Drug Safety-related Labeling Changes (SrLC)
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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.
TRISENOX (NDA-021248)
(ARSENIC TRIOXIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/20/2020 (SUPPL-19)
06/20/2019 (SUPPL-18)
01/12/2018 (SUPPL-15)
5 Warnings and Precautions
5.1 Differentiation Syndrome(additions underlined)
Differentiation syndrome, which may be life-threatening or fatal, has been observed in patients with acute promyelocytic leukemia (APL) treated with TRISENOX. In clinical trials, 16-23% of patients treated with TRISENOX for APL developed differentiation syndrome. Symptoms include unexplained fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusion, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy and multi-organ dysfunction. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, and it has occurred as early as day 1 of induction to as late as the second month induction therapy. When TRISENOX is used in combination with tretinoin, prednisone prophylaxis is advised.
At the first signs of differentiation syndrome, interrupt treatment with TRISENOX and administer dexamethasone 10 mg intravenously twice daily. Continue high-dose steroids until signs and symptoms have abated for at least 3 days.
(additions underlined)
Patients
treated with TRISENOX can develop QTc prolongation,
torsade de pointes, and complete heart
block. In the clinical trials of patients with newly-diagnosed low-risk
APL treated with TRISENOX in combination
with tretinoin, 11% experienced QTc prolongation > 450 msec for men and >
460 msec for women throughout the treatment cycles. In the clinical trial of
patients with relapsed or refractory APL treated with TRISENOX monotherapy, 40%
had at least one ECG tracing with a QTc interval greater than 500 msec. A
prolonged QTc was observed between 1
and 5 weeks after start of TRISENOX infusion, and it usually resolved
by 8 weeks after TRISENOX infusion.There are no data on the effect of TRISENOX on the
QTc interval during the infusion of the drug.
The risk of torsade de pointes is related to the extent of QTc prolongation, concomitant administration of QTc prolonging drugs, a history of torsade de pointes, pre-existing QTc interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. The risk may be increased when TRISENOX is coadministered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B).
Prior to initiating therapy with TRISENOX, assess the QTc interval by electrocardiogram, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong QTc interval. Do not administer TRISENOX to patients with ventricular arrhythmia or prolonged QTc. If possible, discontinue drugs that are known to prolong the QTc interval. If it is not possible to discontinue the interacting drug, perform cardiac monitoring frequently [see Drug Interactions (7)]. During TRISENOX therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. Monitor ECG weekly, and more frequently for clinically unstable patients.
For patients who develop a QTc greater than 500 msec, immediately withhold treatment with TRISENOX and any medication known to prolong the QTc interval. Correct electrolyte abnormalities. When the QTc normalizes, resume TRISENOX at a reduced dose.
(new subsection added)
In the clinical trials, 44% of patients with newly-diagnosed low-risk APL treated with TRISENOX in combination with tretinoin experienced elevated aspartate aminotransferase (AST), alkaline phosphatase, and/or serum bilirubin. These abnormalities resolved with temporary discontinuation of TRISENOX and/or tretinoin. During treatment with TRISENOX, monitor liver chemistries at least 2-3 times per week through recovery from toxicities. Withhold treatment with TRISENOX and/or tretinoin if elevations in AST), alkaline phosphatase, and/or serum bilirubin occur to greater than 5 times the upper limit of normal.
Long-term liver abnormalities can occur in APL patients treated with TRISENOX in combination with tretinoin. In a published series, mild liver dysfunction and hepatic steatosis were seen in 15% and 43%, respectively, of patients at a median of 7 years (range 0-14 years) after treatment with arsenic trioxide in combination with tretinoin.
6 Adverse Reactions
(additions underlined)…
Hepatotoxicity
…
(extensive additions and revisions, please refer to label)
(additions underlined)
The following reactions have been reported from clinical trials and/or worldwide postmarketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.
Cardiac disorders: Ventricular extrasystoles in association with QT prolongation, ventricular tachycardia in association with QT prolongation, including torsade de pointes, atrioventricular block, and congestive heart failure
Nervous system disorders: Peripheral neuropathy, paresis, seizures, confusion
Hematologic disorders: Pancytopenia, bone marrow necrosis
Infections and infestations: Herpes zoster
Investigations: Gamma-glutamyltransferase increased
Musculoskeletal and connective tissue disorders: Bone pain, myalgia, rhabdomyolysis
Respiratory, thoracic, and mediastinal disorders: Differentiation syndrome, like retinoic acid syndrome, has been reported with the use of TRISENOX for the treatment of malignancies other than APL [see Boxed Warning].
