 to 24 hours before administration of the enzyme in order to minimise toxicity, since administering L-asparaginase first may reduce hepatic clearance of vincristine.

When chemotherapy is being given in conjunction with radiation therapy through portals which include the liver, the use of vincristine should be delayed until radiation therapy has been completed.

Vincristine sulphate appears to increase the cellular uptake of methotrexate by malignant cells and this principle has been applied in high-dose methotrexate therapy.

Severe hepatotoxicity, including veno-occlusive disease has been reported in patients treated with a combination of vincristine and dactinomycin for renal carcinoma.

 Pregnancy and lactation

Usage in pregnancy: Caution is necessary with the use of all oncolytic drugs during pregnancy. Both men and women receiving vincristine should be informed of the potential risk of adverse effects. Reliable methods of contraception or abstinence are recommended.

Vincristine can cause foetal harm following maternal or paternal exposure , although there are no adequate and well-controlled studies (see Section 5.3 Preclinical safety data). Women of childbearing potential should be advised to avoid becoming pregnant while receiving vincristine and use effective contraception during treatment.

If vincristine is used during pregnancy or if the patient becomes pregnant while receiving this medicinal product she should be informed of the potential hazard to the foetus.

There are no or limited amount of data from the use of vincristine sulphate in pregnant women. Studies in animals have shown reproductive toxicity

Usage in lactation: There is insufficient information on the excretion of vincristine sulphate in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from vincristine sulphate therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

 Undesirable effects

In general, adverse reactions are reversible and are related to dosage size and cumulative dosage. The use of small amounts of vincristine daily for long periods is not advised. The most common adverse reaction is alopecia; the most troublesome adverse reactions are neuromuscular in origin.

When single weekly doses of vincristine are employed, the adverse reactions of leucopenia, neuritic pain, and constipation are usually of short duration (i.e. less than 7 days). When the dosage is reduced, these reactions may lessen or disappear. They seem to be increased when the calculated amount of medicinal product is given in divided doses. Other adverse reactions, such as alopecia, sensory loss, paraesthesia, difficulty in walking, slapping gait, loss of deep-tendon reflexes and muscle wasting may persist for at least as long as therapy is continued. Generalised sensorimotor dysfunction may become progressively more severe with continued treatment, but the neuromuscular difficulties may persist for prolonged periods in some patients. Re-growth of hair may occur while maintenance therapy continues.

The following adverse reactions have been reported:

Neoplasms benign, malignant and unspecified: The occurrence of secondary malignancies has been reported rarely in patients treated with vincristine in association with other anticancer drugs known to be carcinogenic.

Blood and lymphatic system disorders: Leucopenia; vincristine does not appear to have any constant or significant effect upon the platelets or the red blood cells, however, anemia and thrombocytopenia have been reported. If thrombocytopenia is present when treatment with vincristine sulphate is begun, it may actually improve before the appearance of marrow remission. Clinical consequences of leucopenia may be fever, infections and sepsis. There have been occasional reports of fatal infections during vincristine therapy.

Endocrine disorders: Rare occurrences of a syndrome attributable to inappropriate anti-diuretic hormone secretion have been observed in patients treated with vincristine. There is a high urinary sodium excretion in the presence of hyponatraemia; renal or adrenal disease, hypotension, dehydration, azotaemia and clinical oedema are absent. With fluid deprivation, improvement occurs in the hyponatraemia and in the renal loss of sodium.

Nervous system disorders (often dose limiting): Neuritic pain, sensory loss, paraesthesia, difficulty in walking, slapping gait, loss of deep tendon reflexes, ataxia, paresis, foot drop and cranial nerve palsies, especially ocular palsies and laryngeal nerve paralysis. Frequently, there appears to be a sequence in the development of neuromuscular side effects. Initially, one may encounter only sensory impairment and paraesthesia. With continued treatment, neuritic pain may appear and later, motor difficulties. No reports have yet been made of any agent that can reverse the neuromuscular manifestations of vincristine sulphate. Convulsions, frequently with hypertension, have been reported in a few patients receiving vincristine. Several instances of convulsions followed by coma have been reported in children.

Eye disorders: Transient cortical blindness and optic atrophy with blindness have been reported.

Ear and labyrinth disorders: Treatment with vinca alkaloids has resulted rarely in both vestibular and auditory damage to the eighth cranial nerve. Manifestations include partial or total deafness, which may be temporary or permanent, and difficulties with balance, including dizziness, nystagmus and vertigo. Particular caution is warranted when vincristine sulphate is used in combination with other agents known to be ototoxic, such as the platinum-containing oncolytics.

