Doxorubicin - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS Hand-Foot Syndrome may occur.

Dose modification or discontinuation may be required Embryo-Fetal Toxicity: Can cause fetal harm.

Advise of potential risk to a fetus.

Use effective contraception ( 5.5 , 8.1 , 8.3 ) 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/m 2 to 550 mg/m 2 .

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 ].

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 infusion 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.