DOXORUBICIN HYDROCHLORIDE Dailymed

10 Overdosage

Acute overdosage with doxorubicin hydrochloride causes increased risk of severe mucositis, leukopenia, and thrombocytopenia.

11 Description

The active ingredient in doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride, an anthracycline topoisomerase inhibitor, that is encapsulated in pegylated liposomes for intravenous use.

The chemical name of doxorubicin hydrochloride is (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The molecular formula is C₂₇H₂₉NO₁₁•HCl and the molecular weight is 579.99.

The structural formula is:
Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion. Each single-dose vial contains 20 mg or 50 mg doxorubicin hydrochloride at a concentration of 2 mg/mL (equivalent to 1.87 mg/mL of doxorubicin) and a pH of 6.5. The pegylated liposome carriers are composed of cholesterol, 3.19 mg/mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg/mL; and N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/mL. Each mL also contains ammonium sulfate, approximately 0.6 mg; histidine, 1.55 mg as a buffer; hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (6.0 to 7.0); and sucrose, 94 mg to maintain isotonicity. Greater than 90% of the drug is encapsulated in the pegylated liposomes.

MPEG-DSPE has the following structural formula:
HSPC has the following structural formula:
Representation of a pegylated liposome:

12 Clinical Pharmacology

12.1 Mechanism of Action

The active ingredient of doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride. The mechanism of action of doxorubicin hydrochloride is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.

12.3 Pharmacokinetics

The pharmacokinetic parameters for total doxorubicin following a single dose of doxorubicin hydrochloride liposome injection infused over 30 minutes are presented in Table 8.

Table 8:      Pharmacokinetic Parameters of Total Doxorubicin from Doxorubicin Hydrochloride Liposome Injection in Patients With AIDS- Related Kaposi's Sarcoma

N=23
Mean ± Standard Error
	Dose
Parameter (units)	10 mg/m2	20 mg/m2
Peak Plasma Concentration (µg/mL)	4.12 ± 0.215	8.34 ± 0.49
Plasma Clearance (L/h/m2)	0.056 ± 0.01	0.041 ± 0.004
Steady State Volume of Distribution (L/m2)	2.83 ± 0.145	2.72 ± 0.120
AUC (µg/mL∙h)	277 ± 32.9	590 ± 58.7
First Phase (λ1) Half-Life (h)	4.7 ± 1.1	5.2 ± 1.4
Second Phase (λ1) Half-Life (h)	52.3 ± 5.6	55.0 ± 4.8

Doxorubicin hydrochloride liposome injection displayed linear pharmacokinetics over the range of 10 to 20 mg/m². Relative to doxorubicin hydrochloride liposome injection doses at or below 20 mg/m², the pharmacokinetics of total doxorubicin following a 50 mg/m² doxorubicin hydrochloride liposome injection dose are nonlinear. At this dose, the elimination half-life of doxorubicin hydrochloride liposome injection is longer and the clearance lower compared to a 20 mg/m² dose.

Distribution

Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5-10% free doxorubicin) remains liposome-encapsulated during circulation.

In contrast to doxorubicin, which displays a large volume of distribution (range 700 to 1100 L/m²), the small steady state volume of distribution of liposomal doxorubicin suggests that doxorubicin hydrochloride liposome injection is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of doxorubicin hydrochloride liposome injection has not been determined; the plasma protein binding of doxorubicin is approximately 70%.

Metabolism

Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0.8 to 26.2 ng/mL in the plasma of patients who received 10 or 20 mg/m² doxorubicin hydrochloride liposome injection.

Elimination

The plasma clearance of total doxorubicin from doxorubicin hydrochloride liposome injection was 0.041 L/h/m² at a dose of 20 mg/m². Following administration of doxorubicin hydrochloride, the plasma clearance of doxorubicin is 24 to 35 L/h/m².

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Mutagenicity or carcinogenicity studies have not been conducted with doxorubicin hydrochloride liposome injection, however doxorubicin was shown to be mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. The possible adverse effects on fertility in animals have not been adequately evaluated. Doxorubicin hydrochloride liposome injection resulted in mild to moderate ovarian and testicular atrophy in mice after administration of a single dose of 36 mg/kg (about 2 times the 50 mg/m² human dose on a mg/m² basis). Decreased testicular weights and hypospermia were observed in rats after repeat doses ≥ 0.25 mg/kg/day (about 0.03 times the 50 mg/m² human dose on a mg/m² basis), and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (about 0.4 times the 50 mg/m² human dose on a mg/m² basis).

