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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.
SPRYCEL (NDA-021986)
(DASATINIB)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/08/2023 (SUPPL-27)
5 Warnings and Precautions
5.11 Hepatotoxicity
Newly added subsection:
SPRYCEL may cause hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase [see Adverse Reactions (6.1)]. Monitor transaminases at baseline and monthly or as clinically indicated during treatment. Reduce dose, withhold, or permanently discontinue SPRYCEL based on severity [see Dosage and Administration (2.5)]. When SPRYCEL is administered in combination with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Monitor hepatic function when SPRYCEL is used in combination with chemotherapy.
6 Adverse Reactions
Addition of the following to the bulleted line listing:
Hepatotoxicity [see Warnings and Precautions (5.11)].
6.2 Postmarketing Experience
Additions and/or revisions underlined:
Hepatobiliary disorders: hepatotoxicity
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Newly added section:
Hepatotoxicity
Advise patients that SPRYCEL can cause hepatotoxicity and that patients with previous history of liver diseases may be at risk. Advise patients to seek immediate medical attention if any symptoms suggestive of hepatotoxicity occur, such as abdominal pain, jaundice and scleral icterus, anorexia, bleeding, bruising, and dark-colored urine [see Warnings and Precautions (5.11)].
PATIENT INFORMATION
Additions and/or revisions underlined:
Before taking SPRYCEL, tell your healthcare provider about all of your medical conditions, including if you:
…
- have liver problems
…
SPRYCEL may cause serious side effects, including:
…
Liver problems. SPRYCEL can cause liver problems. People who have had liver problems in the past may be at risk for getting liver problems with SPRYCEL. Your healthcare provider will monitor your liver function as needed during the treatment with SPRYCEL. Call your healthcare provider or get medical help right away if you develop any symptoms of liver problems, including:
stomach-area (abdominal) pain
bleeding
yellowing of your skin or white part of your eyes
bruising
loss of appetite
dark “tea-colored” urine
06/29/2021 (SUPPL-25)
5 Warnings and Precautions
5.9 Embryo-Fetal Toxicity
(Additions and/or revisions are underlined)
Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects of SPRYCEL including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with SPRYCEL and for 30 days after the last dose [see Use in Specific Populations (8.1, 8.3)].
8 Use in Specific Populations
8.3 Females and Males of Reproductive Potential
(Additions and/or revisions are underlined)
SPRYCEL can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with SPRYCEL and for 30 days after the last dose.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
(Additions and/or revisions are underlined)
Cardiovascular Toxicity
Inform patients of the possibility of developing cardiovascular toxicity, including cardiac ischemic events, cardiac-related fluid retention, conduction abnormalities, and TIAs. Advise patients to seek immediate medical attention if symptoms suggestive of cardiovascular toxicity occur, such as chest pain, shortness of breath, palpitations, transient vision problems, or slurred speech [see Warnings and Precautions (5.4)].
Embryo-Fetal Toxicity
Advise pregnant women of the potential risk to a fetus [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)].
Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with SPRYCEL and for 30 days after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking SPRYCEL [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1, 8.3)].
Instructions for Taking SPRYCEL
Missed Dose
Advise patients that if they miss a dose of SPRYCEL, they should take the next scheduled dose at its regular time. The patient should not take two doses at the same time.
Grapefruit Juice
Advise patients not to drink grapefruit juice as it may increase the amount of SPRYCEL in their blood and therefore increase their risk of adverse reactions.
12/21/2018 (SUPPL-21)
5 Warnings and Precautions
5.1 Myelosuppression(Additions and/or revisions are underlined)
In pediatric patients with Ph+ ALL treated with SPRYCEL in combination with chemotherapy, perform CBCs prior to the start of each block of chemotherapy and as clinically indicated. During the consolidation blocks of chemotherapy, perform CBCs every 2 days until recovery.
(Additions and/or revisions are underlined)
Monitor bone growth and development in pediatric patients.
6 Adverse Reactions
6.1 Clinical Trials Experience(Additions and/or revisions are underlined)
The data described below reflect exposure to SPRYCEL administered as single-agent therapy at all doses tested in clinical studies (n=2809), including 324 adult patients with newly diagnosed chronic phase CML, 2388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL, and 97 pediatric patients with chronic phase CML. The median duration of therapy in a total of 2712 adult patients was 19.2 months (range 0 to 93.2 months)…
Chronic Myeloid Leukemia (CML)
Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of pediatric patients with chronic phase CML.
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in Pediatric Patients
The safety of SPRYCEL administered continuously in combination with multiagent chemotherapy was determined in a multicohort study of 81 pediatric patients with newly diagnosed Ph+ ALL. The median duration of therapy was 24 months (range 2 to 27 months).
