Doxorubicin Hydrochloride (Page 2 of 6)

2.6 Preparation and Administration

Preparation
Dilute doxorubicin hydrochloride liposome injection doses up to 90 mg in 250 mL of 5% Dextrose Injection, USP prior to administration. Dilute doses exceeding 90 mg in 500 mL of 5% Dextrose Injection, USP prior to administration. Refrigerate diluted doxorubicin hydrochloride liposome injection at 2°C to 8°C (36°F to 46°F) and administer within 24 hours.
Administration
Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present.
Do not use with in-line filters.
Administer the first dose of doxorubicin hydrochloride liposome injection at an initial rate of 1 mg/min. If no infusion-related adverse reactions are observed, increase the infusion rate to complete the administration of the drug over one hour [see Warnings and Precautions (5.2)]. Do not rapidly flush the infusion line.
Do not mix doxorubicin hydrochloride liposome injection with other drugs.
Management of Suspected Extravasation
Discontinue doxorubicin hydrochloride liposome injection for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:

  • Do not remove the needle until attempts are made to aspirate extravasated fluid
  • Do not flush the line
  • Avoid applying pressure to the site
  • Apply ice to the site intermittently for 15 minute 4 times a day for 3 days
  • If the extravasation is in an extremity, elevate the extremity

2.7 Procedure for Proper Handling and Disposal

Doxorubicin hydrochloride liposome injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 If doxorubicin hydrochloride liposome injection comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.

3 DOSAGE FORMS AND STRENGTHS

Doxorubicin hydrochloride liposome injection: 20 mg/10 mL (2 mg/mL) and 50 mg/25 mL (2 mg/mL) in single-dose vials. The drug product appears as a translucent, red liposomal dispersion.

4 CONTRAINDICATIONS

Doxorubicin hydrochloride liposome injection is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin hydrochloride [see Warnings and Precautions (5.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Cardiomyopathy

Doxorubicin hydrochloride can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin hydrochloride is generally proportional to the cumulative exposure. Include prior use of other anthracyclines or anthracenediones in calculations of cumulative dose. The risk of cardiomyopathy may be increased at lower cumulative doses in patients with prior mediastinal irradiation.
In a clinical study in 250 patients with advanced cancer who were treated with doxorubicin hydrochloride liposome injection, the risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2 to 550 mg/m2. Cardiomyopathy was defined as >20% decrease in resting left ventricular ejection fraction (LVEF) from baseline where LVEF remained in the normal range or a >10% decrease in LVEF from baseline where LVEF was less than the institutional lower limit of normal. Two percent of patients developed signs and symptoms of congestive heart failure without documented evidence of cardiomyopathy.

Assess left ventricular cardiac function (e.g. MUGA or echocardiogram) prior to initiation of doxorubicin hydrochloride liposome injection, during treatment to detect acute changes, and after treatment to detect delayed cardiomyopathy. Administer doxorubicin hydrochloride liposome injection to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

5.2 Infusion-Related Reactions

Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with doxorubicin hydrochloride liposome injection: 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 hypotension. Of 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection in Trial 4, 7% of patients experienced acute infusion-related reactions resulting in dose interruption. All occurred during cycle 1 and none during subsequent cycles. Across multiple studies of doxorubicin hydrochloride liposome injection monotherapy including this and other studies enrolling 760 patients with various solid tumors, 11% of patients had infusion-related reactions. The majority of infusion-related events occurred during the first infusion.

Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation of doxorubicin hydrochloride liposome injection. Initiate doxorubicin hydrochloride liposome injection infusions at a rate of 1 mg/min and increase rate as tolerated [see Dosage and Administration (2.6)]. Withhold doxorubicin hydrochloride liposome injection for Grade 1, 2, or 3 infusion-related reactions and resume at a reduced infusion rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions.

5.3 Hand-Foot Syndrome(HFS)

In Trial 4, the incidence of HFS was 51% of patients in the doxorubicin hydrochloride liposome injection arm and 0.9% of patients in the topotecan arm, including 24% Grade 3 or 4 cases of HFS in doxorubicin hydrochloride liposome injection-treated patients and no Grade 3 or 4 cases in topotecan-treated patients. HFS or other skin toxicity required discontinuation of doxorubicin hydrochloride liposome injection in 4.2% of patients.

HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. Delay doxorubicin hydrochloride liposome injection for the first episode of Grade 2 or greater HFS [see Dosage and Administration (2.5)]. Discontinue doxorubicin hydrochloride liposome injection if HFS is severe and debilitating.

5.4 Secondary Oral Neoplasms

Secondary oral cancers, primarily squamous cell carcinoma, have been reported from postmarketing experience in patients with long-term (more than one year) exposure to doxorubicin hydrochloride liposome injection. These malignancies were diagnosed both during treatment with doxorubicin hydrochloride liposome injection and up to 6 years after the last dose. Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer.