14 Clinical Studies

14.1 Ovarian Cancer

Doxorubicin hydrochloride liposome injection was studied in three open-label, single-arm, clinical studies of 176 patients with metastatic ovarian cancer (Trials 1, 2, and 3). One hundred forty-five of these patients were refractory to both paclitaxel- and platinum-based chemotherapy regimens, defined as disease progression while on treatment or relapse within 6 months of completing treatment. Patients received doxorubicin hydrochloride liposome injection at 50 mg/m² every 3 or 4 weeks for 3-6+ cycles in the absence of dose-limiting toxicity or disease progression.

The median age at diagnosis ranged from 52 to 64 years in the 3 studies, and the range was 22 to 85. Most patients had International Federation of Obstetricians and Gynecologists (FIGO) stage III or IV disease (ranging from 83% to 93%). Approximately one third of the patients had three or more prior lines of therapy (ranging from 22% to 33%).

The primary outcome measure was confirmed response rate based on Southwestern Oncology Group (SWOG) criteria for patients refractory to both paclitaxel- and a platinum-containing regimen. Secondary efficacy parameters were time to response, duration of response, and time to progression.

The response rates for the individual single arm trials are given in Table 9 below.

Table 9:      Response Rates in Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Trials

	Trial 1 (U.S.) N=27	Trial 2 (U.S.) N=82	Trial 3 (non-U.S.) N=36
Response Rate	22.2%	17.1%	0%
95% Confidence Interval	8.6% – 42.3%	9.7% – 27.0%	0.0% – 9.7%

In a pooled analysis of Trials 1-3, the response rate for all patients refractory to paclitaxel and platinum agents was 13.8% (95% CI 8.1% to 19.3%). The median time to progression was 15.9 weeks, the median time to response was 17.6 weeks, and the duration of response was 39.4 weeks.

In Trial 4, a randomized, multicenter, open-label, trial in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy, patients were randomized to receive either doxorubicin hydrochloride liposome injection 50 mg/m² every 4 weeks (n=239) or topotecan 1.5 mg/m² daily for 5 consecutive days every 3 weeks (n=235). Patients were stratified according to platinum sensitivity (response to initial platinum-based therapy and a progression-free interval of greater than 6 months off treatment) and the presence of bulky disease (tumor mass greater than 5 cm in size). The primary outcome measure was time to progression (TTP). Other endpoints included overall survival and objective response rate.

Of the 474 patients, the median age at diagnosis was 60 years (range 25 to 87), 90% were FIGO stage III and IV; 46% were platinum sensitive; and 45% had bulky disease.

There was no statistically significant difference in TTP between the two arms. Results are provided in Table 10.

Table 10: Results of Efficacy AnalysesAnalysis based on investigators' strata for protocol defined ITT population.

	Protocol Defined ITT Population
	Doxorubicin Hydrochloride Liposome Injection (n=239)	Topotecan (n=235)
TTP (Protocol Specified Primary Endpoint)
Median (Months)Kaplan-Meier estimates.	4.1	4.2
p-valuep-value is based on the stratified log-rank test.	0.62
Hazard RatioHazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for doxorubicin hydrochloride liposome injection.	0.96
95% CI for Hazard Ratio	(0.76, 1.20)
Overall Survival
Median (Months)	14.4	13.7
p-valuep-value not adjusted for multiple comparisons.	0.05
Hazard Ratio	0.82
95% CI for Hazard Ratio	(0.68, 1.00)
Response Rate
Overall Response n (%)	47 (19.7)	40 (17.0)
Complete Response n (%)	9 (3.8)	11 (4.7)
Partial Response n (%)	38 (15.9)	29 (12.3)
Median Duration of Response (Months)	6.9	5.9

14.2 AIDS-Related Kaposis Sarcoma

Doxorubicin hydrochloride liposome injection was studied in an open-label, single-arm, multicenter study at a dose of 20 mg/m² every 3 weeks, until disease progression or unacceptable toxicity (Trial 5).

Data is described for a cohort of 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least two cycles of a regimen containing at least two of three treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. Forty-nine of the 77 (64%) patients had received prior doxorubicin hydrochloride.

The median time on study was 5.1 months (range 1 day to 15 months). The median cumulative dose of doxorubicin hydrochloride liposome injection was 154 mg/m²(range 20 to 620 mg/m²). Among the 77 patients, mean age was 38 years (range 24 to 54); 87% were Caucasian, 5% Hispanic, 4% Black, and 4% Asian/Other/Unknown; median CD4 count was 10 cells/mm³; ACTG staging criteria were 78% poor risk for tumor burden, 96% poor risk for immune system, and 58% poor risk for systemic illness at baseline; and mean Karnofsky status score was 74%. All patients had cutaneous or subcutaneous lesions, 40% also had oral lesions, 26% pulmonary lesions, and 14% had lesions of the stomach/intestine.

