Natdox-LP Dosage/Direction for Use

Doxorubicin hydrochloride liposome Injection should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents.
Liposomal doxorubicin exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride.
Posology: Breast cancer/Ovarian cancer: Doxorubicin hydrochloride liposome Injection is administered intravenously at a dose of 50 mg/m² once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment.
Multiple myeloma: Doxorubicin hydrochloride liposome Injection is administered at 30 mg/m² on day 4 of the bortezomib 3 week regimen as a 1 hour infusion administered immediately after the bortezomib infusion. The bortezomib regimen consists of 1.3 mg/m² on days 1, 4, 8, and 11 every 3 weeks. The dose should be repeated as long as patients respond satisfactorily and tolerate treatment. Day 4 dosing of both medicinal products may be delayed up to 48 hours as medically necessary. Doses of bortezomib should be at least 72 hours apart.
AIDS-related KS: Doxorubicin hydrochloride liposome Injection 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 Precautions and Adverse Reactions), immediately discontinue the infusion, give appropriate premedications (antihistamine and/or short acting corticosteroid) and restart at a slower rate.
Guidelines for doxorubicin hydrochloride liposome Injection dose modification: To manage adverse events such as palmar-plantar erythrodysesthesia (PPE), stomatitis or haematological toxicity, the dose may be reduced or delayed. Guidelines for doxorubicin hydrochloride liposome Injection dose modification secondary to these adverse effects are provided in the tables as follows. The toxicity grading in these tables is based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC).
The tables for PPE (Table 2) and stomatitis (Table 3) provide the schedule followed for dose modification in clinical trials in the treatment of breast or ovarian cancer (modification of the recommended 4 week treatment cycle): if these toxicities occur in patients with AIDS-related KS, the recommended 2 to 3 week treatment cycle can be modified in a similar manner.
The table for haematological toxicity (Table 4) provides the schedule followed for dose modification in clinical trials in the treatment of patients with breast or ovarian cancer only. Dose modification in patients with AIDS-KS is addressed in Adverse Reactions. (See Tables 2, 3 and 4.)

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For multiple myeloma patients treated with doxorubicin hydrochloride liposome Injection in combination with bortezomib who experience PPE or stomatitis, the Doxorubicin hydrochloride liposome Injection dose should be modified as described in previous Tables 2 and 3 respectively.
Table 5 as follows provides the schedule followed for other dose modifications in the clinical trial in the treatment of patients with multiple myeloma receiving doxorubicin hydrochloride liposome Injection and bortezomib combination therapy. For more detailed information on bortezomib dosing and dosage adjustments, see the SPC for bortezomib. (See Table 5.)

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Hepatic Impairment: Liposomal doxorubicin pharmacokinetics determined in a small number of patients with elevated total bilirubin levels do not differ from patients with normal total bilirubin; however, until further experience is gained, the doxorubicin hydrochloride liposome Injection dosage in patients with impaired hepatic function should be reduced based on the experience from the breast and ovarian clinical trial programs as follows: at initiation of therapy, if the bilirubin is between 1.2-3.0 mg/dl, the first dose is reduced by 25%. If the bilirubin is > 3.0 mg/dl, the first dose is reduced by 50%. If the patient tolerates the first dose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can be increased to the next dose level, i.e., if reduced by 25% for the first dose, increase to full dose for cycle 2; if reduced by 50% for the first dose, increase to 75% of full dose for cycle 2. The dosage can be increased to full dose for subsequent cycles if tolerated. Doxorubicin hydrochloride liposome Injection can be administered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymes up to 4 x the upper limit of the normal range. Prior to doxorubicin hydrochloride liposome Injection administration, evaluate hepatic function using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase, and bilirubin.
Renal Impairment: As doxorubicin is metabolised by the liver and excreted in the bile, dose modification should not be required. Population pharmacokinetic data (in the range of creatinine clearance tested of 30-156 ml/min) demonstrate that doxorubicin hydrochloride liposome Injection clearance is not influenced by renal function. No pharmacokinetic data are available in patients with creatinine clearance of less than 30 ml/min.
AIDS-related KS patients with splenectomy: As there is no experience with doxorubicin hydrochloride liposome Injection in patients who have had splenectomy, treatment with doxorubicin hydrochloride liposome Injection is not recommended.
Paediatric population: The experience in children is limited. Doxorubicin hydrochloride liposome Injection is not recommended in patients below 18 years of age.
Elderly: Population based analysis demonstrates that age across the range tested (21-75 years) does not significantly alter the pharmacokinetics of doxorubicin hydrochloride liposome Injection.
Method of administration/Direction for Reconstitution: Doxorubicin hydrochloride liposome Injection is administered as an intravenous infusion. For further instructions on preparation and special precautions for handling see Special precautions for disposal and other handling under Cautions for Usage.
Do not administer doxorubicin hydrochloride liposome Injection as a bolus injection or undiluted solution. It is recommended that the doxorubicin hydrochloride liposome Injection infusion line be connected through the side port of an intravenous infusion of 5% (50 mg/ml) dextrose to achieve further dilution and minimize the risk of thrombosis and extravasation. The infusion may be given through a peripheral vein. Do not use with in-line filters. Doxorubicin hydrochloride liposome Injection must not be given by the intramuscular or subcutaneous route (see Special precautions for disposal and other handling under Cautions for Usage).
For doses < 90 mg: dilute doxorubicin hydrochloride liposome Injection in 250 ml 5% (50 mg/ml) dextrose solution for infusion.
For doses ≥ 90 mg: dilute doxorubicin hydrochloride liposome Injection in 500 ml 5% (50 mg/ml) dextrose solution for infusion.
For shelf-life and storage conditions of the reconstituted preparation, see Storage.
Breast cancer/Ovarian cancer/Multiple myeloma: To minimize the risk of infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent doxorubicin hydrochloride liposome Injection infusions may be administered over a 60-minute period.
In those patients who experience an infusion reaction, the method of infusion should be modified as follows: 5% of the total dose should be infused slowly over the first 15 minutes. If tolerated without reaction, the infusion rate may then be doubled for the next 15 minutes. If tolerated, the infusion may then be completed over the next hour for a total infusion time of 90 minutes.
AIDS-related KS: The dose of doxorubicin hydrochloride liposome Injection is diluted in 250 ml 5% (50 mg/ml) dextrose solution for infusion and administered by intravenous infusion over 30 minutes.