Lipisol

Each 10-mg vial contains Doxorubicin hydrochloride 10 mg as a freeze-dried powder and is accompanied by an ampule containing 5 mL of Sterile Water for Injection.

Each 50-mg vial contains Doxorubicin hydrochloride 50 mg as a freeze-dried powder.

Other components of the product include: Methyl p-hydroxybenzoate 1 mg, lactose monohydrate 50 mg.

Lipisol is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius. Lipisol consists of a naphthacenequinone nucleus linked through a glycosidic bond at ring atom 7 to an amino sugar, daunosamine. Chemically, Lipisol hydrochloride is 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis)-. It empirical formula is C₂₇H₂₉NO₁₁·HCl and its molecular weight is 579.99.

Lipisol binds to nucleic acids, presumably by specific intercalation of the planar anthracycline nucleus with the DNA double helix. The anthracycline ring is lipophilic, but the saturated end of the ring system contains abundant hydroxyl groups adjacent to the amino sugar, producing a hydrophilic center. The molecule is amphoteric, containing acidic functions in the ring phenolic groups and a basic function in the sugar amino group. It binds to cell membranes as well as plasma proteins.

Lipisol hydrochloride for Injection, USP is a sterile red-orange lyophilized powder.

Lipisol hydrochloride for Injection, USP is a sterile parenteral, isotonic solution.

Adjuvant Breast Cancer

Lipisol (Lipisol HCl) Injection, USP and Lipisol (Lipisol HCl) for Injection, USP is indicated as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer.

Other Cancers

Lipisol is indicated for the treatment of

Lipisol injection is used together with other medicines to treat cancer of the blood, lymph system, bladder, breast, stomach, lungs, ovaries, thyroid, nerves, kidneys, bones, and soft tissues, including muscles and tendons. It may also be used to treat other kinds of cancer, as determined by your doctor.

Lipisol belongs to the group of medicines known as antineoplastics. It seems to interfere with the growth of cancer cells, which are then eventually destroyed by the body. Since the growth of normal body cells may also be affected by Lipisol, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern. Some effects may not occur until months or years after the medicine is used.

Before you begin treatment with Lipisol, you and your doctor should talk about the benefits Lipisol will do as well as the risks of using it.

Lipisol is to be given only by or under the direct supervision of your doctor.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, Lipisol is used in certain patients with the following medical conditions:

• Autoimmune deficiency syndrome (AIDS)–associated Kaposi's sarcoma (a type of cancer of the skin and mucous membranes that is more common in patients with AIDS)
• Cancer of the adrenal cortex (the outside layer of the adrenal gland)
• Cancer of the cervix
• Cancer of the endometrium
• Cancer of the esophagus
• Cancers of the head and neck
• Cancer of the liver
• Cancer of the pancreas
• Cancer of the prostate
• Cancer of the thymus (a small organ found under the breast bone)
• Carcinoid tumors
• Chronic lymphocytic leukemia (a type of cancer of the blood and lymph system)
• Ewing's sarcoma (a type of cancer found in the bone)
• Gestational trophoblastic tumors (tumors in the uterus or womb)
• Hepatoblastoma (a certain type of liver cancer that occurs in children)
• Multiple myeloma (a certain type of cancer of the blood)
• Non–small cell lung cancer (a certain type of lung cancer usually associated with prior smoking, passive smoking, or radon exposure)
• Retinoblastoma (a type of eye cancer found primarily in children)
• Tumors in the ovaries

Recommended Dose

Adjuvant Breast Cancer

The recommended dose of Lipisol is 60 mg/m2 administered as an intravenous bolus on day 1 of each 21 day treatment cycle, in combination with cyclophosphamide, for a total of four cycles.

Metastatic Disease, Leukemia, or Lymphoma

Dose Modifications

Cardiac Impairment

Discontinue Lipisol in patients who develop signs or symptoms of cardiomyopathy.

Hepatic Impairment

Lipisol is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin >5.0 mg/dL).

Decrease the dose of Lipisol in patients with elevated serum total bilirubin concentrations as follows:

Preparation and Administration

Preparation or Lipisol (Lipisol HCl) for Injection, USP;

Reconstitute Lipisol hydrochloride for injection with 0.9% Sodium Chloride Injection to obtain a final concentration of 2 mg per mL as follows:

Gently shake vial until the contents have dissolved.

