PHARMORUBICIN CS INJECTION 10 mg/5 ml

INJECTION

**4.2 Dose and method of administration** **Dosage** **NOTE:** The recommended lifetime cumulative dose limit of Pharmorubicin is 900 mg/m2 body surface area. _**Intravenous Administration**_ Under conditions of normal recovery from drug-induced toxicity (particularly bone marrow depression and stomatitis), the recommended dosage schedule in adults, as described below, is as a single intravenous injection administered at 21 day intervals. Standard doses are 75 to 90 mg/m2. Pharmorubicin produces predominantly haematological dose limiting toxicities which are predicted from the known dose–response profile of the drug. Based on the patient’s haematological status the physician should determine the choice of dose. Higher doses, up to 135 mg/m2 as a single agent and 120 mg/m2 in combination, every 3–4 weeks have been effective in the treatment of breast cancer. In the adjuvant treatment of early breast cancer patients with positive lymph nodes, doses ranging from 100 mg/m2 to 120 mg/m2 every 3–4 weeks are recommended. Careful monitoring in regards to increased myelosuppression, nausea, vomiting and mucositis are recommended in this high dose setting. Consideration should be given to the administration of lower starting doses (not exceeding 75–90 mg/m2) for heavily pre-treated patients, patients with pre-existing bone marrow depression or in the presence of neoplastic bone marrow infiltration. If Pharmorubicin is used in combination with other cytotoxic drugs with potentially overlapping toxicities, the recommended dose per cycle should be reduced accordingly. _**Intravesical Administration**_ For the treatment of papillary transitional cell carcinoma of the bladder, a therapy of 8 weekly instillations of 50 mg is recommended. In the case of local toxicity (chemical cystitis) a dose reduction up to 30 mg is advised. For carcinoma _in-situ_, depending on the individual tolerability of the patient, the dose may be increased up to 80 mg. For prophylaxis of recurrences after transurethral resection of superficial tumours, 4 weekly administrations of 50 mg followed by 11 monthly instillations at the same dosage are recommended. To avoid undue dilution with the urine, the patient should be instructed not to drink any fluid in the twelve hours prior to instillation. Intravesical administration is not suitable for the treatment of invasive tumours which have penetrated the muscular layer of the bladder wall. **Method of Administration** Pharmorubicin is intended for intravenous or intravesical administration only. It must not be administered by the intramuscular, subcutaneous or oral routes. **_Intravenous Administration_** Care in the intravenous administration of Pharmorubicin will reduce the chance of perivenous infiltration (see Section 4.4 Special warnings and precautions for use, Extravasation – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). It may also decrease the chance of local reactions, such as urticaria and erythematous streaking. It is recommended that Pharmorubicin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection USP or 5% Glucose Injection USP. The tubing should be attached to a Butterfly needle inserted preferably into a large vein. The rate of administration is dependent on the size of the vein and the dosage. To minimise the risk of thrombosis or perivenous extravasation, the usual infusion times range between 3 and 20 minutes. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration. A burning or stinging sensation may be indicative of perivenous infiltration and the infusion should be immediately terminated and restarted in another vein (see Section 4.4 Special warnings and precautions for use, _Extravasation_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). **_Intravesical Administration_** Pharmorubicin, to be instilled using a catheter, should be retained intravesically for 1 hour. The patient should be instructed to void at the end of this time. During instillation, the pelvis of the patient should be rotated to ensure extensive contact of the solution with the vesical mucosa. **Dosage Adjustment** **_Renal Impairment:_** While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, lower starting doses should be considered in patients with severe renal impairment (serum creatinine >5 mg/dL). _**Hepatic Impairment:**_ As clinical toxicity may be increased by the presence of impaired liver function, Pharmorubicin dosage must be reduced if hepatic function is impaired, according to the following table: Serum Bilirubin LevelsRecommended Dose20 – 50 micromole/L1/2 normal doseOver 50 micromole/L1/4 normal dose **_Other Special Populations:_** Haematological toxicity may require dose reduction, delay or suspension of Pharmorubicin therapy. Lower doses may be necessary if Pharmorubicin is used concurrently with other anti-neoplastic agents.