Drug Safety-related Labeling Changes (SrLC)
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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.
DOCEFREZ (NDA-022534)
(DOCETAXEL)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
08/22/2023 (SUPPL-17)
12/09/2022 (SUPPL-16)
02/01/2021 (SUPPL-12)
02/25/2020 (SUPPL-11)
5 Warnings and Precautions
5.2 Hepatic Impairment(subsection revised, additions underlined)
Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death.
Avoid DOCETAXEL INJECTION in patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN.
For patients with isolated elevations of transaminase >1.5 × ULN, consider DOCETAXEL INJECTION dose modifications.
Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of DOCETAXEL INJECTION therapy.
(subsection revised, additions underlined)
Second primary malignancies, notably acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), Non- Hodgkin’s Lymphoma (NHL), and renal cancer, have been reported in patients treated with docetaxel-containing regimens. These adverse reactions may occur several months or years after docetaxel-containing therapy.
Treatment-related AML or MDS has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received docetaxel (T), doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin, and cyclophosphamide. In TAC- treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. Monitor patients for second primary malignancies.
(additions underlined)
…
Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with docetaxel treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. Permanent treatment discontinuation should be considered in patients who experience SCARs.
6 Adverse Reactions
(addition underlined)…
Second Primary Malignancies
…
(additions underlined)
…
Cutaneous: cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, scleroderma-like changes (usually preceded by peripheral lymphedema), severe palmar-plantar erythrodysesthesia and permanent alopecia have been reported.
…
Hypersensitivity: anaphylactic shock with fatal outcome in patients who received premedication. Severe hypersensitivity reactions with fatal outcome have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.
…
Second primary malignancies: second primary malignancies, including AML, MDS, NHL, and renal cancer, have been reported in patients treated with DOCETAXEL INJECTION-containing regimens.
8 Use in Specific Populations
8.1 Pregnancy(subsection revised, additions underlined)
Risk Summary
Based on findings in animal reproduction studies and its mechanism of action, DOCETAXEL INJECTION can cause fetal harm when administered to a pregnant woman. data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. DOCETAXEL INJECTION contains alcohol which can interfere with neurobehavioral development [see Clinical Considerations]. In animal reproductive studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused an increased incidence of embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively [see Data]. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. 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.
Clinical Considerations
DOCETAXEL INJECTION contains alcohol. Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development.
…
(subsection revised, revision underlined)
Risk Summary
There is no information regarding the presence of docetaxel in human milk, or on its effects on milk production or the breastfed child. No lactation studies in animals have been conducted. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with DOCETAXEL INJECTION and for 1 week after the last dose.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions underlined)
…
Second Primary Malignancies
Advise patients on the risk of second primary malignancies during treatment with DOCETAXEL INJECTION.
…
Neurologic Reactions
Advise patients that neurosensory symptoms or peripheral neuropathy may occur. Instruct patients to immediately report neurologic reactions to their healthcare provider.
…
Other Common Adverse Reactions
Advise patients that other common adverse reactions associated with DOCETAXEL INJECTION may include alopecia (cases of permanent hair loss have been reported), asthenia, anorexia, dysgeusia, mucositis, myalgia, nail disorders, or pain. Instruct patients to report these reactions to their healthcare provider if serious events occur.
…
Lactation
Advise women not to breastfeed during DOCETAXEL INJECTION treatment and for 1 week after the last dose.
Infertility
Advise males of reproductive potential that DOCETAXEL INJECTION may impair fertility
…
(additions and revisions, please refer to label for complete information)
01/08/2019 (SUPPL-7)
5 Warnings and Precautions
5.13 Embryo-Fetal Toxicity(title changed, additions and revisions underlined)
Based on findings from animal reproduction studies and its mechanism of action, DOCETAXEL INJECTION can cause fetal harm when administered to a pregnant woman. Limited available data are not sufficient to inform use of DOCETAXEL INJECTION in pregnant women. In animal reproduction studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesiscaused embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area respectively. Advise pregnant and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiation of DOCETAXEL INJECTION. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of DOCETAXEL INJECTION. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the last dose of DOCETAXEL INJECTION.
(additions underlined)
…
Three breast
cancer patients with severe liver impairment (bilirubin >1.7 times ULN)
developed fatal gastrointestinal bleeding associated with severe drug-induced
thrombocytopenia. In gastric cancer patients treated with docetaxel in
combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or
neutropenic infection occurred in 12% of patients receiving G-CSF compared to
28% who did not. Patients receiving TCF should be closely monitored during the
first and subsequent cycles for febrile neutropenia and neutropenic infection.
(new subsection added)
Enterocolitis and neutropenic colitis (typhlitis) have occurred in patients treated with DOCETAXEL INJECTION alone and in combination with other chemotherapeutic agents, despite the coadministration of G-CSF. Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Enterocolitis and neutropenic enterocolitis may develop at any time, and could lead to death as early as the first day of symptom onset. Monitor patients closely from onset of any symptoms of gastrointestinal toxicity. Inform patients to contact their healthcare provider with new, or worsening symptoms of gastrointestinal toxicity.
