Dexrazoxane

DEXRAZOXANE- dexrazoxane hydrochloride injection, powder, lyophilized, for solution
Almaject, Inc.

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1 INDICATIONS AND USAGE

Dexrazoxane for Injection is indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m² and who will continue to receive doxorubicin therapy to maintain tumor control. Do not use with the initiation of doxorubicin therapy [see Warnings and Precautions (5.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

Administer Dexrazoxane for Injection via intravenous infusion over 15 minutes. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH.

The recommended dosage ratio of Dexrazoxane for Injection to doxorubicin is 10:1 (e.g., 500 mg/m² Dexrazoxane for Injection to 50 mg/m² doxorubicin). Do not administer doxorubicin before Dexrazoxane for Injection. Administer doxorubicin within 30 minutes after the completion of Dexrazoxane for Injection infusion.

2.2 Dose Modifications

Dosing in Patients with Renal Impairment
Reduce Dexrazoxane for Injection dosage in patients with moderate to severe renal impairment (creatinine clearance values less than 40 mL/min) by 50% (Dexrazoxane for Injection to doxorubicin ratio reduced to 5:1; such as 250 mg/m² Dexrazoxane for Injection to 50 mg/m² doxorubicin) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

Dosing in Patients with Hepatic Impairment
Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, reduce the Dexrazoxane for Injection dosage proportionately (maintaining the 10:1 ratio) in patients with hepatic impairment.

2.3 Preparation and Administration

Preparation and Handling of Infusion Solution
Reconstitute Dexrazoxane for Injection with Sterile Water for Injection, USP. Reconstitute with 50 mL for a Dexrazoxane for Injection 500 mg vial to give a concentration of 10 mg/mL. Dilute the reconstituted solution further with Lactated Ringer’s Injection, USP to a concentration of 1.3 to 3.0 mg/mL in intravenous infusion bags for intravenous infusion.

Following reconstitution with Sterile Water for Injection, USP, Dexrazoxane for Injection is stable for 30 minutes at room temperature or if storage is necessary, up to 3 hours from the time of reconstitution when stored under refrigeration, 2° to 8°C (36° to 46°F). The pH of the resultant solution is 1.0 to 3.0. DISCARD UNUSED SOLUTIONS. The diluted infusion solutions are stable for one hour at room temperature or if storage is necessary, up to 4 hours when stored under refrigeration, 2° to 8°C (36° to 46°F). The infusion solutions have a pH of 3.5 to 5.5. DISCARD UNUSED SOLUTIONS.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Solutions containing a precipitate should be discarded.

Use caution when handling and preparing the reconstituted solution. The use of gloves is recommended. If Dexrazoxane for Injection powder or solutions contact the skin or mucosae, wash exposed area immediately and thoroughly with soap and water. Follow special handling and disposal procedures¹.

Administration
Do not mix Dexrazoxane for Injection with other drugs.

Administer the final diluted solution of Dexrazoxane for Injection by intravenous infusion over 15 minutes before the administration of doxorubicin. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH. Administer doxorubicin within 30 minutes after the completion of Dexrazoxane for Injection infusion.

3 DOSAGE FORMS AND STRENGTHS

Dexrazoxane for Injection is available in 500 mg single dose vials as sterile, pyrogen-free lyophilized.

4 CONTRAINDICATIONS

Do not use Dexrazoxane for Injection with non-anthracycline chemotherapy regimens.

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Dexrazoxane for Injection may add to the myelosuppression caused by chemotherapeutic agents. Obtain a complete blood count prior to and during each course of therapy, and administer Dexrazoxane for Injection and chemotherapy only when adequate hematologic parameters are met.

5.2 Concomitant Chemotherapy

Only use Dexrazoxane for Injection in those patients who have received a cumulative doxorubicin dose of 300 mg/m² and are continuing with doxorubicin therapy. Do not use with chemotherapy initiation as Dexrazoxane for Injection may interfere with the antitumor activity of the chemotherapy regimen. In a trial conducted in patients with metastatic breast cancer who were treated with fluorouracil, doxorubicin, and cyclophosphamide (FAC) with or without Dexrazoxane for Injection starting with their first cycle of FAC therapy, patients who were randomized to receive Dexrazoxane for Injection had a lower response rate (48% vs. 63%) and shorter time to progression than patients who were randomized to receive placebo.