Two analyses of tumor response were used: one based on investigator assessment of changes in lesions based on modified ACTG criteria (partial response defined as no new lesions, sites of disease, or worsening edema; flattening of ≥50% of previously raised lesions or area of indicator lesions decreasing by ≥50%; and response lasting at least 21 days with no prior progression), and one based on changes in up to five prospectively indentified representative indicator lesions (partial response defined as flattening of ≥50% of previously raised indicator lesions, or >50% decrease in the area of indicator lesions and lasting at least 21 days with no prior progression).

Of the 77 patients, 34 were evaluable for investigator assessment and 42 were evaluable for indicator lesion assessment; analyses of tumor responses are shown in Table 11.

Table 11: Response in Patients with Refractory¹ AIDS-Related Kaposi's Sarcoma

Investigator Assessment	All Evaluable Patients (n=34)	Evaluable Patients Who Received Prior Doxorubicin (n=20)
Response  There were no complete responses in this population.
Partial (PR)	27%	30%
Stable	29%	40%
Progression	44%	30%
Duration of PR (Days)
Median	73	89
Range	42+ – 210+	42+ – 210+
Time to PR (Days)
Median	43	53
Range	15 – 133	15 – 109
Indicator Lesion Assessment	All Evaluable Patients (n=42)	Evaluable Patients Who Received Prior Doxorubicin (n=23)
Response
Partial (PR)	48%	52%
Stable	26%	30%
Progression	26%	17%
Duration of PR (Days)
Median	71	79
Range	22+ – 210+	35 – 210+
Time to PR (Days)
Median	22	48
Range	15 – 109	15 – 109

Retrospective efficacy analyses were performed in two trials that had subsets of patients who received single-agent doxorubicin hydrochloride liposome injection and who were on stable antiretroviral therapy for at least 60 days prior to enrollment and until a response was demonstrated. In one trial, 7 of 17 (40%) patients had a durable response (median duration not reached but was longer than 11.6 months). In the second trial, 4 of 11 patients (40%) on a stable antiretroviral therapy demonstrated durable responses.

14.3 Multiple Myeloma

The efficacy of doxorubicin hydrochloride liposome injection in combination with bortezomib was evaluated in Trial 6, a randomized, open-label, international, multicenter study in 646 patients who had not previously received bortezomib and whose disease progressed during or after at least one prior therapy. Patients were randomized (1:1) to receive either doxorubicin hydrochloride liposome injection (30 mg/m²) administered IV on day 4 following bortezomib (1.3 mg/m² IV on days 1, 4, 8 and 11) or bortezomib alone every 3 weeks for up to 8 cycles or until disease progression or unacceptable toxicity. Patients who maintained a response were allowed to receive further treatment. The median number of cycles in each treatment arm was 5 (range 1-18).

The baseline demographics and clinical characteristics of the patients with multiple myeloma were similar between treatment arms (Table 12).

Table 12: Summary of Baseline Patient and Disease Characteristics

Patient Characteristics	Doxorubicin Hydrochloride Liposome Injection + Bortezomib n=324	bortezomib n=322
Median age in years (range)	61 (28, 85)	62 (34, 88)
% Male/female	58 / 42	54 / 46
% Caucasian/Black/other	90 / 6 / 4	94 / 4 / 2
Disease Characteristics
% with IgG/IgA/Light chain	57 / 27 / 12	62 / 24 / 11
% β2-microglobulin group
≤2.5 mg/L	14	14
>2.5 mg/L and ≤5.5 mg/L	56	55
>5.5 mg/L	30	31
Serum M-protein (g/dL): Median (Range)	2.5 (0–10.0)	2.7 (0–10.0)
Urine M-protein (mg/24 hours): Median (Range)	107 (0–24883)	66 (0–39657)
Median Months Since Diagnosis	35.2	37.5
% Prior Therapy
One	34	34
More than one	66	66
Prior Systemic Therapies for Multiple Myeloma
Corticosteroid (%)	99	>99
Anthracyclines	68	67
Alkylating agent (%)	92	90
Thalidomide/lenalidomide (%)	40	43
Stem cell transplantation (%)	57	54

The primary outcome measure was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease or death due to progressive disease. The combination arm demonstrated significant improvement in TTP. As the prespecified primary objective was achieved at the interim analysis, patients in the bortezomib monotherapy group were then allowed to receive the doxorubicin hydrochloride liposome injection + bortezomib combination. Efficacy results are as shown in Table 13 and Figure 1.

