oxaliplatin injection 5 WARNINGS AND PRECAUTIONS

Prescribing Information

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

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

Oxaliplatin can cause acute and delayed neuropathy. Reduce the dose or permanently discontinue Oxaliplatin for persistent neurosensory reactions based on the severity of the adverse reaction [see Dosage and Administration (2.2)].

Acute Neuropathy

Acute neuropathy typically presents as a reversible, primarily peripheral sensory neuropathy that occurs within hours or 2 days following a dose, resolves within 14 days, and frequently recurs with further dosing. The symptoms can be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed. The acute, reversible pattern of sensory neuropathy was observed in about 56% of patients who received Oxaliplatin with fluorouracil/leucovorin. In any individual cycle, acute neuropathy occurred in approximately 30% of patients. For grade 3 peripheral sensory neuropathy, the median time to onset was 9 cycles for adjuvant treatment and 6 cycles for previously treated advanced colorectal cancer.

An acute syndrome of pharyngolaryngeal dysesthesia occurred in 1% to 2% (grade 3–4) of patients previously untreated for advanced colorectal cancer. Subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing) occurred in patients previously treated for advanced colorectal cancer.

Avoid topical application of ice for mucositis prophylaxis or other conditions, because cold temperature can exacerbate acute neurological symptoms.

Delayed Neuropathy

Delayed neuropathy typically presents as a persistent (greater than 14 days), primarily peripheral sensory neuropathy that is usually characterized by paresthesias, dysesthesias, and hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception). These forms of neuropathy occurred in 48% of patients receiving Oxaliplatin. Delayed neuropathy can occur without any prior acute neuropathy. Most patients (80%) who developed grade 3 persistent neuropathy progressed from prior grade 1 or 2 reactions. These symptoms may improve in some patients upon discontinuation of Oxaliplatin.

Adjuvant treatment

In the adjuvant treatment trial, neuropathy was graded using NCI CTC, version 1 as summarized in Table 3.

Table 3: Grading for Neuropathy in Adjuvant Treatment Trial
Grade	Definition
0	No change or none
1	Mild paresthesias, loss of deep tendon reflexes
2	Mild or moderate objective sensory loss, moderate paresthesias
3	Severe objective sensory loss or paresthesias that interfere with function
4	Not applicable

Peripheral sensory neuropathy occurred in 92% of patients (all grades), including 13% of patients (grade 3) who received Oxaliplatin with fluorouracil/leucovorin. At the 28-day follow-up after the last treatment cycle, 60% of patients had any grade (grade 1=40%, grade 2=16%, grade 3=5%) peripheral sensory neuropathy, decreasing to 39% at 6 months of follow-up (grade 1=31%, grade 2=7%, grade 3=1%) and 21% at 18 months of follow-up (grade 1=17%, grade 2=3%, grade 3=1%).

Advanced colorectal cancer

In the advanced colorectal cancer trials, neuropathy was graded using the neurotoxicity scale summarized in Table 4.

Table 4: Grading for Neuropathy in Advanced Colorectal Cancer Trials
Grade	Definition
1	Resolved and did not interfere with functioning
2	Interfered with function but not daily activities
3	Pain or functional impairment that interfered with daily activities
4	Persistent impairment that is disabling or life-threatening

Neuropathy occurred in 82% (all grades) of patients previously untreated for advanced colorectal cancer, including 19% grade 3–4; and in 74% (all grades) of patients previously treated for advanced colorectal cancer, including 7% grade 3–4.

5.3 Severe Myelosuppression

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 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 for sepsis or septic shock. Dose reduce Oxaliplatin 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

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 in patients who develop PRES.

5.5 Pulmonary Toxicity

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 until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis. Permanently discontinue Oxaliplatin for confirmed interstitial lung disease or pulmonary fibrosis.

5.6 Hepatotoxicity

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

QT prolongation and ventricular arrhythmias, including fatal torsade de pointes, have been reported with Oxaliplatin [see Adverse Reactions (6.2)].

Avoid Oxaliplatin 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 and periodically during treatment.