Ear and labyrinth disorders: Deafness
Neoplasms benign, malignant and unspecified: Melanoma, pancreatic cancer, squamous cell carcinoma
Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis
7 Drug Interactions
(additions underlined)
…
Drugs That Can Lead to Hepatotoxicity
Concomitant use of these drugs and TRISENOX, particularly when given in combination with tretinoin, may increase the risk of serious hepatotoxicity. Discontinue or replace with an alternative drug that does not cause hepatotoxicity while the patient is using TRISENOX.
Monitor liver function tests more frequently in patients when it is not feasible to avoid concomitant use.
8 Use in Specific Populations
8.1 Pregnancy(additions underlined)
Risk Summary
Based on the mechanism of action and findings in animal studies, TRISENOX can cause fetal harm when administered to a pregnant woman. Arsenic trioxide was embryolethal and teratogenic in rats when administered on gestation day 9 at a dose approximately 10 times the recommended human daily dose on a mg/m² basis (see Data). A related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at a dose approximately 5 times the projected human dose on a mg/m² basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m² basis. There are no studies with the use of TRISENOX in pregnant women, and limited published data on arsenic trioxide use during pregnancy are insufficient to inform a drug- associated risk of major birth defects and miscarriage. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, 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 2-4% and 15-20%, respectively.
Data
Human Data
One patient was reported to deliver a live infant with no reported congenital anomalies after receiving arsenic trioxide during the first five months of pregnancy. A second patient became pregnant three months after discontinuing arsenic trioxide and was reported to have a normal pregnancy outcome. A third patient was a pregnant healthcare provider who experienced dermal contact with liquid arsenic trioxide and had a normal pregnancy outcome after treatment and monitoring. A fourth patient who became pregnant while receiving arsenic trioxide had a miscarriage.
…
(additions underlined)
Risk Summary
Arsenic trioxide is excreted in human milk. There is no information on the effects of arsenic trioxide on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child from TRISENOX, discontinue breastfeeding during treatment with TRISENOX and for two weeks after the final dose.
(additions underlined)
Pregnancy Testing
TRISENOX can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing in females of reproductive potential prior to initiation of treatment with TRISENOX.
Contraception
Females
Advise females of reproductive potential to use effective contraception during and after treatment with TRISENOX and for six months after the final dose.
Males
Advise males with female sexual partners of reproductive potential to use effective contraception during and after treatment with TRISENOX and for three months after the final dose.
Infertility
Males
Based on testicular toxicities including decreased testicular weight and impaired spermatogenesis observed in animal studies, TRISENOX may impair fertility in males of reproductive potential.
(additions underlined)
The safety and efficacy of TRISENOX in combination with tretinoin in pediatric patients has not been established.
The safety and efficacy of TRISENOX as a single agent for treatment of pediatric patients with relapsed or refractory APL is supported by the pivotal phase 2 study in 40 patients with relapsed or refractory APL. Five patients below the age of 18 years (age range: 5 to 16 years) were treated with TRISENOX at the recommended dose of 0.15 mg/kg/day. A literature review included an additional 17 patients treated with arsenic trioxide for relapsed or refractory APL, with ages ranging from 4 to 21 years. No differences in efficacy and safety were observed by age.
(additions underlined)
Use of TRISENOX in combination with tretinoin in newly-diagnosed adult patients with low- risk APL is supported by a randomized, controlled trial that included 16 patients between the ages of 60 and 70 years. No differences in efficacy and safety were observed by age. A literature review included an additional 77 patients treated with arsenic trioxide in combination with tretinoin as part of induction and consolidation therapy for low and high risk APL, with ages ranging from 60 to 84 years. These studies showed lower survival rates in older patients. Monitor elderly patients frequently during treatment with TRISENOX.
The safety and efficacy of TRISENOX as a single agent in older patients with relapsed or refractory APL is supported by the pivotal phase 2 study in 40 patients with relapsed or refractory APL. Six patients age 65 and above (age range: 65 to 73 years) were treated with TRISENOX at the recommended dose. A literature review included an additional 4 patients treated with arsenic trioxide for relapsed or refractory APL with ages ranging from 69 to 72 years. No differences in efficacy and safety were observed by age.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions underlined)
Differentiation Syndrome
Advise patients that symptoms of APL differentiation syndrome include fever, sudden weight gain, dizziness/lightheadedness, labored breathing, and accumulation of fluid in the lungs, heart, and chest. This syndrome is managed by immediate treatment with high-dose corticosteroids. Advise patients to immediately report any of these symptoms.
…
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.
Advise females and males of reproductive potential to use effective contraception during treatment with TRISENOX. Advise females to use effective contraception for six months and males to use effective contraception for three months after completing treatment with TRISENOX.
Potential Effect on Male Fertility
Advise male patients of the potential risk to future fertility following treatment with TRISENOX, as decreased testicular weight and impaired spermatogenesis have been reported in animal studies.
Lactation
Advise females to discontinue breastfeeding during treatment with TRISENOX and for two weeks after treatment with TRISENOX.