BDLYPO

BDLYPO

doxorubicin

Manufacturer:

BDR Pharmaceutical

Distributor:

Qualimed

Marketer:

Ambica
Full Prescribing Info
Contents
Doxorubicin HCl (pegylated liposomal).
Description
Each mL contains: Doxorubicin Hydrochloride BP 2 mg, Water for Injections BP q.s.
Action
Pharmacology: Pharmacodynamics: The active ingredient of BDLYPO 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.
Pharmacokinetics: BDLYPO is a long-circulating pegylated liposomal formulation of doxorubicin hydrochloride. Pegylated liposomes contain surface-grafted segments of the hydrophilic polymer methoxypolyethylene glycol (MPEG). These linear MPEG groups extend from the liposome surface creating a protective coating that reduces interactions between the lipid bilayer membrane and the plasma components. This allows the BDLYPO liposomes to circulate for prolonged periods in the blood stream. Pegylated liposomes are small enough (average diameter of approximately 100 nm) to pass intact (extravasate) through defective blood vessels supplying tumours. Evidence of penetration of pegylated liposomes from blood vessels and their entry and accumulation in tumours has been seen in mice with C-26 colon carcinoma tumours and in transgenic mice with KS-like lesions. The pegylated liposomes also have a low permeability lipid matrix and internal aqueous buffer system that combine to keep doxorubicin hydrochloride encapsulated during liposome residence time in circulation.
The plasma pharmacokinetics of BDLYPO in humans differ significantly from those reported in the literature for standard doxorubicin hydrochloride preparations. At lower doses (10 mg/m2-20 mg/m2) BDLYPO displayed linear pharmacokinetics. Over the dose range of 10 mg/m2-60mg/m2 BDLYPO displayed non-linear pharmacokinetics. Standard doxorubicin hydrochloride displays extensive tissue distribution (volume of distribution: 700 to 1,100 L/m2) and a rapid elimination clearance (24 to 73 L/h/m2). In contrast, the pharmacokinetic profile of BDLYPO indicates that BDLYPO is confined mostly to the vascular fluid volume and that the clearance of doxorubicin from the blood is dependent upon the liposomal carrier. Doxorubicin becomes available after the liposomes are extravasated and enter the tissue compartment.
At equivalent doses, the plasma concentration and AUC values of BDLYPO which represent mostly pegylated liposomal doxorubicin hydrochloride (containing 90% to 95% of the measured doxorubicin) are significantly higher than those achieved with standard doxorubicin hydrochloride preparations.
BDLYPO should not be used interchangeably with other formulations of doxorubicin hydrochloride.
Indications/Uses
BDLYPO 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.
BDLYPO 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).
It 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.
Dosage/Direction for Use
BDLYPO should only be administered under the supervision of a qualified oncologist specialised in the administration of cytotoxic agents.
BDLYPO exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin hydrochloride.
It 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.
BDLYPO 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.
Dosage Modifications: Because drugs exhibits nonlinear pharmacokinetics at 50 mg/m2, dosage adjustments may cause non-proportionally greater change in plasma level and drug exposure.
If grade 2 or higher adverse events occur, decreases dosage or delay therapy; do not increase dosage later.
In hepatic impairment, reduce normal dosage by 50% if serum bilirubin level is 1.2 to 3 mg/dL or by 25% if bilirubin level exceeds 3 mg/dL.
Modifications According to Toxicity Level: Grade 1 Palmar-Plantar Erythrodysesthesia [hand-foot syndrome (HFSI)]: Continue dosing. If patient previously had Grade 3 or 4 toxicity, delay dosing up to 2 weeks and decrease dosage by 25%.
Grade 2 HFS: Delay dosing up to 2 weeks or until resolved to Grade 0 to 1. If no resolution occurs after 2 weeks, discontinue drug. If resolved to Grade 0 to 1 within 2 weeks and there are no Grade 3 to 4 HFS toxicities, continue treatment at previous dosage and return to original dosing interval. If patient previously experienced Grade 3 to 4 toxicity, continue treatment with 25% dosage reduction and return to original dosing interval.
Grade 3 HFS: Delay dosing up to 2 weeks or until resolved to Grade 0 to 1. Decrease dosage by 25% and return to original dosing interval. If no resolution occurs after 2 weeks, discontinue drug.
Grade 4 HFS: Delay dosing up to 2 weeks or until resolved to Grade 0 to 1. Decrease dosage by 25% and return to original dosing interval. If no resolution occurs after 2 weeks, discontinue drug.
Grade 1 hematologic toxicity (absolute neutrophil count [ANC] 1,500 to 1,900/mm3; platelets, 75,000 to 1,50,000/mm3); No dosage reduction is necessary.
Grade 2 hematologic toxicity (ANC 1,000 to less than 1,500/mm3, platelets, 50,000 to less than 75,000/mm3): Wait until ANC is 1,500/mm3 or above and platelet count is 75,000/mm3 or above, then redose with no dosage reduction.
Grade 4 hematologic toxicity (ANC below 500/mm3; platelets below 25,000/mm3): Wait until ANC is 1500/mm3; or above and platelet count is 75,000/mm3 or above, then redose at 25% dosage reduction or continue full dose with cytokine support.
Grade 1 stomatitis: Redose unless patient experienced previous Grade 3 or 4 toxicity. If so, delay dosing up to 2 weeks and decrease dosage by 25%. Return to original dosing interval.
Delay dosing up to 2 weeks or until resolved to Grade 0 to 1. If no resolution occurs after 2 weeks, discontinue drug. If resolved to Grade 0 to 1 within 2 weeks and there is no Grade 3 to 4 stomatitis, continue treatment at previous dosage and return to original dosing interval. If patients previously experienced Grade 3 to 4 toxicity, continue treatment with 25% dosage reduction and return to original dosing interval.
