Eriox 20mg / 1.5ml. 80mg / 6ml Infusion. Solution

1. Breast cancer: ERIOX, in combination with doxorubicin, is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition. ERIOX monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer, after failure of cytotoxic therapy. ERIOX, in combination with capecitabine, is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.

2. Non-small cell lung cancer: ERIOX, in combination with cisplatin, is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer, who have not previously received chemotherapy for this condition. ERIOX is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer, even after failure of platinum-based chemotherapy.

3. Ovarian cancer: ERIOX is indicated, after failure of first-line or subsequent chemotherapy, for treatment of metastatic carcinoma of the ovary.

4. Prostate cancer: ERIOX in combination with prednisone or prednisolone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.

ERIOX should be administered by intravenous infusion only. A premedication consisting of a corticosteroid (see below for prostate cancer), such as oral dexamethasone 16 mg per day (e.g. 8 mg twice daily) for 3 days, starting one day prior to ERIOX administration, unless contra-indicated, can be used.

1. Breast cancer: In first-line treatment, ERIOX 75 mg/mu00b2 is administered in combination therapy with doxorubicin (50 mg/mu00b2). For the second line monotherapy for previously treated patients, the recommended dosage of ERIOX therapy is 100 mg/mu00b2 in monotherapy. In combination with capecitabine, the recommended dose of ERIOX is 75 mg/mu00b2 every three weeks, combined with capecitabine at 1250 mg/mu00b2 orally twice daily (within 30 minutes after a meal) for 2 weeks followed by 1-week rest period.

2. Non-small cell lung cancer: In combination therapy (chemotherapy nau00efve patients) the recommended dosage regimen is ERIOX 75 mg/mu00b2 immediately followed by cisplatin 75 mg/mu00b2 over 30-60 minutes. In monotherapy (for previously treated patients) the recommended dosage of ERIOX therapy is 100 mg/mu00b2 as a single agent.

3. Ovarian cancer: The recommended dosage of ERIOX therapy is 100 mg/mu00b2.

4. Prostate cancer: The recommended dose of ERIOX is 75 mg/mu00b2. Prednisone or prednisolone 5 mg orally twice daily is administered continuously.

Patients should be observed closely, especially during the first and second infusion of ERIOX, because of the risk of hypersensitivity reactions.

ERIOX is contraindicated in patients who have a history of severe hypersensitivity reactions to the medicine or polysorbate 80. ERIOX should not be used in patients with baseline neutrophil count of <1500 cells/mmu00b3. Pregnancy and lactation as ERIOX is teratogenic in animals. The safe use of ERIOX in children has not been established. ERIOX should not be used in patients with severe liver impairment since there is no data available (see WARNINGS and SPECIAL PRECAUTIONS and DOSAGE AND DIRECTIONS FOR USE). Contraindications for other medicines also apply when combined with ERIOX.

ERIOX should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. The incidence of treatment-related mortality associated with ERIOX therapy is increased in patients with abnormal liver function and in patients receiving higher doses. ERIOX should generally not be given to patients with serum bilirubin levels > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase levels >2.5 x ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity and toxic death. Patients with isolated elevations of transaminase >1.5 x ULN also had a higher rate of febrile neutropenia grade 4, but did not have an increased incidence of toxic death. Bilirubin, AST or ALT and alkaline phosphatase values should be obtained prior to each cycle of ERIOX therapy and reviewed by the treating physician. ERIOX therapy should not be given to patients with neutrophil counts of <1500 cells/mmu00b3. In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving ERIOX.

There have been no formal clinical studies to evaluate the drug interactions of ERIOX. In vitro studies have shown that the metabolism of ERIOX may be modified by the concomitant administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit the enzyme competitively) cytochrome P450-3A such as cyclosporine, ketoconazole, erythromycin and troleandomycin. As a result, caution should be exercised when treating patients with these drugs as concomitant therapy, since there is a potential for a significant interaction. ERIOX is highly protein bound (> 95 %). Although the possible in vivo interaction of ERIOX with concomitantly administered medication has not been investigated formally, in vitro interactions with tightly protein-bound drugs such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of ERIOX. In addition, dexamethasone did not affect protein binding of ERIOX. ERIOX did not influence the binding of digitoxin. In the doxorubicin/ERIOX combination, the clearance of ERIOX was increased. Dexamethasone did not affect protein binding of ERIOX. When used in combination, ERIOX does not influence the clearance of doxorubicin and the plasma levels of doxorubicinol (a doxorubicin metabolite). However, the clearance of ERIOX was increased. Clearance of ERIOX in combination therapy with cisplatin was similar to that observed following monotherapy. The pharmacokinetic profile of cisplatin administered shortly after ERIOX infusion is similar to that observed with cisplatin alone. There is no effect by capecitabine on the pharmacokinetics of docetaxel (C max and AUC) and no effect by docetaxel on the pharmacokinetics of the main capecitabine metabolite 5'-DFUR. There is no effect of prednisone on the pharmacokinetics of ERIOX.

Pregnancy and lactation are contra-indicated as ERIOX is teratogenic in animals.

Not provided in the text.

Neutropenia is the most frequent adverse reaction of ERIOX and occurs in almost all patients. Severe neutropenia (grade 3 - 4) occurred in 99 % of patients on combination therapy with doxorubicin. Neutrophil nadirs occurred at a median of 7 days but this interval may be shorter in heavily pre-treated patients. Frequent monitoring of complete blood counts should be conducted on all patients receiving ERIOX. Patients should be re-treated with ERIOX only after neutrophils recover to a level > 1500 cells/mmu00b3. In the case of severe neutropenia (<500 cells/mmu00b3 for seven days or more) during a course of ERIOX therapy, a reduction in dose for subsequent courses of therapy and the use of appropriate symptomatic measures are recommended.

Hypersensitivity reactions: Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of ERIOX, thus facilities for the treatment of hypotension and bronchospasm should be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require interruption of therapy. However, more severe reactions, such as hypotension with a reduction of more than 20 mmHg, bronchospasm or generalised rash/erythema require immediate discontinuation of the infusion and appropriate symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with ERIOX.

In case of overdose, the patient should be kept in a specialised unit and vital functions closely monitored. There is no known antidote for ERIOX overdosage. The primary anticipated complications of overdosage would consist of neutropenia, mucositis, cutaneous reactions and paraesthesia. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.