Fatal adverse reactions occurred in 3 patients (4%), all of which were due to infections. Eight (10%) patients experienced adverse reactions leading to treatment discontinuation, including fungal sepsis, hepatotoxicity in the setting of graft versus host disease, thrombocytopenia, CMV infection, pneumonia, nausea, enteritis and drug hypersensitivity.
The most common serious adverse reactions (incidence greater than or equal to 10%) were pyrexia, febrile neutropenia, mucositis, diarrhea, sepsis, hypotension, infections (bacterial, viral and fungal), hypersensitivity, vomiting, renal insufficiency, abdominal pain, and musculoskeletal pain.
The incidence of common adverse reactions (incidence >20%) on study are shown in Table 14:
The incidence of common adverse reactions attributed by the investigator to SPRYCEL (reported at a frequency of ?10%, all grades and grade 3/4, respectively) on study (N=81), included febrile neutropenia (23%, 23%), nausea (21%, 4%), vomiting (19%, 4%), mucositis (17%, 6%),
musculoskeletal pain (17%, 2%), abdominal pain (16%, 5%), diarrhea (16%, 7%), rash (15%, 0%),
fatigue (12%, 0%), pyrexia (12%, 6%), and headache (12%, 5%).
CTCAE grade 3/4 laboratory abnormalities in pediatric patients with Ph+ ALL treated with SPRYCEL in combination with chemotherapy are shown in Table 15.
8 Use in Specific Populations
8.4 Pediatric Use(Additions and/or revisions are underlined)
Ph+ CML in Chronic Phase
The safety and effectiveness of SPRYCEL monotherapy have been demonstrated in pediatric patients with newly diagnosed chronic phase CML. There are no data in children under 1 year of age. Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of patients.
Ph+ ALL
The safety and effectiveness of SPRYCEL in combination with chemotherapy have been demonstrated in pediatric patients one year and over with newly diagnosed Ph+ ALL. Use of SPRYCEL in pediatric patients is supported by evidence from one pediatric study. There are no data in children under 1 year of age. One case of grade 1 osteopenia was reported.
Pediatric Patients with Difficulty Swallowing Tablets
Five patients with Ph+ ALL 2 to 10 years of age received at least one dose of SPRYCEL tablet dispersed in juice on Study CA180372. The exposure for dispersed tablets was 36% lower as compared to intact tablets in pediatric patients. Due to the limited available clinical data, it is unclear whether dispersing SPRYCEL tablets significantly alters the safety and/or efficacy of SPRYCEL
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION11/15/2018 (SUPPL-23)
6 Adverse Reactions
6.3 Postmarketing Experience(addition underlined)
…
Blood and lymphatic system disorders: thrombotic microangiopathy
11/09/2017 (SUPPL-20)
5 Warnings and Precautions
5.10 Effects on Growth and Development in Pediatric Patients(new subsection added)
In pediatric trials of SPRYCEL in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia. Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment.
(additions underlined)
SPRYCEL can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade greater than or equal to 3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving SPRYCEL. The incidence of Grade 3/4 hemorrhage, occurred in 5.8% of adult patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The most frequent site of hemorrhage was gastrointestinal. Most bleeding events in clinical studies were associated with severe thrombocytopenia. In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro.
Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage.
(additions underlined)
SPRYCEL may cause fluid retention. After 5 years of follow-up in the adult randomized newly diagnosed chronic phase CML study (n=258), Grade 3 or 4 fluid retention was reported in 5% of patients, including 3% of patients with Grade 3 or 4 pleural effusion. In adult patients with newly diagnosed or imatinib-resistant or -intolerant chronic phase CML, Grade 3 or 4 fluid retention occurred in 6% of patients treated with SPRYCEL at the recommended dose (n=548). In adult patients with advanced phase CML or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), Grade 3 or 4 fluid retention was reported in 8% of patients, including Grade 3 or 4 pleural effusion reported in 7% of patients. In pediatric patients with chronic phase CML, cases of Grade 1 or 2 fluid retention were reported in 10.3% of patients.
…
6 Adverse Reactions
(addition underlined)…
Effects on growth and development in pediatric patients
(extensive additions and revisions, please refer to label)
(additions underlined)
The following additional adverse reactions were reported in adult and pediatric patients (n=2809) in SPRYCEL CML and Ph+ ALL clinical studies at a frequency of greater than or equal to10%, 1%–<10%, 0.1%–<1%, or <0.1%. These adverse reactions are included based on clinical relevance.