Protect reconstituted solution from light.

Preparation for Continuous

Intravenous Infusion

Dilute Lipisol solution or reconstituted solution in 0.9% Sodium Chloride Injection or 5% Dextrose Injection, USP. Protect from light following preparation until completion of infusion.

Administration

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter.

Storage of vials of Lipisol (Lipisol HCl) Injection, USP or Lipisol (Lipisol HCl) for Injection, USP following reconstitution under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15º to 30ºC (59º to 86ºF)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution.

Administration by

Intravenous Injection:

Administration by Continuous

Intravenous Infusion:

Management of Suspected Extravasation

Discontinue Lipisol for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:

Incompatibility with Other Drugs

Do not admix Lipisol with other drugs. If Lipisol is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of Lipisol.

Procedures for Proper Handling and Disposal

Handle and dispose of Lipisol consistent with recommendations for the handling and disposal of hazardous drugs.1

Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. Do not abrade the skin by using a scrub brush. Seek medical attention.

See also:
What is the most important information I should know about Lipisol?

Hypersensitivity reactions to any of the components of Lipisol or to Lipisol HCl.

Lipisol should not be used to treat AIDS-KS that may be effectively treated with local therapy or systemic α-interferon.

Use in pregnancy & lactation: Lipisol should not be administered during pregnancy or while breastfeeding.

Lipisol is embryotoxic in rats and embryotoxic and abortifacient in rabbits. Teratogenicity cannot be ruled out. There is no experience with Lipisol in pregnant women. Therefore, administration to pregnant women is not recommended. Women of childbearing potential should be advised to avoid pregnancy while they or their male partner are receiving Lipisol and in 6 months following discontinuation of Lipisol therapy.

It is not known whether Lipisol is excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Lipisol, mothers should discontinue nursing prior to taking this drug. Health experts recommend that HIV-infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV.

Use Lipisol as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Lipisol. Talk to your pharmacist if you have questions about this information.
• Lipisol is usually administered as an injection at your doctor's office, hospital, or clinic. Ask your doctor any questions that you may have about Lipisol.
• Do not use Lipisol if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.
• Drinking extra fluids while you are using Lipisol is recommended. Check with your doctor for instructions.
• Your doctor may prescribe another medicine to lessen nausea and vomiting that can occur when using Lipisol. Discuss any questions with your doctor.
• If you spill Lipisol on your skin, wash it off right away with soap and water and contact your doctor.
• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Dispose of properly after use. Ask your doctor or pharmacist to explain local regulations for proper disposal.
• If you miss a dose of Lipisol, contact your doctor immediately.

Ask your health care provider any questions you may have about how to use Lipisol.

Use: Labeled Indications

Breast cancer: Treatment component of adjuvant therapy (multi-agent) in women with evidence of axillary lymph node involvement following resection of primary breast cancer

Metastatic cancers or disseminated neoplastic conditions: Treatment of acute lymphoblastic leukemia, acute myeloid leukemia, Wilms tumor, neuroblastoma, soft tissue and bone sarcomas, breast cancer, ovarian cancer, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared with other cell types

Off Label Uses

Endometrial carcinoma

Data from a large, randomized phase III trial supports the use of Lipisol (in combination with cisplatin) in the management of advanced endometrial carcinoma.

See also:
What other drugs will affect Lipisol?

Lipisol is a major substrate of cytochrome P450 (CYP450) CYP3A4 and CYP2D6 and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4, CYP2D6 and/or P-gp (eg, verapamil) resulting in increased concentration and clinical effect of Lipisol. Inducers of CYP3A4 (eg, phenobarbital, phenytoin, St. John's wort) and P-gp inducers may decrease the concentration of Lipisol.

Lipisol is mainly used in combination with other cytotoxic agents. Additive toxicity may occur, especially with regard to bone marrow/haematologic and gastrointestinal effects.

Adjuvant Chemotherapy Involving Lipisol: It is not recommended that Lipisol be used routinely as adjuvant chemotherapy in any tumour category. The activity of Lipisol in combination with other drugs is affected not only by the nature of the drug itself, but also by the schedule of administration. It is strongly recommended that in situations where Lipisol is intended for use as adjuvant chemotherapy, higher authorities as well as the hospital ethical committee be consulted.

