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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
DOXORUBICIN HYDROCHLORIDE (NDA-050629)
(DOXORUBICIN HYDROCHLORIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/20/2019 (SUPPL-28)
Boxed Warning
(Additions and/or revisions underlined)
Cardiomyopathy: Myocardial damage, including acute left ventricular failure, can occur with doxorubicin hydrochloride. The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 1% - 20% for cumulative doses ranging from 300 mg/m2 to 500 mg/m2 when doxorubicin hydrochloride is administered every 3 weeks. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess left ventricular ejection fraction (LVEF) before and regularly during and after treatment with doxorubicin hydrochloride.
Secondary Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines, including doxorubicin hydrochloride.
Extravasation and Tissue Necrosis: Extravasation of doxorubicin hydrochloride can result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting. Immediately terminate the drug and apply ice to the affected area.
4 Contraindications
(Additions and/or revisions underlined)
Doxorubicin Hydrochloride Injection/for Injection are contraindicated in patients with:
Severe myocardial insufficiency
Recent (occurring within the past 4-6 weeks) myocardial infarction
Severe persistent drug-induced myelosuppression
Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL)
Severe hypersensitivity reaction to doxorubicin hydrochloride, including anaphylaxis
5 Warnings and Precautions
5.1 Cardiomyopathy and Arrhythmias(Additions and/or revisions underlined)
Cardiomyopathy
Doxorubicin hydrochloride can result in myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy is generally proportional to the cumulative exposure. Include prior doses of other anthracyclines or anthracenediones in calculations of total cumulative dosage for doxorubicin hydrochloride. Cardiomyopathy may develop during treatment or up to several years after completion of treatment and can include decrease in LVEF and signs and symptoms of congestive heart failure (CHF). The probability of developing cardiomyopathy is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin hydrochloride, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at a dose of 450 mg/m2, and 6 to 20% at a dose of 500 mg/m2, when doxorubicin hydrochloride is administered every 3 weeks. There is an additive or potentially synergistic increase in the risk of cardiomyopathy in patients who have received radiotherapy to the mediastinum or concomitant therapy with other known cardiotoxic agents, such as cyclophosphamide and trastuzumab.
Pericarditis and myocarditis have also been reported during or following doxorubicin hydrochloride treatment.
Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of Doxorubicin Hydrochloride Injection/for Injection, during treatment to detect acute changes, and after treatment to detect delayed cardiotoxicity. Increase the frequency of assessments as the cumulative dose exceeds 300 mg/m2. Use the same method of assessment of LVEF at all time points. Discontinue Doxorubicin Hydrochloride Injection/for Injection in patients who develop signs or symptoms of cardiomyopathy.
Consider the use of dexrazoxane to reduce the incidence and severity of cardiomyopathy due to doxorubicin hydrochloride administration in patients who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m2 and who will continue to receive doxorubicin hydrochloride.
Arrhythmias
Doxorubicin hydrochloride can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours after doxorubicin hydrochloride administration and at any time point during treatment. Tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia, can occur. Electrocardiographic changes, including non-specific ST-T wave changes, atrioventricular and bundle-branch block can also occur. These electrocardiographic changes may be transient and self-limited and may not require a dosage modification of doxorubicin hydrochloride.
(Additions and/or revisions underlined)
The risk of developing secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is increased following treatment with doxorubicin hydrochloride. Cumulative incidences ranged from 0.2% at five years to 1.5% at 10 years in two separate trials involving the adjuvant treatment of women with breast cancer. These leukemias generally occur within 1 to 3 years of treatment.
(Additions and/or revisions underlined)
Extravasation of doxorubicin hydrochloride can cause severe local tissue injury manifesting as blistering, ulceration, and necrosis requiring wide excision of the affected area and skin grafting. Extravasation should be considered if a patient experiences a burning or stinging sensation or shows other evidence indicating peri-venous infiltration or extravasation; however, extravasation may be present in patients who do not experience a stinging or burning sensation or when blood return is present on aspiration of the infusion needle.
When given via a peripheral venous line, infuse Doxorubicin Hydrochloride Injection/for Injection over 10 minutes or less to minimize the risk of thrombosis or perivenous extravasation.
If extravasation is suspected, immediately discontinue the intravenous injection or continuous intravenous infusion. Apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days. In adults, if appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation.