…
General Disorders and Administration-Site Conditions: Greater than or equal to10% – peripheral edema, face edema; 1%–<10% – asthenia, chest pain, chills; 0.1%–<1% – malaise, other superficial edema, peripheral swelling; <0.1% – gait disturbance.
…
Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular weakness, musculoskeletal stiffness; 0.1%–<1% – rhabdomyolysis, tendonitis, muscle inflammation, osteonecrosis, arthritis; <0.1% – epiphyses delayed fusion (reported at 1%–<10% in the pediatric studies), growth retardation (reported at 1%–<10% in the pediatric studies).
7 Drug Interactions
7.1 Effect of Other Drugs on Dasatinib(subsection revised, additions underlined)
Strong CYP3A4 Inhibitors
The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations. Increased dasatinib concentrations may increase the risk of toxicity. Avoid concomitant use of strong CYP3A4 inhibitors. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a SPRYCEL dose reduction.
Strong CYP3A4 Inducers
The coadministration of SPRYCEL with strong CYP3A inducers may decrease dasatinib concentrations. Decreased dasatinib concentrations may reduce efficacy. Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a SPRYCEL dose increase.
Gastric Acid Reducing Agents
The coadministration of SPRYCEL with a gastric acid reducing agent may decrease the concentrations of dasatinib. Decreased dasatinib concentrations may reduce efficacy.
Do not administer H2 antagonists or proton pump inhibitors with SPRYCEL. Consider the use of antacids in place of H2 antagonists or proton pump inhibitors. Administer the antacid at least 2 hours prior to or 2 hours after the dose of SPRYCEL. Avoid simultaneous administration of SPRYCEL with antacids.
8 Use in Specific Populations
8.4 Pediatric Use(subsection revised, additions underlined)
The safety and efficacy of SPRYCEL in 97 pediatric patients with chronic phase CML were evaluated in two pediatric studies (a Phase I, open-label, non-randomized dose-ranging trial and a Phase II, open-label, non-randomized trial). Fifty-one patients (exclusively from the Phase II trial) were newly diagnosed with chronic phase CML and 46 patients (17 from the Phase I trial and 29 from the Phase II trial) were resistant or intolerant to previous treatment with imatinib. The majority of patients were treated with SPRYCEL tablets 60 mg/m2 once daily (maximum dose of 100 mg once daily for patients with high BSA). Patients were treated until disease progression or unacceptable toxicity. The safety profile of dasatinib in pediatric subjects was comparable to that reported in studies in adult subjects with chronic phase CML. Monitor bone growth and development in pediatric patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions underlined)
…
Pulmonary Arterial Hypertension
Patients should be informed of the possibility of developing pulmonary arterial hypertension (dyspnea, fatigue, hypoxia, and fluid retention) and advised to seek medical attention promptly if those symptoms arise.
Tumor Lysis Syndrome
Patients should be informed to immediately report and seek medical attention for any symptoms such as nausea, vomiting, weakness, edema, shortness of breath, muscle cramps, and seizures, which may indicate tumor lysis syndrome.
Growth and Development in Pediatric Patients
Pediatric patients and their caregivers should be informed of the possibility of developing bone growth abnormalities, bone pain, or gynecomastia and advised to seek medical attention promptly if those symptoms arise.
…
Gastrointestinal Complaints
Patients should be informed that they may experience nausea, vomiting, or diarrhea with SPRYCEL. If these symptoms are bothersome or persistent, they should seek medical attention.
Advise patients using antacids to avoid taking SPRYCEL and antacids less than 2 hours apart.
What is SPRYCEL?
SPRYCEL is a prescription medicine used to treat:
...
children with Ph+ CML in chronic phase.
…
What are the possible side effects of SPRYCEL? SPRYCEL may cause serious side effects, including:
…
Slowing of growth and development in children. Effects on bone growth and development in children with chronic phase CML have happened with SPRYCEL and can sometimes be severe.
…
How should I store SPRYCEL?
Store SPRYCEL at room temperature between 68°F to 77°F (20°C to 25°C).
Ask your healthcare provider or pharmacist about the right way to throw away expired or unused SPRYCEL.
Wear latex or nitrile gloves when handling tablets that have accidentally been crushed or broken.
Females who are pregnant should not handle crushed or broken SPRYCEL tablets.
Keep SPRYCEL and all medicines out of the reach of children.
…
08/10/2017 (SUPPL-19)
6 Adverse Reactions
6.4 Postmarketing Experience(Additions and/or revisions are underlined)
Renal and urinary disorders: nephrotic syndrome
09/27/2016 (SUPPL-18)
6 Adverse Reactions
6.3 Postmarketing Experience (addition underlined)Infections: hepatitis B virus reactivation