Cyclophosphamide: Concurrent cyclophosphamide treatment sensitises the heart to the cardiotoxic effects of Lipisol. Lipisol may exacerbate cyclophosphamide cystitis.

Cyclosporin: The addition of cyclosporin to Lipisol may result in increases in area under the concentration-time curve (AUC) for both Lipisol and doxorubicinol, possibly due to a decrease in clearance of the parent drug and a decrease in metabolism of doxorubicinol. Literature reports suggest that adding cyclosporin to Lipisol results in more profound and prolonged hematologic toxicity than that observed with Lipisol alone. Coma and seizures have also been described with concomitant administration of cyclosporin and Lipisol.

Heparin: Lipisol should not be mixed with heparin since it has been reported that these drugs are incompatible to the extent that a precipitate may form.

Mediastinal Radiotherapy: Concurrent mediastinal radiotherapy and Lipisol may be associated with enhanced myocardial toxicity of Lipisol.

Paclitaxel: Paclitaxel can cause increased plasma-concentration of Lipisol and/or its metabolites when given prior to Lipisol. Certain data indicate that this effect is minor when anthracycline is administered prior to paclitaxel.

Propranolol: In view of the finding that Lipisol and propranolol, have both been shown to inhibit cardiac mitochondrial CoQ10 enzymes, it is possible that such a drug interaction may result in an additive cardiotoxic effect.

Radiotherapy: Concurrent radiotherapy and Lipisol treatment may be associated with increased radiation toxicity ie, skin reactions and mucositis.

Sorafenib: Both increases (21-47%) and no change in the AUC of Lipisol were observed with concomitant treatment with sorafenib 400 mg twice daily. The clinical significance of these findings is unknown.

See also:
What are the possible side effects of Lipisol?

Breast Cancer Patients: About 509 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with Lipisol (n=254) at a dose of 50 mg/m² every 4 weeks or Lipisol (n=255) at a dose of 60 mg/m² every 3 weeks in a phase III clinical trial (I97-328). In Lipisol-treated patients, the most frequently reported treatment-related adverse effects included PPE (48%) and nausea (37%). These effects were mostly mild and reversible, with severe (grade III) cases reported in 17% and 3%, respectively and no reported incidences of life-threatening (grade IV) cases for either PPE or nausea. Infrequently, these effects resulted in permanent treatment discontinuation (7% and 0%, respectively). Mucositis (23% vs 13%; grade III/IV 4% vs 2%) and stomatitis (22% vs 15%; grade III/IV 5% vs 2%) were reported more commonly with Lipisol than with Lipisol. The following common adverse events were reported more often with Lipisol than with Lipisol: Nausea (53% vs 37%; grade III/IV 5% vs 3%), vomiting (31% vs 19%; grade III/IV 4% vs <1%) and neutropenia (10% vs 4%; grade III/IV 8% vs 2%). Pronounced alopecia (or total hair loss) was seen in only 7% of Lipisol-treated patients as compared with 54% of patients treated with Lipisol. The average duration of the most common severe (grade III/IV) events for both groups was ≤30 days.

Anemia, neutropenia, leukopenia and thrombocytopenia were infrequently reported at incidences of 5%, 4%, 2% and 1%, respectively. Life-threatening (grade IV) hematologic effects were reported at incidences of <1%. The need for either growth factor support or transfusion support was minimal (5.1% and 5.5% of patients, respectively).

Clinically significant laboratory abnormalities (grades III and IV) in this breast cancer group included increases in total bilirubin (2.4%) and AST (1.6%). Increases in ALT were less frequent (<1%). Clinically significant hematologic measurements were infrequent as measured by leukopenia (4.3%), anemia (3.9%), neutropenia (1.6%) and thrombocytopenia (1.2%). Sepsis was reported at an incidence of 1%. No clinically significant increases in serum creatinine were reported.