5.3 Cardiac Toxicity

Treatment with Dexrazoxane for Injection does not completely eliminate the risk of anthracycline-induced cardiac toxicity. Monitor cardiac function before and periodically during therapy to assess left ventricular ejection fraction (LVEF). In general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage.

5.4 Secondary Malignancies

Secondary malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been reported in studies of pediatric patients who have received Dexrazoxane for Injection in combination with chemotherapy. Dexrazoxane for Injection is not indicated for use in pediatric patients. Some adult patients who received Dexrazoxane for Injection in combination with anti-cancer agents known to be carcinogenic have also developed secondary malignancies, including AML and MDS.
Razoxane is the racemic mixture, of which dexrazoxane is the S(+)-enantiomer. Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated chronically with oral razoxane. In these patients, the total cumulative dose of razoxane ranged from 26 to 480 grams and the duration of treatment was from 42 to 319 weeks. One case of T-cell lymphoma, one case of B-cell lymphoma, and six to eight cases of cutaneous basal cell or squamous cell carcinoma have also been reported in patients treated with razoxane. Long-term administration of razoxane to rodents was associated with the development of malignancies [see Nonclinical Toxicology (13.1)].

5.5 Embryo-Fetal Toxicity

Dexrazoxane for Injection can cause fetal harm when administered to pregnant women. Dexrazoxane administration during the period of organogenesis resulted in maternal toxicity, embryotoxicity and teratogenicity in rats and rabbits at doses significantly lower than the clinically recommended dose [see Use in Specific Populations (8.1)]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment [see Use in Specific Populations (8.6)].

6 ADVERSE REACTIONS

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 in other trials and may not reflect the rates observed in clinical practice.
The adverse reaction profile described in this section was identified from randomized, placebo controlled, double-blind studies in patients with metastatic breast cancer who received the combination of the FAC chemotherapy regimen with or without Dexrazoxane for Injection. The dose of doxorubicin was 50 mg/m² in each of these trials. Treatment was administered every three weeks until disease progression or cardiac toxicity.
Patients in clinical trials who received FAC with Dexrazoxane for Injection experienced more severe leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without Dexrazoxane for Injection [see Warnings and Precautions (5.1)].
Table 1 below lists the incidence of adverse reactions for patients receiving FAC with either Dexrazoxane for Injection or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving Dexrazoxane for Injection or placebo with FAC beginning with their first course of therapy (columns 1 and 3, respectively). Adverse experiences occurring at course 7 and beyond for patients who received placebo with FAC during the first six courses and who then received either Dexrazoxane for Injection or placebo with FAC are also displayed (columns 2 and 4, respectively).The adverse reactions listed below in Table 1 demonstrate that the frequency of adverse reaction “Pain on Injection” has been greater for Dexrazoxane for Injection arm, as compared to placebo.

Table 1

Adverse Reaction	Percentage (%) of Breast Cancer Patients With Adverse Reaction
	FAC + Dexrazoxane for Injection		FAC + Placebo
	Courses 1- 6 N = 413	Courses ≥ 7N = 102	Courses 1- 6N = 458	Courses ≥ 7N = 99
Alopecia	94	100	97	98
Nausea	77	51	84	60
Vomiting	59	42	72	49
Fatigue/Malaise	61	48	58	55
Anorexia	42	27	47	38
Stomatitis	34	26	41	28
Fever	34	22	29	18
Infection	23	19	18	21
Diarrhea	21	14	24	7
Pain on Injection	12	13	3	0
Sepsis	17	12	14	9
Neurotoxicity	17	10	13	5
Streaking/Erythema	5	4	4	2
Phlebitis	6	3	3	5
Esophagitis	6	3	7	4
Dysphagia	8	0	10	5
Hemorrhage	2	3	2	1
Extravasation	1	3	1	2
Urticaria	2	2	2	0
Recall SkinReaction	1	1	2	0