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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.
OXALIPLATIN (NDA-022160)
(OXALIPLATIN)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/31/2024 (SUPPL-16)
Boxed Warning
Additions and/or revisions underlined:
WARNING: HYPERSENSITIVITY REACTIONS, INCLUDING ANAPHYLAXIS
Serious and fatal hypersensitivity adverse reactions, including anaphylaxis, can occur with oxaliplatin within minutes of administration and during any cycle. Oxaliplatin is contraindicated in patients with hypersensitivity reactions to oxaliplatin and other platinum-based drugs [see Contraindications (4)].
Immediately and permanently discontinue oxaliplatin for hypersensitivity reactions and administer appropriate treatment for management of the hypersensitivity reaction [see Warnings and Precautions (5.1)].
4 Contraindications
Additions and/or revisions underlined:
Oxaliplatin Injection is contraindicated in patients with a history of a hypersensitivity reaction to oxaliplatin or other platinum-based drugs. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)].
5 Warnings and Precautions
5.1 Hypersensitivity Reactions
Additions and/or revisions underlined:
Serious and fatal hypersensitivity reactions, including anaphylaxis, can occur with oxaliplatin within minutes of administration and during any cycle. Grade 3-4 hypersensitivity reactions, including anaphylaxis, occurred in 2% to 3% of patients with colon cancer who received oxaliplatin. Hypersensitivity reactions, including rash, urticaria, erythema, pruritus, and rarely, bronchospasm and hypotension, were similar in nature and severity to those reported with other platinum-based drugs.
Oxaliplatin is contraindicated in patients with hypersensitivity reactions to platinum-based drugs [see Contraindications (4)]. Immediately and permanently discontinue oxaliplatin for hypersensitivity reactions and administer appropriate treatment for management of hypersensitivity reactions.
5.2 Peripheral Sensory Neuropathy
Subsection title revised
Extensive changes; please refer to label for complete information
5.3 Severe Myelosuppression
Subsection title revised
Grade 3 or 4 neutropenia occurred in 41% to 44% of patients with colorectal cancer who received oxaliplatin with fluorouracil/leucovorin. Sepsis, neutropenic sepsis and septic shock, including fatal outcomes, occurred in patients who received oxaliplatin [see Adverse Reactions (6.1, 6.2)].
Grade 3 or 4 thrombocytopenia occurred in 2% to 5% of patients with colorectal cancer who received oxaliplatin with fluorouracil/leucovorin.
Monitor complete blood cell count at baseline, before each subsequent cycle and as clinically indicated. Delay Oxaliplatin Injection until neutrophils are greater than or equal to 1.5 × 109/L and platelets are greater than or equal to 75 × 109/L. Withhold Oxaliplatin Injection for sepsis or septic shock. Dose reduce Oxaliplatin Injection after recovery from grade 4 neutropenia, febrile neutropenia or grade 3-4 thrombocytopenia as recommended [see Dosage and Administration (2.2)].
5.4 Posterior Reversible Encephalopathy Syndrome
Newly added subsection:
PRES occurred in less than 0.1% of patients across clinical trials [see Adverse Reactions (6.1)]. Signs and symptoms of PRES can include headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Confirm the diagnosis of PRES with magnetic resonance imaging. Permanently discontinue Oxaliplatin Injection in patients who develop PRES.
5.5 Pulmonary Toxicity
Additions and/or revisions underlined:
Oxaliplatin has been associated with pulmonary fibrosis (less than 1% of patients), which may be fatal [see Adverse Reactions (6.1)].
In the adjuvant treatment trial, the combined incidence of cough and dyspnea was 7.4% (any grade), including less than 1% (grade 3) in the oxaliplatin arm. One patient died from eosinophilic pneumonia in the oxaliplatin arm.
In the previously untreated advanced colorectal cancer trial, the combined incidence of cough, dyspnea, and hypoxia was 43% (any grade), including 7% (grade 3-4) in the oxaliplatin with fluorouracil/leucovorin arm.
In case of unexplained respiratory symptoms, such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, withhold Oxaliplatin Injection until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis. Permanently discontinue Oxaliplatin Injection for confirmed interstitial lung disease or pulmonary fibrosis.
5.6 Hepatotoxicity
Additions and/or revisions underlined:
In the adjuvant treatment trial, increased transaminases (57% vs 34%) and alkaline phosphatase (42% vs 20%) occurred more commonly in the oxaliplatin arm than in the fluorouracil/leucovorin arm [see Adverse Reactions (6.1)]. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions.
Consider evaluating patients who develop abnormal liver tests or portal hypertension, which cannot be explained by liver metastases, for hepatic vascular disorders. Monitor liver function tests at baseline, before each subsequent cycle, and as clinically indicated.
