LIPODOX

Sun Pharma Global FZE

For the use of an Oncologist or a Cancer Hospital or a Laboratory only.Doxorubicin Hydrochloride Liposome InjectionLIPODOX  LIPODOX 50(Pegylated Liposomal)

FULL PRESCRIBING INFORMATION: CONTENTS*

• Dosage Form:
• Composition:
• Description:
  • Clinical Pharmacology
  • Mechanism of Action
  • Pharmacokinetics
• Indications:
• Contraindications:
• Warnings and Precautions:
• Pregnancy & Lactation
• Drug Interactions:
• Side effects:
• Overdosage:
• Dosage and Administration:
• Incompatibilities:
• Storage & Handling:
• Expiry Date:
• Presentation:
• Dear Healthcare Provider letter
• PRINCIPAL DISPLAY PANEL-Lipodox
• PRINCIPAL DISPLAY PANEL-Lipodox 50

FULL PRESCRIBING INFORMATION

Dosage Form:

Composition:

Description:

Lipodox is doxorubicin hydrochloride encapsulated in long circulating pegylated Liposomes. Liposomes are microscopic vesicles composed of a phospholipid bilayer that are capable of encapsulating active drugs. The pegylated Liposomes of doxorubicin are formulated with surface bound methoxypolyethylene glycol (MPEG), a process often referred to as pegylation, to protect liposomes from detection by the mononuclear phagocyte system (MPS) and to increase blood circulation time.

Pegylated liposomes have a half life of approximately 55 hours in humans. They are stable in blood and direct measurement of liposomal doxorubicin shows that atleast 90% of the drug remains liposome encapsulated during circulation.

It is hypothesized that because of their small size and persistence in the circulation, the pegylated doxorubicin liposomes are able to penetrate the altered and often compromised vasculature of tumors. Once the pegylated liposomes distribute to the tissue compartment, the encapsulated doxorubicin HCL becomes available. The exact mechanism of release is not understood.

Clinical Pharmacology

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. It is indicated for the treatment of metastatic carcinoma of the ovary, metastatic breast cancer and AIDS related Kaposis Sarcoma (KS).

Mechanism of Action

Pharmacokinetics

Indications:

Lipodox is indicated for the treatment of metastatic carcinoma of the ovary in patients with disease that is refractory to both paclitaxel and platinum based chemotherapy regimens. Refractory disease is defined as disease that has progressed while on treatment or within 6 months of completing treatment.

Lipodox is indicated as monotherapy for the treatment of metastatic breast cancer, where there is an increased cardiac risk.

Contraindications:

• History of hypersensitivity reactions to the conventional formulation of doxorubicin or to any other components of this formulation.
• Nursing mothers.

Warnings and Precautions:

Experience with large cumulative doses of liposomal doxorubicin is very limited. Liposomal doxorubicin’s cardiac risk and its risk compared to conventional doxorubicin formulations have not been  adequately evaluated. At present, therefore, the warnings related to the use of conventional formulations of doxorubicin should be observed.

It is recommended that all patients receiving liposomal doxorubicin 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 liposomal doxorubicin 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 liposomal doxorubicin therapy and repeated periodically during treatment. The evaluation of left ventricular function is considered to be mandatory before each additional administration of liposomal doxorubicin that exceeds a lifetime cumulative anthracycline dose of 450 mg/m².

Whenever cardiomyopathy is suspected i.e., the left ventricular ejection fraction has substantially decreased relative to pretreatment 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.

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 liposomal doxorubicin therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury.

Caution should be observed in patients who have received other anthracyclines and the total dosage of doxorubicin hydrochloride given should take into account any previous or concomitant therapy with other anthracyclines or related compounds. Cardiac toxicity may also occur at cumulative anthracycline doses lower than 450 mg/m² in patients with prior mediastinal irradiation or in those receiving concurrent cyclophosphamide therapy.

Congestive cardiac failure due to cardiomyopathy may occur suddenly, without prior ECG changes and may also be encountered several weeks after discontinuation of therapy. Patients with a history of cardiovascular disease should be administered liposomal doxorubicin only when the potential benefit of treatment outweighs the risk.

Acute infusion related reactions characterized by flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea and/or hypotension have been reported with liposomal doxorubicin. In most patients these reactions resolve over the course of several hours to a day once the infusion is terminated or when the rate of infusion is slowed.

Liposomal doxorubicin should be administered at the initial rate of 1 mg/min to minimize the risk of infusion reactions.

Serious and sometimes life threatening or fatal allergic/anaphylactoid like infusion reactions have been reported. Medications to treat such reactions and emergency equipment should be available for immediate use.

Moderate and reversible myelosupression has been observed in ovarian and breast cancer patients who received liposomal doxorubicin with anemia being the most common hematologic adverse event followed by leucopenia, thrombocytopenia and neutropenia.

Myelosuppression can be a dose limiting adverse event in patients with AIDS associated with Kaposi s sarcoma who already present with baseline myelosuppression. Again leucopenia seemed to be the most common haematological adverse event in this population.

Because of the potential for bone marrow suppression, careful hematologic monitoring including white blood cell, neutrophil, platelet counts and hemoglobin/hematocrit should be done. Hematologic toxicity may require dose reduction or delay or suspension of therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in the discontinuation of treatment and in rare cases death. Hematologic toxicity may be more severe when liposomal doxorubicin is administered in combination with other agents that cause bone marrow suppression. Dosage should be reduced in patients with impaired hepatic function.

Prior to liposomal doxorubicin administration evaluation of hepatic function is recommended using conventional clinical laboratory tests such as SGOT, SGPT, alkaline phosphatase and bilirubin.