In 150 patients with advanced breast cancer who had failed a prior 1st- or 2nd-line taxane-containing chemotherapy regimen and were subsequently treated with Lipisol at a dose of 50 mg/m² every 4 weeks in a phase III clinical trial (C/I96-352), the safety profile was consistent with that reported for Lipisol in previous studies using the same dosage regimen. The proportion of patients experiencing clinically significant laboratory abnormalities was low and comparable numerically to the 254 breast cancer patients receiving Lipisol as 1st-line therapy, with the exception of leukopenia (20%).

Adverse Reactions reported between 1% and 5% in 404 Lipisol-treated breast cancer patients, not previously reported in Lipisol clinical trials (≥1%) were breast pain, leg cramps, edema, leg edema, peripheral neuropathy, oral pain, ventricular arrhythmia, folliculitis, bone pain, musculoskeletal pain, thrombocythemia, cold sores (nonherpetic), fungal infection, epistaxis, upper respiratory tract infection, bullous eruption, dermatitis, erythematous rash, nail disorder, scaly skin, lacrimation and blurred vision.

Ovarian Cancer Patients: About 512 patients with ovarian cancer (a subset of 876 solid tumor patients) were treated with Lipisol at a dose of 50 mg/m² in clinical trials. The most frequently reported treatment-related adverse effects included PPE (46.1%) and stomatitis (38.9%). These effects were mainly mild, with severe (grade III) cases reported in 19.5% and 8%, respectively and life-threatening (grade IV) cases reported in 0.6% and 0.8%, respectively. These resulted infrequently in permanent treatment discontinuation (<5% and <1%, respectively).

Myelosuppression was mostly mild or moderate and manageable. Leukopenia was the most frequently reported hematological adverse effect, followed by anemia, neutropenia and thrombocytopenia. Life-threatening (grade IV) hematologic effects were reported at incidences of 1.6%, 0.4%, 2.9% and 0.2%, respectively. Growth factor support was required infrequently (<5%) and transfusion support was required in approximately 15% of patients.

Other less frequently (1-5%) reported adverse reactions included peripheral edema, oral moniliasis, vasodilatation, mouth ulceration, pruritus, allergic reaction, dehydration, dyspnea, vesiculobullous rash, chills, infection, weight loss, esophagitis, skin disorder, exfoliative dermatitis, cardiovascular disorder, chest pain, dizziness, maculopapular rash, gastritis, myalgia, back pain, depression, insomnia, dysphagia, increased cough, sweating, nausea and vomiting, malaise, taste perversion, urinary tract infection, conjunctivitis, acne, gingivitis, herpes zoster, hypochromic anemia, anxiety, vaginitis, headache, flatulence, dry mouth, cachexia, neuropathy, hypertonia, skin ulcer and dysuria.

In the subset of 410 patients with ovarian cancer, clinically significant laboratory abnormalities occurring in clinical trials with Lipisol included increases in total bilirubin (usually in patients with liver metastases) (5%) and serum creatinine levels (5%). Clinically significant measurements, measured by grades III and IV neutropenia (11.4%), anemia (5.7%) and thrombocytopenia (1.2%) were low. Increases in AST were less frequently (<1%) reported. Sepsis related to leukopenia was observed infrequently (<1%).

Solid Tumor Patients: In a larger cohort of 929 patients with solid tumors (including breast and ovarian cancer) predominantly treated at a dose of 50 mg/m² every 4 weeks, the safety profile and incidence of adverse effects are comparable to those of the patients treated in the pivotal breast and ovarian cancer trials.

AIDS-KS Patients: Open-label and controlled clinical studies on AIDS-KS patients treated with Lipisol at a dose of 20 mg/m² show that myelosuppression was the most frequent side effect considered related to Lipisol, occurring in approximately ½ of the patients.

Leukopenia is the most frequent adverse reaction experienced with Lipisol in this population; neutropenia, anemia and thrombocytopenia have been observed. These effects may occur early on in treatment. Hematological toxicity may require dose reduction, or suspension or delay of therapy. Temporarily suspend Lipisol treatment in patients when the ANC count is <1000/mm³ and/or the platelet count is <50,000/mm³. G-CSF (or GM-CSF) may be given as concomitant therapy to support the blood count when the ANC count is <1000/mm³ in subsequent cycles. The hematological toxicity for breast or ovarian cancer patients is less severe than in the AIDS-KS setting.

Other frequently (≥5%) observed side effects were nausea, asthenia, alopecia, fever, diarrhea, infusion-associated acute reactions and stomatitis.

Respiratory side effects frequently (≥5%) occurred in clinical studies of Lipisol and may be related to opportunistic infections in the AIDS population. Opportunistic infections (OIs) are observed in AIDS-KS patients after administration with Lipisol and are frequently observed in patients with HIV-induced immunodeficiency. The most frequently observed OIs in clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis carinii pneumonia and Mycobacterium avium complex.

Other less frequently (<5%) observed side effects included PPE, oral moniliasis, nausea and vomiting, weight loss, rash, mouth ulceration, dyspnea, abdominal pain, hypersensitivity reactions including anaphylactic reactions, vasodilatation, dizziness, anorexia, glossitis, constipation, paresthesia, retinitis and confusion.

Clinically significant laboratory abnormalities frequently (≥5%) occurred in clinical studies with Lipisol. These included increases in alkaline phosphatase and increases in AST and bilirubin which are believed to be related to the underlying disease and not Lipisol. Reduction in hemoglobin and platelets were less frequently (<5%) reported. Sepsis related to leukopenia was rarely (<1%) observed. Some of these abnormalities may have been related to the underlying HIV infection and not Lipisol.

Multiple Myeloma Patients: Of 646 patients with multiple myeloma who have received at least 1 prior therapy, 318 patients were treated with combination therapy of Lipisol 30 mg/m² as a 1-hr IV infusion administered on day 4 following bortezomib which is administered at 1.3 mg/m² on days 1, 4, 8 and 11, every 3 weeks or with bortezomib monotherapy in a phase III clinical trial..

Neutropenia, thrombocytopenia and anaemia were the most frequently reported hematologic events reported with both combination therapy of Lipisol plus bortezomib and bortezomib monotherapy. The incidence of grade 3 and 4 neutropenia was higher in the combination therapy group than in the monotherapy group (28% vs 14%). The incidence of grade 3 and 4 thrombocytopenia was higher in the combination therapy group than in the monotherapy group (22% vs 14%). The incidence of anaemia was similar in both treatment groups (7% vs 5%).

Stomatitis was reported more frequently in the combination therapy group (16%) than in the monotherapy group (3%) and most cases were grade 2 or less in severity. Grade 3 stomatitis was reported in 2% of patients in the combination therapy group. No grade 4 stomatitis was reported.

Nausea and vomiting were reported more frequently in the combination therapy group (40% and 28%) than in the monotherapy group (32% and 15%) and were mostly grade 1 and 2 in severity.

Treatment discontinuation of one or both agents due to adverse events was seen in 38% of patients. Common adverse events which led to treatment discontinuation of bortezomib and Lipisol included PPE, neuralgia, peripheral neuropathy, peripheral sensory neuropathy, thrombocytopenia, decreased ejection fraction and fatigue.

All Patients: 100 out of 929 patients (10.8%) with solid tumors were described as having an infusion-associated reaction during treatment with Lipisol as defined by the following COSTART terms: Allergic reaction, anaphylactoid reaction, asthma, face edema, hypotension, vasodilatation, urticaria, back pain, chest pains, chills, fever, hypertension, tachycardia, dyspepsia, nausea, dizziness, dyspnea, pharyngitis, rash, pruritus, sweating, injection site reaction and drug interaction. Permanent treatment discontinuation rates were infrequently reported at 2%. A similar incidence of infusion reactions (12.4%) was observed in the pivotal breast cancer trials. The rate of permanent treatment discontinuation was also similar at 1.5%. In patients with multiple myeloma receiving Lipisol plus bortezomib, infusion-associated reactions have been reported at a rate of 3%. In patients with AIDS-KS, infusion-associated reactions were characterised by flushing, shortness of breath, facial edema, headache, chills, back pain, tightness in the chest and throat and/or hypotension and can be expected at the rate of 5-10%. Very rarely, convulsions have been observed in relation to infusion reactions. In all patients, infusion-associated reactions occurred primarily during the 1st infusion. Temporarily stopping the infusion usually resolves these symptoms without further therapy. In nearly all patients, Lipisol treatment can be resumed after all symptoms have resolved without recurrence. Infusion reactions rarely recur after the 1st treatment cycle with Lipisol.