The altered pharmacokinetics and preferential tissue distribution of liposomal doxorubicin that contributes to enhanced skin toxicity and mucositis compared to free doxorubicin may play a role in the development of oral secondary malignancies with long-term use.

5.5 Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. At doses approximately 0.12 times the recommended clinical dose, doxorubicin hydrochloride liposome injection was embryotoxic and abortifacient in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling.

  • Cardiomyopathy [see Warnings and Precautions (5.1)]
  • Infusion-Related Reactions [see Warnings and Precautions (5.2)]
  • Hand-Foot Syndrome [see Warnings and Precautions (5.3)]
  • Secondary Oral Neoplasms [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.
The safety data reflect exposure to doxorubicin hydrochloride liposome injection in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma, and 318 patients with multiple myeloma. The most common adverse reactions (>20%) observed with doxorubicin hydrochloride liposome injection are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.
The following tables present adverse reactions from clinical trials of single-agent doxorubicin hydrochloride liposome injection in ovarian cancer and AIDS-Related Kaposi’s sarcoma.
Patients With Ovarian Cancer
The safety data described below are from Trial 4, which included 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection 50 mg/m2 once every 4 weeks for a minimum of four courses in a randomized, multicenter, open-label study. In this trial, patients received doxorubicin hydrochloride liposome injection for a median number of 3.2 months (range 1 day to 25.8 months). The median age of the patients is 60 years (range 27 to 87), with 91% Caucasian, 6% Black, and 3% Hispanic or Other. Table 3 presents the hematologic adverse reactions from Trial 4.

Table 3: Hematologic Adverse Reactions in Trial 4
Doxorubicin Hydrochloride Liposome Injection Patients(n=239) Topotecan(n=235)
Neutropenia500 — <1,000/mm3 <500/mm3 8 %4.2% 14%62%
Anemia6.5 — <8 g/dL< 6.5 g/dL 5 %0.4% 25%4.3%
Thrombocytopenia10,000 — <50,000/mm3 <10,000/mm3 1.3%0% 17%17%

Table 4 presents the non-hematologic adverse reactions from Trial 4.

Table 4: Non-Hematologic Adverse Reactions in Trial 4
Non-Hematologic Adverse Reaction 10% or Greater Doxorubicin Hydrochloride Liposome Injection (%) treated (n=239) Topotecan (%) treated (n=235)
All grades Grades 3-4 All grades Grades 3-4
Body as a Whole
Asthenia 40 7 52 8
Fever 21 0.8 31 6
Mucous Membrane Disorder 14 3.8 3.4 0
Back Pain 12 1.7 10 0.9
Infection 12 2.1 6 0.9
Headache 11 0.8 15 0
Digestive
Nausea 46 5 63 8
Stomatitis 41 8 15 0.4
Vomiting 33 8 44 10
Diarrhea 21 2.5 35 4.2
Anorexia 20 2.5 22 1.3
Dyspepsia 12 0.8 14 0
Nervous
Dizziness 4.2 0 10 0
Respiratory
Pharyngitis 16 0 18 0.4
Dyspnea 15 4.1 23 4.3
Cough increased 10 0 12 0
Skin and Appendages
Hand-foot syndrome 51 24 0.9 0
Rash 29 4.2 12 0.4
Alopecia 19 N/A 52 N/A

The following additional adverse reactions were observed in patients with ovarian cancer with doses administered every four weeks (Trial 4).
Incidence 1% to 10%
Cardiovascular: vasodilation, tachycardia, deep vein thrombosis, hypotension, cardiac arrest.
Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus.
Hematologic and Lymphatic: ecchymosis.
Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia.
Nervous: somnolence, dizziness, depression.
Respiratory: rhinitis, pneumonia, sinusitis, epistaxis.
Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne.
Special Senses: conjunctivitis, taste perversion, dry eyes.
Urinary: urinary tract infection, hematuria, vaginal moniliasis.
Patients With AIDS-Related Kaposi’s Sarcoma
The safety data described is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma (KS) enrolled in four open-label, uncontrolled trials of doxorubicin hydrochloride liposome injection administered at doses ranging from 10 to 40 mg/m2 every 2 to 3 weeks. Demographics of the population were: median age 38.7 years (range 24 to 70); 99% male; 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of doxorubicin hydrochloride liposome injection every 2 to 3 weeks with a median exposure of 4.2 months (range 1 day to 26.6 months). The median cumulative dose was 120 mg/m2 (range 3.3 to 798.6 mg/m2); 3% received cumulative doses of greater than 450 mg/m2.
Disease characteristics were: 61% poor risk for KS tumor burden, 91% poor risk for immune system, and 47% poor risk for systemic illness; 36% were poor risk for all three categories; median CD4 count 21 cells/mm3 (51% less than 50 cells/mm3); mean absolute neutrophil count at study entry approximately 3,000 cells/mm3.
Of the 693 patients with concomitant medication information, 59% were on one or more antiretroviral medications [35% zidovudine (AZT), 21% didanosine (ddI), 16% zalcitabine (ddC), and 10% stavudine (D4T)]; 85% received PCP prophylaxis (54% sulfamethoxazole/trimethoprim); 85% received antifungal medications (76% fluconazole); 72% received antivirals (56% acyclovir, 29% ganciclovir, and 16% foscarnet) and 48% patients received colony-stimulating factors (sargramostim/filgrastim) during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS-related Kaposi’s sarcoma and included myelosuppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Tables 5 and 6 summarize adverse reactions reported in patients treated with doxorubicin hydrochloride liposome injection for AIDS-related Kaposi’s sarcoma in a pooled analysis of the four trials.

