Lipodox

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with doxorubicin liposomal, especially:

• cyclophosphamide; or

• mercaptopurine.

This list is not complete. Other drugs may interact with doxorubicin liposomal, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common

• Black, tarry stools
• blistering, peeling, redness, or swelling of the palms of the hands or bottoms of the feet
• blood in the urine or stools
• chills
• cough or hoarseness
• facial swelling
• fever
• headache
• loss of strength and energy
• lower back or side pain
• numbness, pain, tingling, or unusual sensations in the palms of the hands or bottoms of the feet
• painful or difficult urination
• pinpoint red spots on the skin
• shortness of breath
• sore throat
• sores in the mouth and on the lips
• unusual bleeding or bruising
• unusual tiredness or weakness

Less common

• Pain at the injection site
• skin rash or itching

Rare

• Chest pain
• decreased urine output
• dilated neck veins
• extreme fatigue
• irregular breathing
• irregular heartbeat
• swelling of the face, fingers, feet, or lower legs
• tightness in the chest
• weight gain
• yellowing of the eyes and skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Creamy white, curd-like patches in mouth or throat
• diarrhea
• loss of appetite
• nausea
• pain when eating or swallowing
• sore throat
• swallowing problems
• vomiting

Less common

• Anxiety
• back pain
• bad, unusual, or unpleasant aftertaste
• burning, dry, or itching eyes
• change in skin color
• constipation
• dizziness
• excessive tearing
• itching
• joint pain
• muscle aches
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• trouble sleeping

Rare

• Abnormal thinking
• change in sense of smell
• chills
• clumsiness, unsteadiness, trembling, or problems with muscle coordination
• cough
• fever
• general feeling of discomfort or illness
• shivering
• sweating

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• If you have an allergy to doxorubicin or any other part of Lipodox.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding or plan to breast-feed.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Concentrate for Intravenous infusion

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.

 

Lipodox is also indicated for the treatment of AIDS related Kaposi’s Sarcoma in patients with extensive mucocutaneous or visceral disease that has progressed on prior combination therapy (consisting of two of the following agents: a vinca alkaloid, bleomycin and standard doxorubicin or another anthracycline) or in patients who are intolerant to such therapy.

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.

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

 

Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalisation, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis.

Breast Cancer/Ovarian cancer: Lipodox should be administered intravenously at a dose of 50 mg/m2 at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion related adverse events are observed, the rate of infusion can be increased to complete administration of the drug over one hour. The patient should be dosed once every 4 weeks, for as long as the patient responds satisfactorily or tolerates treatment.
 
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.

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.

Dose modification guidelines: There should be careful monitoring of the patient for toxicity. Adverse events such as PPE, hematologic toxicities and stomatitis may be managed by dose delays and adjustments. Following the first appearance of a grade 2 or higher adverse event, the dosing should be adjusted or delayed as described in the following tables. Once the dose has been reduced, it should not be increased at a later time.
  

PALMAR- PLANTAR ERYTHRODYSESTHESIA
Toxicity Grade	Dose Adjustment
1-(Mild erythema, swelling or desquamation not interfering with daily activities).	Redose unless patient has experienced previous grade 3 or 4 toxicity. If so, delay upto 2 weeks and decrease dose by 25%. Return to original dose interval.
2- (Erythema, desquamation or swelling interfering with but not precluding normal physical activities, small blisters or ulceration less than 2 cm in diameter).	Delay dosing upto 2 weeks or until resolved to grade 0-1. If after 2 weeks there is no resolution, Lipodox should be discontinued.
3- (Blistering, ulceration or swelling interfering with walking or normal daily activities; cannot wear regular clothing).	Delay dosing upto 2 weeks or until resolved to grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Lipodox should be discontinued.
4- (Diffuse or local process causing infectious complications, or a bed ridden state or hospitalization).	Delay dosing upto 2 weeks or until resolved to grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Lipodox should be discontinued

 

STOMATITIS
Toxicity Grade	Dose Adjustment
1- (Painless ulcers, erythema or mild soreness).	Redose unless patient has experienced grade 3 or 4 toxicity. If so, delay upto 2 weeks and decrease dose by 25%. Return to original dose interval.
2- (Painful erythema, edema or ulcers but can eat).	Delay dosing upto 2 weeks or until resolved to grade 0-1. If after 2 weeks there is no resolution, Lipodox should be discontinued.
3- (Painful erythema, edema or ulcers and cannot eat).	Delay dosing upto 2 weeks or until resolved to grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Lipodox should be discontinued.
4- (Requires parenteral or enteral support).	Delay dosing upto 2 weeks or until resolved to grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Lipodox should be discontinued.