5.7 QT Interval Prolongation and Ventricular Arrhythmias
Subsection title revision
Additions and/or revisions underlined:
QT prolongation and ventricular arrhythmias, including fatal torsade de pointes, have been reported with oxaliplatin [see Adverse Reactions (6.2)].
Avoid Oxaliplatin Injection in patients with congenital long QT syndrome. Monitor electrocardiograms (ECG) in patients with congestive heart failure, bradyarrhythmias, and electrolyte abnormalities and in patients taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics [see Drug Interactions (7.1)]. Monitor and correct electrolyte abnormalities prior to initiating Oxaliplatin Injection and periodically during treatment.
5.8 Rhabdomyolysis
Additions and/or revisions underlined:
Rhabdomyolysis, including fatal cases, has been reported with oxaliplatin [see Adverse Reactions (6.2)]. Permanently discontinue Oxaliplatin Injection for any signs or symptoms of rhabdomyolysis.
5.9 Hemorrhage
Newly added subsection:
The incidence of hemorrhage in clinical trials was higher on the oxaliplatin combination arm compared to the fluorouracil/leucovorin arm. These reactions included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant treatment trial, 2 patients died from intracerebral hemorrhage [see Adverse Reactions (6.1)].
Prolonged prothrombin time and INR occasionally associated with hemorrhage have been reported in patients who received oxaliplatin with fluorouracil/leucovorin while on anticoagulants [see Adverse Reactions (6.2)]. Increase frequency of monitoring in patients who are receiving Oxaliplatin Injection with fluorouracil/leucovorin and oral anticoagulants [see Drug Interactions (7.3)].
Thrombocytopenia and immune-mediated thrombocytopenia have been observed with oxaliplatin. Rapid onset of thrombocytopenia and greater risk of bleeding have been observed in immune-mediated thrombocytopenia. In this case, consider discontinuing Oxaliplatin Injection.
6 Adverse Reactions
Additions and/or revisions underlined:
Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
Peripheral Sensory Neuropathy [see Warnings and Precautions (5.2)]
Severe Myelosuppression [see Warnings and Precautions (5.3)]
Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.4)]
Pulmonary Toxicity [see Warnings and Precautions (5.5)]
Hepatotoxicity [see Warnings and Precautions (5.6)]
QT Interval Prolongation and Ventricular Arrhythmias [see Warnings and Precautions (5.7)]
Rhabdomyolysis [see Warnings and Precautions (5.8)]
- Hemorrhage [see Warnings and Precautions (5.9)]
6.1 Clinical Trials Experience
Extensive changes; please refer to label for complete information
6.2 Postmarketing Experience
Additions and/or revisions underlined:
General: angioedema, anaphylactic shock
Cardiovascular: QT prolongation leading to ventricular arrhythmias, including fatal torsade de pointes; bradyarrhythmia
Neurological: loss of deep tendon reflexes, dysarthria, Lhermitte’s sign, cranial nerve palsies, fasciculations, convulsion
Hearing and vestibular system: deafness
Infections: septic shock, including fatal outcomes
Infusion-related reactions and hypersensitivity reactions: laryngospasm
Hepatic and gastrointestinal: severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis, ileus, intestinal obstruction, pancreatitis, sinusoidal obstruction syndrome, perisinusoidal fibrosis which rarely may progress, focal nodular hyperplasia, esophagitis
Musculoskeletal and connective tissue disorders: rhabdomyolysis, including fatal outcomes.
Platelet, bleeding, and clotting disorders: immuno-allergic thrombocytopenia, prolonged prothrombin time and INR in patients receiving anticoagulants
Blood disorders: secondary leukemia
Red blood cell: hemolytic uremic syndrome, immuno-allergic hemolytic anemia
Renal: acute tubular necrosis, acute interstitial nephritis, acute renal failure
Respiratory: interstitial lung diseases (sometimes fatal) and pneumonia (including fatal outcomes)
Vision: decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following treatment discontinuation)
Injury, poisoning, and procedural complications: fall-related injuries
7 Drug Interactions
7.1 Drugs that Prolong the QT Interval
Newly added subsection
QT interval prolongation and ventricular arrhythmias can occur with oxaliplatin [see Warnings and Precautions (5.7)]. Avoid coadministration of oxaliplatin with medicinal products with a known potential to prolong the QT interval.
7.2 Use with Nephrotoxic Products
Newly added subsection
Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds [see Clinical Pharmacology (12.3)]. Avoid coadministration of oxaliplatin with medicinal products known to cause nephrotoxicity.