Cardiac disorders: Chemotherapy combinations which have included vincristine, when given to patients previously treated with mediastinal radiation, have been associated with coronary artery disease and myocardial infarction. Causality has not been established.

Vascular disorders: Hypertension and hypotension have occurred.

Respiratory disorders: Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids

Gastro-intestinal disorders: Constipation, abdominal cramps, paralytic ileus, diarrhoea, weight loss, nausea, vomiting, oral ulceration, intestinal necrosis and/or perforation, and anorexia have occurred. The constipation which may be encountered responds well to such usual measures as enemas and laxatives. Constipation may take the form of upper colon impaction and the rectum may be found to be empty on physical examination. Colicky abdominal pain, coupled with an empty rectum, may mislead the clinician. A flat film of the abdomen is useful in demonstrating this condition. A routine prophylactic regimen against constipation is recommended for all patients receiving vincristine sulphate. Paralytic ileus may occur, particularly in young children. The ileus will reverse itself upon temporary discontinuance of vincristine and with symptomatic care.

Skin and subcutaneous tissue disorders: Alopecia, rash.

Musculoskeletal, connective tissue and bone disorders: Muscle wasting, jaw pain, pharyngeal pain, parotid gland pain, bone pain, back paid, limb pain and myalgias have been reported; pain in these areas may be severe.

Renal and urinary disorders: Polyuria, dysuria and urinary retention due to bladder atony have occurred. Other drugs known to cause urinary retention (particularly in the elderly) should, if possible, be discontinued for the first few days following administration of vincristine.

General disorders: Rare cases of allergic-type reactions, such as anaphylaxis, rash and oedema, temporally related to vincristine therapy have been reported in patients receiving vincristine as a part of multi-drug chemotherapy regimens.

Other: Fever, headache, injection site reaction

Reporting of suspected adverse reactions

 Overdose

Side effects following the use of vincristine are dose related. In children under 13 years of age, death has occurred following doses of vincristine that were 10 times those recommended for therapy. Severe symptoms may occur in this patient group following dosages of 3 to 4 mg/m2. Adults can be expected to experience severe symptoms after single doses of 3 mg/m2 or more. Therefore, following administration of doses higher than those recommended patients can be expected to experience side-effects in an exaggerated fashion. Supportive care should include the following: (a) prevention of side-effects resulting from the syndrome of inappropriate antidiuretic hormone secretion (this would include restriction of fluid intake and perhaps the administration of a diuretic affecting the function of the loop of Henle and the distal tubule); (b) administration of anticonvulsants; (c) use of enemas or cathartics to prevent ileus (in some instances, decompression of the gastrointestinal tract may be necessary); (d) monitoring the cardiovascular system; (e) determining daily blood counts for guidance in transfusion requirements.

Folinic acid has been observed to have a protective effect in normal mice which were administered lethal doses of vincristine. Isolated case reports suggest that folinic acid may be helpful in treating humans who have received an overdose. A suggested schedule is to administer 100 mg of folinic acid intravenously every 3 hours for 24 hours and then every 6 hours for at least 48 hours. Theoretical tissue levels of vincristine derived from pharmacokinetic data are predicted to remain significantly elevated for at least 72 hours. Treatment with folinic acid does not eliminate the need for the above-mentioned supportive measures.

Most of an intravenous dose of vincristine is excreted into the bile after rapid tissue binding. Because only very small amounts of the drug appear in dialysate, haemodialysis is not likely to be helpful in cases of overdosage.

Enhanced faecal excretion of parenterally administered vincristine has been demonstrated in dogs pre-treated with cholestyramine. There are no published clinical data on the use of cholestyramine as an antidote in humans.

There are no published clinical data on the consequences of oral ingestion of vincristine. Should oral ingestion occur, the stomach should be evacuated followed by oral administration of activated charcoal and a cathartic.

 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agent - vinca alkaloid.

ATC Code: L01C A02

Vincristine is an antineoplastic drug with broad-spectrum anti-tumor activity in man. The drug may act by mitotic inhibition, causing an arrest of cell division in metaphase. The drug is relatively marrow-sparing and is thus suitable for use in combination with other cancer chemotherapeutic agents.

 Pharmacokinetic properties

Vincristine is poorly absorbed orally. The clearance of the drug after rapid intravenous injection follows a triphasic decay pattern: a very rapid steep descent (alpha phase); a narrow-middle region (beta-phase) and a much longer terminal region (gamma phase). The terminal phase half-life of the drug varies from 15-155 hours.

Dosing with the drug more frequently than once weekly is therefore probably unnecessary.

Vincristine is primarily excreted by the biliary route.

Patients with impaired hepatic or biliary function, as evidenced by a raised serum alkaline phosphatase, have been shown to have a significantly prolonged vincristine elimination half-life.