Table13: Efficacy of Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib in the Treatment of Patients With Multiple Myeloma

Endpoint	Doxorubicin Hydrochloride Liposome Injection + Bortezomib n=324	Bortezomib n=322
Time to ProgressionKaplan Meier estimate.
Progression or death due to progression (n)	99	150
Censored (n)	225	172
Median in days (months)	282 (9.3)	197 (6.5)
95% CI	250; 338	170; 217
Hazard ratioHazard ratio based on stratified Cox proportional hazards regression. A hazard ratio < 1 indicates an advantage for doxorubicin hydrochloride liposome injection+bortezomib.	0.55
(95% CI)	(0.43, 0.71)
p-valueStratified log-rank test.	<0.001
Response (n)RR as per EBMT criteria.	303	310
% Complete Response (CR)	5	3
% Partial Response (PR)	43	40
% CR + PR	48	43
p-valueCochran-Mantel-Haenszel test adjusted for the stratification factors.	0.25
Median Duration of Response (months)	10.2	7.0
(95% CI)	(10.2; 12.9)	(5.9; 8.3)

Figure 1- Time to Progression Kaplan-Meier Curve
At the final analysis of survival, 78% of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had died after a median follow up of 8.6 years. The median survival was 33 months in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 31 months in the bortezomib monotherapy group. There was no difference observed in overall survival at the final analysis [HR for doxorubicin hydrochloride liposome injection + bortezomib vs. bortezomib = 0.96 (95% CI 0.80, 1.14)].

Seventy-eight percent of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had received subsequent therapy.

15 References

• "Hazardous Drugs", OSHA, http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 How Supplied/storage And Handling

Doxorubicin hydrochloride liposome injection is a sterile, translucent, red liposomal dispersion in 10-mL or 25-mL glass, single-dose vials.

The following individually cartoned vials are available:

Table 14

vial concentration	vial size	NDC #s
20 mg/10 mL (2 mg/mL)	10-mL	70748-339-01
50 mg/25 mL (2 mg/mL)	25-mL	70748-340-01

Refrigerate unopened vials of doxorubicin hydrochloride liposome injection at 2°C to 8°C (36°F to 46°F). Do not freeze. Discard unused portion.

Doxorubicin hydrochloride liposome injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

17 Patient Counseling Information

Cardiomyopathy

Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.1)].

Infusion-Related Reactions

Advise patients about the symptoms of infusion-related reactions and to seek immediate medical attention if they develop any of these symptoms [see Warnings and Precautions (5.2)].

Myelosuppression

Advise patients to contact their healthcare provider for a new onset fever or symptoms of infection.

Hand-Foot Syndrome

Advise patients to notify their healthcare provider if they experience tingling or burning, redness, flaking, bothersome swelling, small bulers, or small sores on the palms of their hands or soles of their feet (symptoms of Hand-Foot Syndrome) [see Warnings and Precautions (5.3)].

Stomatitis

Advise patients to notify their healthcare provider if they develop painful redness, swelling, or sores in the mouth (symptoms of stomatitis).

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)].

Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations (8.2)].

Infertility

Advise females and males of reproductive potential that doxorubicin hydrochloride liposome injection may cause temporary or permanent infertility [see Use in Specific Populations (8.3)].

Discoloration of Urine and Body Fluids

Inform patients that following doxorubicin hydrochloride liposome injection administration, a reddish-orange color to the urine and other body fluids may be observed. This nontoxic reaction is due to the color of the product and will dissipate as the drug is eliminated from the body.

Manufactured by:

ForDoz Pharma Corporation

East Windsor, NJ 08520, USA

Distributed by:

Lupin Pharmaceuticals, Inc.

Baltimore, MD 21202, USA

May 2024

Package Label.principal Display Panel

NDC 70748-339-01

DOXOrubicin Hydrochloride Liposome Injection

20 mg/10 mL

(2 mg/mL)

Discard unused portion.

LIPOSOMAL FORMULATION – DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride

For Intravenous Infusion Only After Dilution.

Rx only

Cytotoxic

Refrigerate, 2° to 8°C (36° to 46°F). Do not Freeze.

Note: Liposomal formulation.

Recommended Dosage: See prescribing information.

Vial Label: 10 mL Single-Dose Vial
Carton Label:
NDC 70748-340-01

DOXOrubicin Hydrochloride Liposome Injection

50 mg/25 mL

(2 mg/mL)

Discard unused portion.

LIPOSOMAL FORMULATION – DO NOT SUBSTITUTE FOR DOXORUBICIN Hydrochloride

For Intravenous Infusion Only After Dilution.

Rx only

Cytotoxic

Refrigerate, 2° to 8°C (36° to 46°F). Do not Freeze.

Note: Liposomal formulation.

Recommended Dosage: See prescribing information.

Vial Label: 25 mL Single-Dose Vial
Carton Label: