Doxorubicin HCl Liposome Injection (Doxil®)
Manufacturer: Tibotec Therapeutics, Division of Ortho Biotech Products, LP, Johnson & Johnson
Updated Approval: The U.S. Food and Drug Administration (FDA) has granted full approval to doxorubicin HCl lipo-some injection for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.
Originally, under the accelerated approval, this product was indicated for the treatment of patients with metastatic ovarian cancer that had not responded to chemotherapy regimens comprising paclitaxel (e.g., Taxol®, Bristol-Myers Squibb) and platinum (e.g., Platinol® [cisplatin], Bristol-Myers Squibb). This approval was based on tumor response rates from three phase 2 studies. According to the terms of the approval, Johnson & Johnson’s pharmaceutical research and development arm completed a randomized phase 3 clinical study to demonstrate the drug’s clinical benefit in patients with relapsed ovarian cancer.
The study showed that there was no significant difference in time to median disease progression (P = .67) between doxorubicin HCl liposome injection (4.1 months) and topotecan HCl (Hycamtin®, GlaxoSmithKline) (4.2 months) in patients with epithelial ovarian cancer. Thus, the label has been updated to include survival, time to disease progression, and tumor response rate.
Description: Doxorubicin is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. Doxorubicin HCl is the established name for (8S,10S)-10-[(3-amino-2,3,6-tri-deoxy-a-L-lyxo-hexopyranosyr)oxy]-8-glycolyl-7,8,9, 10-tetrahydro-6,8,11-trihydroxy-L-methoxy-5,12-naphthacene-dione HCl.
Doxil® is provided as a sterile, translucent, red liposomal dispersion in 10-ml single-use glass vials. Each vial contains 20 mg of doxorubicin HCl at a concentration of 2 mg/ml and a pH of 6.5. The STEALTH® liposome carriers are composed of N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-di-stearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/ml; fully hydrogenated soy phosphatidyl choline (HSPC), 9.58 mg/ml; and cholesterol, 3.19 mg/ml. Each milliliter also contains ammonium sulfate, approximately 2 mg; histidine as a buffer; hydrochloric acid and/or sodium hydroxide for pH control; and sucrose to maintain isotonicity. More than 90% of the drug is encapsulated in the liposomes.
Indications: Doxorubicin HCl liposome injection is indicated for the treatment of:
- metastatic carcinoma of the ovary in patients with disease that is refractory to paclitaxel and platinum. Refractory is defined as disease that has progressed while the patient was receiving treatment or within six months of the patient’s completing treatment.
- acquired immunodeficiency-related Kaposi’s sarcoma in patients with disease that has progressed with previous combination chemotherapy or in patients who are intolerant to such therapy.
Pharmacology: The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and to the agent’s cell membrane lipid-binding activities. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin’s cytocidal activity.
Doxorubicin’s cellular membrane-binding activity may affect several cellular functions. Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases, and de-hydrogenases generates highly reactive species, including the hydroxyl free radical OH. Formation of free radicals has been implicated in doxorubicin cardiotoxicity by means of copper (Cu II) and iron (Fe III) reduction at the cellular level. Cells treated with doxorubicin manifest the characteristic morphological changes associated with apoptosis (programmed cell death). Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. Apcalis Oral Jelly
Boxed Warning: Experience with doxorubicin liposome injection at high cumulative doses is too limited to have established its effects on the myocardium. Therefore, it should be assumed that the injection has myocardial toxicity similar to that of conventional formulations of doxorubicin HCl.
Doxorubicin should be not administered to patients with a history of cardiovascular disease unless the benefits outweigh the risks. Acute infusion-related reactions have occurred in up to 10% of patients treated with doxorubicin. Serious and sometimes life-threatening or fatal allergic or anaphylactoid infusion reactions have been reported. Medications and emergency equipment to treat such reactions should be available for immediate use.
Severe myelosuppression may occur. The dosage should be reduced in patients with impaired hepatic function. Accidental substitution of doxorubicin liposome injection for doxo-rubicin HCl has resulted in severe side effects. Thus, no substitutions should be made.
The use of doxorubicin liposome injection should be limited to physicians experienced in the use of cancer chemotherapeu-tic agents. Caution should be observed in patients who have received other anthracyclines, and the total dose of doxorubicin HCl should take into account any previous or concomitant therapy with other anthracyclines or related compounds. generic cialis in uk
Congestive heart failure or cardiomyopathy may arise after discontinuation of therapy. Patients with a history of cardiovascular disease should receive doxorubicin liposome injection only when the potential benefits of treatment outweigh the risks. Cardiac function should be carefully monitored.
The most definitive test for anthracycline myocardial injury is the endomyocardial biopsy. Other methods, such as echocardiography and gated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be used to monitor potential cardiac tox-icity during doxorubicin liposome injection therapy. If these test results indicate possible cardiac injury associated with this treatment, the benefits of continued therapy must be carefully weighed against the risks of myocardial injury.
In patients with ovarian cancer, myelosuppression was generally moderate and reversible. Anemia was the most common hematological adverse drug event (ADE) (52.6%), followed by leukopenia (a white blood cell [WBC] count below 4,000 mm3, 42.2%), thrombocytopenia (24.2%), and neutropenia (an absolute neutrophil cell [ANC] count below 1,000 mm3) 19.0%).
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In all patients, because of the potential for bone marrow suppression, careful hematological monitoring is required during the use of doxorubicin liposome injection. Monitoring should include WBC, ANC, and platelet counts as well as hemoglobin and hematocrit levels. With the recommended dosage schedule, leukopenia is usually transient. Patients with hemato-logical toxicity may require a smaller dose or a delay or suspension of the injections. Persistent, severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death.
Doxorubicin HCl liposome injection may potentiate the toxicity of other anticancer therapies. In particular, hematological toxicity is sometimes more severe when the injections are given in combination with other agents that cause bone marrow suppression.
Up to 10% of treated patients experience 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, or hypotension. In most patients, these reactions resolve over the course of several hours to a day after the infusion is terminated. In some patients, the reactions resolve when the rate of infusion is slowed.
Serious and sometimes life-threatening or fatal allergic or anaphylactoid infusion reactions have been reported. Emergency equipment and medications to treat any reactions should be available for immediate use.
Most infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin; these presumably represent a reaction to the liposomes or one of the surface components. eriacta
Among ovarian cancer patients, 37.4% experienced palmarplantar erythrodysesthesia (PPE). These cutaneous eruptions are characterized by swelling, pain, erythema, and sometimes desquamation of the skin on the hands and feet, with 16.4% of the patients reporting grade 3 or 4 events. Thirteen patients (3.5%) discontinued treatment because of PPE or other skin toxicity.
Conclusion: The new approval of doxorubicin HCl lipo-some injection makes it available to patients whose ovarian cancer has progressed and has stopped responding to other chemotherapy. A phase 3 comparison clinical trial showed that the injection was as effective as a similar chemotherapy.