 

HEMATOLOGICAL TOXICITY
Grade	ANC	Platelets	Modification
1	1500 - 1900	75,000 - 150,000	Resume treatment with no dose reduction.
2	1000 - <1500	50,000 - <75,000	Wait until ANC ≥ 1500 and platelets ≥ 75,000; redose with no dose reduction.
3	500 - 999	25,000 - <50,000	Wait until ANC ≥ 1500 and platelets ≥ 75,000; redose with no dose reduction.
4	<500	<25,000	Wait until ANC ≥ 1500 and platelets ≥ 75,000; redose at 25% dose reduction or continue full dose with cytokine support.

Pediatric patients: Safety and effectiveness in patients less than 18 years of age is not established.

Elderly: No overall differences were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

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 liposomal doxorubicin dosage in patients with impaired hepatic function should be reduced based on the experience from the breast and ovarian clinical trial programmes as follows: At initiation of therapy, if 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. Liposomal doxorubicin can be administered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymes upto 4 x the upper limit of the normal range. Prior to liposomal doxorubicin administration the hepatic function should be evaluated 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 will not be required. Population pharmacokinetic data (in the range of creatinine clearance of 30-156 ml/min) demonstrate that liposomal doxorubicin clearance is not influenced by renal function. No pharmacokinetic data are available in patients with creatinine clearance of less than 30 ml/min.
 

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.

Caution should be exercised in the handling and preparation of liposomal doxorubicin. The use of gloves is required. If Lipodox comes into contact with skin or mucosa, immediately wash thoroughly with soap or water. It should be handled and disposed off in a manner consistent with other anticancer drugs.

NDC 47335-083-50
25 ml
Doxorubicin Hydrochloride Liposome Injection
Lipodox 50
2 mg/ml
(Pegylated Liposomal)
Concentrate for Infusion
LIPOSOMAL FORMULATION
DO NOT SUBSTITUTE

Lipodox  doxorubicin hydrochloride injectable, liposomal

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:47335-082 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXORUBICIN HYDROCHLORIDE (DOXORUBICIN) DOXORUBICIN HYDROCHLORIDE 2 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength N-(CARBONYL-METHOXYPOLYETHYLENE GLYCOL 2000)-1,2-DISTEAROYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE, SODIUM SALT   CHOLESTEROL   AMMONIUM SULFATE   HISTIDINE   SUCROSE   HYDROCHLORIC ACID   SODIUM HYDROXIDE   HYDROGENATED SOYBEAN LECITHIN

Packaging # Item Code Package Description 1 NDC:47335-082-50 1 VIAL, SINGLE-USE (1 VIAL) in 1 PACKAGE 1 10 mL in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date Unapproved drug for use in drug shortage 02/09/2012

Lipodox 50  doxorubicin hydrochloride injectable, liposomal

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:47335-083 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXORUBICIN HYDROCHLORIDE (DOXORUBICIN) DOXORUBICIN HYDROCHLORIDE 2 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength N-(CARBONYL-METHOXYPOLYETHYLENE GLYCOL 2000)-1,2-DISTEAROYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE, SODIUM SALT   CHOLESTEROL   AMMONIUM SULFATE   HISTIDINE   SUCROSE   HYDROCHLORIC ACID   SODIUM HYDROXIDE   HYDROGENATED SOYBEAN LECITHIN

Packaging # Item Code Package Description 1 NDC:47335-083-50 1 VIAL, SINGLE-USE (1 VIAL) in 1 PACKAGE 1 25 mL in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date Unapproved drug for use in drug shortage 02/09/2012

Labeler - Sun Pharma Global FZE (864347344)

Establishment
Name	Address	ID/FEI	Operations
Sun Pharmaceutical Industries Limited		725959238	MANUFACTURE(47335-082, 47335-083), ANALYSIS(47335-082, 47335-083)

Revised: 05/2012   Sun Pharma Global FZE

Common side effects of Lipodox include: severe anemia, severe erythrodysesthesia syndrome, nausea, vomiting, diarrhea, stomatitis, erythrodysesthesia syndrome, alopecia, anemia, asthenia, bone marrow depression, neutropenia, thrombocytopenia, and anorexia. Other side effects include: asthma, syncope, severe neutropenia, back pain, chest pain, dyspnea, facial edema, fever, headache, hypotension, pruritus, skin rash, tachycardia, pharyngitis, and chills. See below for a comprehensive list of adverse effects.