7.3 Use with Anticoagulants
Newly added subsection
Prolonged prothrombin time and INR occasionally associated with hemorrhage have been reported in patients who received oxaliplatin with fluorouracil/leucovorin while on anticoagulants [see Warnings and Precautions (5.9), Adverse Reactions (6.2)]. Increase frequency of monitoring in patients who are receiving oxaliplatin with fluorouracil/leucovorin and oral anticoagulants.
8 Use in Specific Populations
8.4 Pediatric Use
Extensive changes; please refer to label for complete information
8.5 Geriatric Use
Additions and/or revisions underlined:
In the adjuvant treatment trial [see Clinical Studies (14.1)], 400 patients who received oxaliplatin with fluorouracil/leucovorin were greater than or equal to 65 years. The effect of oxaliplatin in patients greater than or equal to 65 years was not conclusive. Patients greater than or equal to 65 years receiving oxaliplatin experienced more diarrhea and grade 3-4 neutropenia (45% vs 39%) compared to patients less than 65 years.
In the previously untreated advanced colorectal cancer trial [see Clinical Studies (14.2)], 99 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the greater than or equal to 65 years patients as in the overall study population. Adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope.
In the previously treated advanced colorectal cancer trial [see Clinical Studies (14.3)], 55 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. No overall differences in effectiveness were observed between these patients and younger adults. Adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, and fatigue.
No significant effect of age on the clearance of ultrafiltrable platinum has been observed [see Clinical Pharmacology (12.3)].
8.6 Patients with Renal Impairment
Subsection title revised
Additions and/or revisions underlined:
The AUC of unbound platinum in plasma ultrafiltrate was increased in patients with renal impairment [see Clinical Pharmacology (12.3)]. No dose reduction is recommended for patients with mild (creatinine clearance 50 to 79 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal impairment, calculated by Cockcroft-Gault equation. Reduce the dose of Oxaliplatin Injection in patients with severe renal impairment (creatinine clearance less than 30 mL/min) [see Dosage and Administration (2.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Extensive changes; please refer to label for complete information
PATIENT INFORMATION
Extensive changes; please refer to label for complete information
04/10/2020 (SUPPL-12)
5 Warnings and Precautions
Embryo-Fetal Toxicity(Newly added subsection)
Based on findings from animal studies and its mechanism of action, Oxaliplatin Injection can cause fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for at least 9 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for 6 months after the final dose [see Use in Specific Populations (8.1, 8.3)].
8 Use in Specific Populations
Lactation(PLLR conversion. Please refer to label for complete information.)
(PLLR conversion. Please refer to label for complete information.)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(Newly added information)
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for 9 months after the final dose [see Use in Specific Populations (8.3)].
Advise males with female partners of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for 6 months after the final dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].
Lactation
Advise women not to breastfeed during treatment with Oxaliplatin Injection and for 3 months after the final dose [see Use in Specific Populations (8.2)].
Infertility
Advise females and males of reproductive potential that Oxaliplatin Injection may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].
(Additions and/or revisions underlined)
Females who are able to become pregnant should avoid becoming pregnant and should use effective birth control during treatment with
Oxaliplatin Injection and for 9 months after the last dose of Oxaliplatin Injection. Males with female sexual
partners who are able to become pregnant should use effective birth control during treatment with Oxaliplatin
Injection and for 6 months after the last dose of Oxaliplatin Injection.
Talk with your doctor and nurse about your level of activity during treatment with Oxaliplatin Injection. Follow their instructions.
You can ask your doctor or pharmacist for information about Oxaliplatin Injection that is written for health professionals.
What are the ingredients in Oxaliplatin Injection?
Active ingredient: oxaliplatin
Concentrate for solution for infusion inactive ingredients: lactose monohydrate and water for injection.
04/20/2016 (SUPPL-10)
5 Warnings and Precautions
Severe Neutropenia
- Grade 3 or 4 neutropenia occurred in 41 to 44% of patients with colorectal cancer treated with oxaliplatin in combination with 5-flurouracil (5-FU) and leucovorin compared to 5% with 5-FU plus leucovorin alone. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin, including fatal outcomes.
- Delay oxaliplatin until neutrophils are = 1.5 x 109/L. Withhold oxaliplatin for sepsis or septic shock. Dose reduce oxaliplatin after recovery from Grade 4 neutropenia or febrile neutropenia.
Cardiovascular Toxicity
- QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been reported in postmarketing experiences following oxaliplatin administration. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating oxaliplatin and monitor these electrolytes periodically during therapy. Avoid oxaliplatin in patients with congenital long QT syndrome.
Rhabdomyolysis
- Rhabdomyolysis, including fatal cases, has been reported in patients treated with oxaliplatin. Discontinue oxaliplatin if any signs or symptoms of rhabdomyolysis occur.
6 Adverse Reactions
Post Marketing Experience… QT prolongation, septic shock, and rhabdomyolysis…