Radiation induced toxicity to the myocardium, mucosae, skin and liver have been reported to be increased by the administration of doxorubicin HCl.

Given the difference in pharmacokinetic profiles and dosing schedules, liposomal doxorubicin should not be used interchangeably with other formulations of doxorubicin hydrochloride.

Pregnancy & Lactation

Liposomal doxorubicin is embryotoxic at doses of 1 mg/kg/day in rats and embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about one eighth the 50 mg/m² human dose on a mg/m² basis).

There are no adequate and well controlled studies in pregnant women. If Lipodox is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs during the first few months following treatment with Lipodox, the prolonged half life of the drug must be considered. Women of child bearing potential should be advised to avoid pregnancy.

It is not known whether this drug is excreted in human milk. Because many drugs, including anthracyclines, are excreted in breast milk and because of the potential of serious adverse effects in nursing infants from Lipodox, mothers should discontinue nursing prior to taking this drug.

Drug Interactions:

Although no formal studies have been done with liposomal doxorubicin, caution should be exercised in the concomitant use of drugs known to interact with the conventional form of doxorubicin.

Liposomal doxorubicin, like other doxorubicin hydrochloride preparations, may potentiate the toxicity of other anticancer therapies. During clinical trials in patients with solid tumors (including breast and ovarian cancer) who have received concomitant cyclophosphamide or taxanes, no new additive toxicities were noted.

Exacerbation of cyclophosphamide induced hemorrhagic cystitis and enhancement of hepatotoxicity of 6-mercaptopurine have also been reported with standard doxorubicin hydrochloride.

Side effects:

The adverse effects reported in 1-5% of breast cancer patients are breast pain, leg cramps, edema, leg edema, peripheral neuropathy, oral pain, ventricular arrhythmia, folliculitis, bone pain, musculoskeletal pain, cold sores (non herpetic), fungal infection, epistaxis, upper respiratory tract infection, bullous eruption, dermatitis, erythematous rash, nail disorder, scaly skin, lacrimation and blurred vision.

AIDS-KS patients: Adverse effects associated with the discontinuation of treatment are bone marrow suppression, cardiac adverse events, infusion related reactions, toxoplasmosis, palmar-plantar erythrodysesthesia, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumour and allergy to penicillins.

Adverse reactions reported in ≥ 5% of patients include hematological side effects such as neutropenia, anemia, thrombocytopenia and non hematological side events such as nausea, asthenia, fever, alopecia, increased alkaline phosphatase, vomiting, hypochromic anemia, diarrhea, stomatitis and oral moniliasis.

Side effects reported in 1-5% of patients which may be possibly drug related are headache, back pain, infection, allergic reaction, chills, chest pain, hypotension, tachycardia, herpes simplex, rash, itching, mouth ulceration, glossitis, constipation, aphthous stomatitis, anorexia, dysphagia, abdominal pain, hemolysis, increased prothrombin time, increased SGPT, weight loss, hypocalcemia, hyperbilirubinemia, hyperglycemia, dyspnea, albuminuria, pneumonia, retinitis, emotional lability, dizziness and somnolence.

Overdosage:

Acute overdosage with doxorubicin causes increases in mucositis, leukopenia and thrombocytopenia.

Dosage and Administration:

The median time to response in clinical trials was reported to be 4 months therefore, a minimum of 4 courses is recommended. To manage adverse effects such as PPE, stomatitis or hematologic toxicity the doses may be delayed or reduced. Concomitant or pretreatment with antiemetics should be considered.

AIDS-KS patients: Lipodox should be administered intravenously at a dose of 20 mg/m² over 30 minutes once every three weeks for as long as the patient responds satisfactorily and tolerates treatment.

General information: Do not administer as a bolus injection or an undiluted solution. Rapid infusion may increase the risk of infusion related reactions. No compatibility data are available for liposomal doxorubicin and therefore, it is not recommended that it be mixed with other drugs.

If any signs and symptoms of extravasation are observed, the infusion must be immediately terminated and restarted in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction.

Lipodox must not be given by the intramuscular or the subcutaneous route.

Preparation for intravenous administration: The appropriate dose of liposomal doxorubicin upto a maximum of 90 mg must be diluted in 250 ml of 5% Dextrose Injection USP prior to administration. Doses exceeding 90 mg should be diluted in 500 ml of 5% dextrose injection USP prior to administration. Aseptic technique must be strictly observed since no preservative or bacteriostatic agents is present in Lipodox. Diluted liposomal doxorubicin should be refrigerated at 2°C to 8°C and administered within 24 hours. Lipodox should not be used with in line filters and should not be mixed with other drugs. It should not be used with any other diluent other than Dextrose injection 5%. Partially used vials should be discarded.

Lipodox is not a clear solution but a transluscent, red liposomal dispersion.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present.

Doxorubicin is not a vesicant but should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of liposomal doxorubicin, extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should be immediately terminated and restarted in another vein. The application of ice over the side of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction.

Incompatibilities:

Storage & Handling:

Expiry Date:

Presentation:

Lipodox is available as 2 mg/ml concentrate solution for infusion in 5 ml and 10 ml vials.

Dear Healthcare Provider letter

• Online: www.fda.gov/medwatch/report.htm
• Regular Mail: use postage-paid FDA form 3500 available at www.fda.gov/MedWatch/getforms.htm. Mail to: MedWatch, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: +1-800-FDA-0178

PRINCIPAL DISPLAY PANEL-Lipodox

PRINCIPAL DISPLAY PANEL-Lipodox 50