Grade 3 stomatitis: Delay dosing up to 2 weeks or until resolved to Grade 0 to 1. Decrease dosage by 25% dosage reduction and return to original dosing interval. If no resolution occurs after 2 weeks, discontinue drug.
Grade 4 stomatitis: Delay dosing up to 2 weeks or until resolved to Grade 0 to 1. Decrease dosage by 25% and return to original dosing interval. If no resolution occurs after 2 weeks, discontinue drug.
Overdosage
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.
Toxicity and Overdose: Acute overdose causes increased mucositis, leucopenia and thrombocytopenia.
Treat severely myelosupressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.
Contraindications
Hypersensitivity to the active substance or to α-(2-[1,2-distearoyl-snglycero(3)phosphooxy]ethylcarbamoyl)-ω-methoxypoly(oxyethylen)-40 sodium salt (MPEG-DSPE), fully hydrogenated soy phosphatidylcholine (HSPC), cholesterol, ammonium sulphate, sucrose, histidine, water for injections, hydrochloric acid & sodium hydroxide.
BDLYPO must not be used to treat AIDS-KS that may be treated effectively with local therapy or systemic alfa-interferon.
Warnings
Irreversible myocardial toxicity leading to heart failure may occur as total dosage approaches 550 mg/m2. Previous use of other anthracyclines or anthracenediones increases risk of cardiotoxicity and reduces total dose that can be given without cardiotoxicity. Cardiotoxicity also may occur at lower cumulative doses in patients who have had previous mediastinal irradiation or are receiving cyclophosphamide concurrently.
Drug should be given to patients with history of cardiovascular disease only when benefits overweighs risk.
Acute infusion-related reactions have occurred in up to 10% of patients. These reactions usually resolve within several hours to 1 day after infusion is solved or terminated. Serious and sometimes life-threatening or fatal allergic infusion reactions have been reported.
Drugs to treat such reactions, as well as emergency equipment, should be available for immediate use.
Drug should be given at initial rate 1 mg/minute to minimize the risk of infusion reactions.
Severe bone marrow depression may occur.
Dosage should be reduced in patients with impaired hepatic function.
Accidental substitution of drug for doxorubicin hydrochloride has caused severe side effects.
Doxorubicin Liposomal should not be substituted for conventional doxorubicin on per mg basis.
Special Precautions
Special Considerations: Monitor patient carefully. Most adverse events can be managed by reducing dosage or delaying dosing.
Monitor liver function tests frequently.
Carefully monitor cardiac function to minimize cardiotoxicity risk. In adults, severe cardiotoxicity may occur precipitously, without antecedent ECG changes.
Although bone marrow depression may be moderate and reversible, monitor CBC with differential frequently.
Observe for signs and symptoms of HPS (swelling, pain, erythema and for some patients, skin desquamation on hands and feet) which may become severe, requiring drug withdrawal.
Adverse Reactions
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 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 (see Dosage & Administration). 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 BDLYPO 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 (BDLYPO + bortezomib) were nausea (40%), diarrhoea (35%), neutropaenia (33%), thrombocytopaenia (29%), vomiting (28%), fatigue (27%), and constipation (22%).
Drug Interactions
No formal medicinal product interaction studies have been performed with BDLYPO, 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. BDLYPO, 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.
Caution For Usage
Preparation and Administration: Follow hazardous drug guidelines for preparation, handling and administration.
Consider pretreatment with allopurinol because of hyperuricemia risk.
Drug causes lower incidence of emesis than doxorubicin hydrochloride, but patients still require pretreatment with or concomitant use of antiemetics.
Liposomal encapsulation can substantially affect drug's functional properties. Also, different liposomal products may vary in chemical composition and physical form. Do not substitute.
Drug is not a clear solution but a translucent, red liposomal dispersion.
Do not give drug I.M. or subcutaneously or as bolus injection or undiluted solution. Do not mix with other drugs or use bacteriostatic agents (such as benzyl alcohol). Do not use in-line fillers.
Dilute appropriate dose (to maximum of 90 mg) in 250 mL D5W. Do not use other diluents. Strictly observe aseptic technique (drug contains no preservative or bacteriostatic agent).
Rapid infusion may increase risk of infusion-related reactions (most of which occur during first infusion). Administer at initial rate of 1 mg/minute to help minimize risk of infusion reactions. If no infusion reaction occurs, increase rate to complete infusion over 1 hour.
Always administer into free-flowing I.V. line with good blood return.
Drug is irritant (but not vesicant). Take precautions to avoid extravasations. With I.V. use, extravasations may occur with or without accompanying stinging or burning sensation, even if blood returns well on needle aspiration. If signs or symptoms of extravasations occur, stop infusion immediately and restart in another vein. Applying ice over extravasations site for 30 minutes may help relieve local reaction.
Storage
Store at temperatures between 2° to 8°C.
Do not freeze.
ATC Classification
L01DB01 - doxorubicin ; Belongs to the class of cytotoxic antibiotics, anthracyclines and related substances. Used in the treatment of cancer.
Presentation/Packing
Soln for infusion (conc) (vial) 2 mg/mL x 10 mL x 1's.
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