(Additions and/or revisions underlined)
Doxorubicin hydrochloride can cause myelosuppression. In Study 1, the incidence of severe myelosuppression was: grade 4 leukopenia (0.3%), grade 3 leukopenia (3%), and grade 4 thrombocytopenia (0.1%). A dose-dependent, reversible neutropenia is the predominant manifestation of myelosuppression from doxorubicin hydrochloride.(Additions and/or revisions underlined)
Doxorubicin hydrochloride can cause myelosuppression. In Study 1, the incidence of severe myelosuppression was: grade 4 leukopenia (0.3%), grade 3 leukopenia (3%), and grade 4 thrombocytopenia (0.1%). A dose-dependent, reversible neutropenia is the predominant manifestation of myelosuppression from doxorubicin hydrochloride.
When doxorubicin hydrochloride is administered every 21 days, the neutrophil count reaches its nadir 10 to 14 days after administration with recovery usually occurring by day 21.
Obtain complete blood counts prior to each treatment and carefully monitor patients during treatment for possible clinical complications due to myelosuppression. Delay next dose of Doxorubicin Hydrochloride Injection/for Injection if severe myelosuppression has not improved. Consider dose reduction for patients with prolonged myelosuppression based on severity of reaction.
(Additions and/or revisions underlined)
The clearance of doxorubicin is decreased in patients with elevated serum bilirubin with an increased risk of toxicity. Doxorubicin Hydrochloride Injection/for Injection is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL). Reduce the dose of Doxorubicin Hydrochloride Injection/for Injection in patients with serum bilirubin levels of 1.2 to 5 mg/dL. Obtain liver tests including ALT, AST, alkaline phosphatase, and bilirubin prior to and during therapy.
(Additions and/or revisions underlined)
Doxorubicin hydrochloride can induce tumor lysis syndrome in patients with rapidly growing tumors. Evaluate blood uric acid levels, potassium, calcium, phosphate, and creatinine after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome.
(Additions and/or revisions underlined)
Doxorubicin hydrochloride can increase radiation-induced toxicity to the myocardium, mucosa, skin, and liver. Radiation recall, including but not limited to cutaneous and pulmonary toxicity, can occur in patients who receive doxorubicin hydrochloride after prior radiation therapy.
(Additions and/or revisions underlined)
Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection/for Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection/for 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. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses lower than the recommended human dose. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection/for Injection and for 6 months after treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection/for Injection and for 3 months after treatment. Advise males with pregnant partners to use condoms during treatment with Doxorubicin Hydrochloride Injection/for Injection and for at least 10 days after the final dose.
6 Adverse Reactions
(Additions and/or revisions underlined)
The following clinically significant adverse reactions are described elsewhere in the labeling.
- Cardiomyopathy and Arrhythmias
Secondary Malignancies
Extravasation and Tissue Necrosis
Severe Myelosuppression
Tumor Lysis Syndrome
Radiation Sensitization and Radiation Recall
(Additions and/or revisions underlined)
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Breast Cancer
The safety data below were collected from 1492 women who received doxorubicin hydrochloride at a dose of 60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 (AC) every 3 weeks for 4 cycles for the adjuvant treatment of axillary lymph node positive breast cancer.
The median number of cycles received was 4. Selected adverse reactions reported in this study are provided in Table 2. No treatment-related deaths were reported in patients on either arm of the study.
(Additions and/or revisions underlined)
The following adverse reactions have been identified during postapproval use of Doxorubicin Hydrochloride Injection/for Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiac – Cardiogenic shock
Cutaneous – Skin and nail hyperpigmentation, oncolysis, rash, itching, photosensitivity, urticaria, acral erythema, palmar plantar erythrodysesthesia
Gastrointestinal – Nausea, mucositis, stomatitis, necrotizing colitis, typhlitis, gastric erosions, gastrointestinal tract bleeding, hematochezia, esophagitis, anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation of the oral mucosa
Hypersensitivity – Anaphylaxis
Laboratory Abnormalities – Increased ALT, increased AST
Neurological – Peripheral sensory and motor neuropathy, seizures, coma
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Risk Summary
Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection/for Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection/for 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. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and embryotoxic in rabbits when administered during organogenesis at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m2. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
Doxorubicin hydrochloride was teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) when administered during the period of organogenesis in rats. Teratogenicity and embryotoxicity were also seen using discrete periods of treatment. The most susceptible was the 6- to 9-day gestation period at doses of 1.25 mg/kg/day and greater. Characteristic malformations included esophageal and intestinal atresia, tracheo-esophageal fistula, hypoplasia of the urinary bladder, and cardiovascular anomalies. Doxorubicin hydrochloride was embryotoxic (increase in embryofetal deaths) and abortifacient at 0.4 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) in rabbits when administered during the period of organogenesis.