Table 5: Hematologic Adverse Reactions Reported in Patients With AIDS-Related Kaposi’s Sarcoma
*
This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy.
This includes only subjects with AIDS-KS who had available data from the 4 pooled trials.
Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n=74*) Total Patients With AIDS-Related Kaposi’s Sarcoma (n=720)
Neutropenia
< 1,000/mm3 46% 49%
< 500/mm3 11% 13%
Anemia
< 10 g/dL 58% 55%
< 8 g/dL 16% 18%
Thrombocytopenia
< 150,000/mm3 61% 61%
< 25,000/mm3 1.4% 4.2%
Table 6: Non-Hematologic Adverse Reactions Reported in ≥ 5% of Patients With AIDS-Related Kaposi’s Sarcoma
*
This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy
This includes only subjects with AIDS-KS who had available adverse event data from the 4 pooled trials
Adverse Reactions Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n=77*) Total Patients With AIDS-Related Kaposi’s Sarcoma (n=705)
Nausea 18% 17%
Asthenia 7% 10%
Fever 8% 9%
Alopecia 9% 9%
Alkaline Phosphatase Increase 1.3% 8%
Vomiting 8% 8%
Diarrhea 5% 8%
Stomatitis 5% 7%
Oral Moniliasis 1.3% 6%

The following additional adverse reactions were observed in 705 patients with AIDS-related Kaposi’s sarcoma.
Incidence 1% to 5%
Body as a Whole: headache, back pain, infection, allergic reaction, chills.
Cardiovascular: chest pain, hypotension, tachycardia.
Cutaneous: herpes simplex, rash, itching.
Digestive: mouth ulceration, anorexia, dysphagia.
Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.
Other: dyspnea, pneumonia, dizziness, somnolence.
Incidence Less Than 1%
Body As A Whole: sepsis, moniliasis, cryptococcosis.
Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia.
Digestive: hepatitis.
Metabolic and Nutritional Disorders: dehydration.
Respiratory: cough increase, pharyngitis.
Skin and Appendages: maculopapular rash, herpes zoster.
Special Senses: taste perversion, conjunctivitis.
Patients With Multiple Myeloma The safety data described are from 318 patients treated with doxorubicin hydrochloride liposome injection (30 mg/m2) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every 3 weeks, in a randomized, open-label, multicenter study (Trial 6). In this trial, patients in the doxorubicin hydrochloride liposome injection + bortezomib combination group were treated for a median number of 4.5 months (range 21 days to 13.5 months). The population was 28 to 85 years of age (median age 61), 58% male, 90% Caucasian, 6% Black, and 4% Asian and Other. Table 7 lists adverse reactions reported in 10% or more of patients treated with doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma.

Table 7: Frequency of Treatment-Emergent Adverse Reactions Reported in ≥10% Patients Treated for Multiple Myeloma With Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib
*
Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS.
Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.
Adverse Reaction D oxorubicin Hydrochloride Liposome Injection + Bortezomib (n=318) Bortezomib (n=318)
Any (%) Grade 3-4 Any (%) Grade 3-4
Blood and lymphatic system disorders
Neutropenia 36 32 22 16
Thrombocytopenia 33 24 28 17
Anemia 25 9 21 9
General disorders and administration site conditions
Fatigue 36 7 28 3
Pyrexia 31 1 22 1
Asthenia 22 6 18 4
Gastrointestinal disorders
Nausea 48 3 40 1
Diarrhea 46 7 39 5
Vomiting 32 4 22 1
Constipation 31 1 31 1
Mucositis/Stomatitis 20 2 5 <1
Abdominal pain 11 1 8 1
Infections and infestations
Herpes zoster 11 2 9 2
Herpes simplex 10 0 6 1
Investigations
Weight decreased 12 0 4 0
Metabolism and Nutritional disorders
Anorexia 19 2 14 <1
Nervous system disorders
Peripheral Neuropathy * 42 7 45 11
Neuralgia 17 3 20 4
Paresthesia/dysesthesia 13 <1 10 0
Respiratory, thoracic and mediastinal disorders
Cough 18 0 12 0
Skin and subcutaneous tissue disorders
Rash 22 1 18 1
Hand-foot syndrome 19 6 <1 0

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