(additions underlined)
…
Patients who have previously experienced a hypersensitivity reaction to paclitaxel may develop a hypersensitivity reaction to docetaxel that may include severe or fatal reactions such as anaphylaxis. Monitor patients with a previous history of hypersensitivity to paclitaxel closely during initiation of DOCETAXEL INJECTION therapy. Hypersensitivity reactions may occur within a few minutes following initiation of a DOCETAXEL INJECTION infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of DOCETAXEL INJECTION.
(additions underlined)
Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received docetaxel (T), doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin and cyclophosphamide.In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up.
6 Adverse Reactions
(additions underlined)The most serious adverse reactions from DOCETAXEL INJECTION are:
· Toxic Deaths
· Hepatic Impairment
· Hematologic Effects
· Enterocolitis and Neutropenic Colitis
· Hypersensitivity Reactions
· Fluid Retention
· Acute Myeloid Leukemia
· Cutaneous Reactions
Neurologic Reactions
Eye Disorders
Asthenia
Alcohol Content
…
(extensive additions and revisions, please refer to label)
(additions underlined)
…
Body as a whole: diffuse pain, chest pain, radiation recall phenomenon, injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) at the site of previous extravasation.
Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction. Ventricular arrhythmia including ventricular tachycardia has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5- fluorouracil and/or cyclophosphamide, and may be associated with fatal outcome.
Cutaneous: very rare cases of cutaneous lupus erythematosus and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema. In some cases multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported. Cases of permanent alopecia have been reported.
Gastrointestinal: enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, has been reported with a potential fatal outcome. Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, intestinal obstruction, ileus, and dehydration as a consequence to gastrointestinal events have been reported.
…
Hypersensitivity: rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication. Hypersensitivity reactions with potential fatal outcome have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.
…
Metabolism and nutrition disorders: electrolyte imbalance, including cases of hyponatremia hypokalemia, hypomagnesemia, and hypocalcemia has been reported.
8 Use in Specific Populations
8.1 Pregnancy(PLLR conversion)
Risk Summary
Based on findings in animal reproduction studies and its mechanism of action, DOCETAXEL INJECTION can cause fetal harm when administered to a pregnant woman. Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused an increased incidence of embryo-fetal toxicities, including intra-uterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
Intravenous administration of greater than or equal to 0.3 and 0.03 mg/kg/day docetaxel to pregnant rats and rabbits, respectively, during the period of organogenesis caused an increased incidence of intrauterine mortality, resorptions, reduced fetal weights and fetal ossification delays. Maternal toxicity was also observed at these doses, which were approximately 0.02 and 0.003 times the daily maximum recommended human dose based on body surface area, respectively.
(PLLR conversion)
Risk Summary
There is no information regarding the presence of docetaxel in human milk, or on its effects on milk production or the breast-fed child. No lactation studies in animals have been conducted. Because of the potential for serious adverse reactions in a breast-fed child from docetaxel exposure, including toxic death, hepatotoxicity, neutropenia, and acute myeloid leukemia, advise women not to breastfeed during treatment with DOCETAXEL INJECTION and for 2 weeks after the last dose.
(PLLR conversion)
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating DOCETAXEL INJECTION.
Contraception
Females
DOCETAXEL INJECTION can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of DOCETAXEL INJECTION.
Males
Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the last dose of DOCETAXEL INJECTION .
Infertility Males
Based on findings in animal studies, DOCETAXEL INJECTION may impair fertility in males of reproductive potential
(additions and revisions underlined)
The alcohol content of DOCETAXEL INJECTION should be taken into account when given to pediatric patients.
The efficacy of docetaxel in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of docetaxel in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults.
Another formulation of docetaxel has been studied in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluoruracil (TCF).
…
Docetaxel in Combination
Docetaxel was studied in combination with cisplatin and 5-fluorouracil (TCF) versus cisplatin and 5-fluorouracil (CF) for the induction treatment of nasopharyngeal carcinoma (NPC) in pediatric patients prior to chemoradiation consolidation. Seventy-five patients (median age 16 years, range 9 to 21 years) were randomized (2:1) to docetaxel (75 mg/m2) in combination with cisplatin (75 mg/m2) and 5-fluorouracil (750 mg/m²) (TCF) or to cisplatin (80 mg/m2) and 5-fluorouracil (1,000 mg/m2/day) (CF). The primary endpoint was the CR rate following induction treatment of NPC. One patient out of 50 in the TCF group (2%) had a complete response while none of the 25 patients in the CF group had a complete response.
…
Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m2 in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). Docetaxel clearance was 17.9±8.75 L/h/m2, corresponding to an AUC of 4.2±2.57 mcg.h/mL.
In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults.
(additions underlined)
…
Breast Cancer
In the adjuvant breast cancer trial (TAX316), docetaxel in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients.
Gastric Cancer
Among the 221 patients treated with docetaxel in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates greater than or equal to 10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored.
Head and Neck Cancer
Among the 174 and 251 patients who received the induction treatment with docetaxel in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively.
These clinical studies of docetaxel in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(extensive additions and revisions, please refer to label)
(reformatted and additions, please refer to label)