Stomatitis has been reported in patients receiving continuous infusions of conventional Lipisol HCl and was frequently reported in patients receiving Lipisol. It did not interfere with patients completing therapy and no dosage adjustments are generally required, unless stomatitis is affecting a patient's ability to eat. In this case, the dose interval may be extended by 1-2 weeks or the dose reduced.

Palmar-plantar erythrodysesthesia is characterised by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after 2 or 3 cycles of treatment. In most patients, it clears in 1 or 2 weeks, with or without treatment with corticosteroids. Pyridoxine at a dose of 50-150 mg/day has been used for the prophylaxis and treatment of PPE. Other strategies to prevent and treat PPE, which may be initiated 4-7 days after treatment with Lipisol includes 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). It appears to be dose- and schedule-related and can be reduced by extending the dose interval of 1-2 weeks or reducing the dose. This reaction can be severe and debilitating in some patients, however, and may require discontinuation of treatment.

An increased incidence of congestive heart failure is associated with Lipisol therapy at cumulative lifetime doses >450 mg/m² or at lower doses for patients with cardiac risk factors. Endomyocardial biopsies on 9 of 10 AIDS-KS patients receiving cumulative doses of Lipisol >460 mg/m² indicate no evidence of anthracycline-induced cardiomyopathy. The recommended dose of Lipisol for AIDS-KS patients is 20 mg/m² every 2-3 weeks. The cumulative dose at which cardiotoxicity would become a concern for these AIDS-KS patients (>400 mg/m²) would require >20 courses of Lipisol therapy over 40-60 weeks.

In addition, endomyocardial biopsies were performed in 8 solid tumor patients with cumulative anthracycline doses of 509-1680 mg/m². The range of Billingham cardiotoxicity scores was grades 0-1.5. These grading scores are consistent with no or mild cardiac toxicity.

In the pivotal phase III trial versus Lipisol, 10/254 patients randomized to receive Lipisol (treated at a dose of 50 mg/m² every 4 weeks) versus 48/255 patients randomized to receive Lipisol (treated at a dose of 60 mg/m² every 3 weeks) met the protocol-defined criteria for cardiac toxicity during treatment and/or follow-up. Cardiac toxicity was defined as a decrease of ≥20 points from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range or a decrease of ≥10 points if the LVEF became abnormal (less than the lower limit for normal). Patients were also assessed for signs and symptoms of congestive heart failure (CHF). None of the 10 Lipisol patients who had cardiac toxicity by LVEF criteria developed signs and symptoms of CHF. In contrast, 10 of 48 Lipisol patients who had cardiac toxicity by LVEF criteria also developed signs and symptoms of CHF.

As with other DNA-damaging antineoplastic agents, secondary acute myeloid leukemias and myelodysplasias have been reported in patients having received combined treatment with Lipisol. Therefore, any patient treated with Lipisol should be kept under hematological supervision.

In patients with solid tumors, including a subset of patients with breast and ovarian cancers, treated at a dose of 50 mg/m²/cycle with lifetime cumulative anthracycline doses up to 1532 mg/m², the incidence of clinically significant cardiac dysfunction was low. Of the 929 patients treated with Lipisol 50 mg/m²/cycle, baseline measurement of LVEF and at least one follow-up measurement were conducted in 418 patients and assessed by MUGA scan. Of these 418 patients, 88 patients had a cumulative anthracycline dose of >400 mg/m², an exposure level associated with an increased risk of cardiovascular toxicity with the conventional formulation of Lipisol. Only 13 of these 88 patients (15%) had at least one clinically significant change in their LVEF, defined as an LVEF value <45% or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (who received a cumulative dose of 944 mg/m²), discontinued study treatment because of clinical symptoms of CHF.

Although local necrosis following extravasation has been reported very rarely, Lipisol should be considered an irritant. Animal studies indicate that administration of Lipisol HCl as a liposomal formulation reduces the potential for extravasation injury. If any signs or symptoms of extravasation occur (eg, stinging, erythema), the infusion should be immediately terminated and restarted in another vein. The application of ice over the site of extravasation for approximately 30 min may be helpful in alleviating the local reaction. Lipisol must not be given by the IM or SC route.

Recall of skin reaction due to prior radiotherapy has rarely occurred with Lipisol administration.