(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)
Summary
Doxorubicin was measured in the milk of one lactating patient after therapy with 70 mg/m2 of doxorubicin hydrochloride given as a 15-minute intravenous infusion. The peak milk concentration at 24 hours after treatment was 4.4-fold greater than the corresponding plasma concentration. Doxorubicin was detectable in the milk up to 72 hours. There are no data on the effects of doxorubicin hydrochloride on the breastfed child or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Doxorubicin Hydrochloride Injection/for Injection and for 10 days after the final dose.
(Newly added subsection)
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating Doxorubicin Hydrochloride Injection/for Injection.
Contraception
Females
Doxorubicin Hydrochloride Injection/for Injection can cause fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use highly effective contraception during treatment with Doxorubicin Hydrochloride Injection/for Injection and for 6 months after treatment.
Males
Doxorubicin hydrochloride may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Due to the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection/for Injection and for 3 months after treatment. Males with pregnant partners should use condoms during treatment and for at least 10 days after the final dose.
Infertility
Females
In females of reproductive potential, Doxorubicin hydrochloride may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment.
(Additions and/or revisions underlined)
Based on postmarketing reports, pediatric patients treated with doxorubicin hydrochloride are at risk for developing late cardiovascular dysfunction. Risk factors include young age at treatment (especially < 5 years), high cumulative doses and receipt of combined modality therapy.
Long-term periodic cardiovascular monitoring is recommended for all pediatric patients who have received doxorubicin hydrochloride. Doxorubicin hydrochloride, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure and may also contribute to gonadal impairment, which is usually temporary.
There are no recommended dose adjustments based on age. Doxorubicin clearance was increased in patients aged 2 years to 20 years as compared to adults, while doxorubicin clearance was similar in infants less than 2 years as compared to adults.
(Additions and/or revisions underlined)
The clearance of doxorubicin was reduced in patients with elevated serum total bilirubin levels.
Doxorubicin Hydrochloride Injection/for Injection is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin levels greater than 5mg/dL).
Reduce the dose of Doxorubicin Hydrochloride Injection/for Injection in patients with serum total bilirubin levels greater than 1.2 mg/dL.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 Patient Counseling Information(Extensive changes; please refer to label)
(Extensive changes; please refer to label)
08/09/2019 (SUPPL-29)
7 Drug Interactions
7.1 Other Drugs on Doxorubicin Hydrochloride Injection/for Injection
(Additions and/or revisions are underlined)
Inhibitors of CYP3A4, CYP2D6, and P-gp
Concomitant use of doxorubicin hydrochloride with inhibitors of CYP3A4, CYP2D6, or P-glycoprotein (P-gp), increased concentrations of doxorubicin, which may increase the incidence and severity of adverse reactions of doxorubicin hydrochloride. Avoid concomitant use of Doxorubicin Hydrochloride Injection/for Injection with inhibitors of CYP3A4, CYP2D6, or P-gp.
Inducers of CYP3A4, CYP2D6, or P-gp
Concomitant use of doxorubicin hydrochloride with inducers of CYP3A4, CYP2D6, or P-gp may decrease the concentration of doxorubicin. Avoid concomitant use of Doxorubicin Hydrochloride Injection/for Injection with inducers of CYP3A4, CYP2D6, or P-gp.
Paclitaxel, when given prior to doxorubicin hydrochloride, increases the plasma-concentrations of doxorubicin and its metabolites. Administer Doxorubicin Hydrochloride Injection/for Injection prior to paclitaxel if used concomitantly.
7.2 Concomitant Use of Trastuzumab
(Additions and/or revisions are underlined)
Patients receiving doxorubicin after stopping treatment with trastuzumab may also be at an increased risk of developing cardiotoxicity. Trastuzumab may persist in the circulation for up to 7 months. Therefore, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, carefully monitor cardiac function.
7.3 Concomitant Use of Dexrazoxane
(Additions and/or revisions are underlined)
Do not administer dexrazoxane as a cardioprotectant at the initiation of doxorubicin hydrochloride-containing chemotherapy regimens. In a randomized trial in women with metastatic breast cancer, initiation of dexrazoxane with doxorubicin hydrochloride-based chemotherapy resulted in a significantly lower tumor response rate (48% vs. 63%; p=0.007) and shorter time to progression compared to doxorubicin hydrochloride-based chemotherapy alone.
7.4 Concomitant Use of 6-Mercaptopurine
(Additions and/or revisions are underlined)
Doxorubicin hydrochloride may potentiate 6-mercaptopurine-induced hepatotoxicity. In
11 patients with refractory leukemia treated with 6-mercaptopurine (500 mg/m2 intravenously daily for 5 days per cycle every 2-3 weeks) and doxorubicin hydrochloride (50 mg/m2 intravenous once per cycle every 2-3 weeks) alone or with vincristine and prednisone, all developed hepatic dysfunction manifested by increased total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.