5.8 Rhabdomyolysis

Rhabdomyolysis, including fatal cases, has been reported with Oxaliplatin [see Adverse Reactions (6.2)]. Permanently discontinue Oxaliplatin for any signs or symptoms of rhabdomyolysis.

5.9 Hemorrhage

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 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.

5.10 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, Oxaliplatin 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 and for 9 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Oxaliplatin and for 6 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

Medication Guide

MEDICATION GUIDE

Patient Information Oxaliplatin (ox-Al-ah-platin) injection for intravenous use
What is the most important information I should know about Oxaliplatin? Oxaliplatin can cause serious allergic reactions, including allergic reactions that can lead to death. Oxaliplatin is a platinum-based medicine. Serious allergic reactions including death can happen in people who take Oxaliplatin and who have had previous allergic reactions to platinum-based medicines. Serious allergic reactions can happen within a few minutes of your Oxaliplatin infusion or any time during your treatment with Oxaliplatin. Get emergency help right away if you: • have trouble breathing • feel like your throat is closing up • chest tightness Call your doctor right away if you have any of the following signs or symptoms of an allergic reaction:
• rash • flushed face • hives • itching • swelling of your lips or tongue, face or eyelids		• wheezing • sudden cough • dizziness or feel faint • sweating • chest pain
See "What are the possible side effects of Oxaliplatin?" for information about other serious side effects.
What is Oxaliplatin? Oxaliplatin is an anti-cancer (chemotherapy) medicine that is used with other anti-cancer medicines called fluorouracil and leucovorin to treat people with: • stage III colon cancer after surgery to remove the tumor • advanced colon or rectal cancer (colorectal cancer) It is not known if Oxaliplatin is safe and effective in children.
Do not receive Oxaliplatin if you are allergic to Oxaliplatin or any of the ingredients in Oxaliplatin or if you are allergic to other platinum-based medicines. See the end of this leaflet for a complete list of the ingredients in Oxaliplatin Injection, USP. Ask your doctor if you are not sure if you have taken a platinum-based medicine.
Before receiving Oxaliplatin, tell your doctor about all of your medical conditions, including if you: • have an infection • have lung, liver, or kidney problems • have bleeding problems • have or had heart problems such as an abnormal heart test called an electrocardiogram (ECG or EKG), a condition called long QT syndrome, an irregular or slow heartbeat, or a family history of heart problems • have had changes in the level of certain blood salt (electrolytes) levels, including potassium, magnesium, and calcium • are pregnant or plan to become pregnant. Oxaliplatin can harm your unborn baby. Tell your doctor right away if you become pregnant or think you may be pregnant during treatment with Oxaliplatin. Females who are able to become pregnant: o Your doctor will do a pregnancy test before you start treatment with Oxaliplatin. o You should use effective birth control (contraception) during treatment with Oxaliplatin and for 9 months after the final dose. Talk to your doctor about forms of birth control that may be right for you. Males with female partners who are able to become pregnant should use effective birth control during treatment with Oxaliplatin and for 6 months after the final dose. • are breastfeeding or plan to breastfeed. It is not known if Oxaliplatin passes into your breast milk. Do not breastfeed during treatment with Oxaliplatin and for 3 months after the final dose. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.
How will I receive Oxaliplatin? • Oxaliplatin is given to you into your vein through an intravenous (IV) tube. • Your doctor will prescribe Oxaliplatin in a dose that is right for you. • Your doctor may change how often you receive Oxaliplatin, your dose, or how long your infusion will take. • You and your doctor will decide how many Oxaliplatin treatments you will receive. • It is very important that you do exactly what your doctor and nurse tell you to do. • Some medicines may be given to you before Oxaliplatin to help prevent nausea and vomiting. • Each treatment course is given to you over 2 days. You will receive Oxaliplatin on the first day only. • There are usually 14 days (2 weeks) between each chemotherapy treatment course. • It is important for you to keep all of your medical appointments. Call your doctor if you miss an appointment. There may be special instructions for you. Treatment Day 1: • Oxaliplatin and leucovorin will be given through a thin plastic tube into a vein (intravenous infusion or IV) and given for 2 hours. You will be watched by a healthcare provider during this time. • Right after the Oxaliplatin and leucovorin are given, 2 doses of fluorouracil will be given. The first dose is given right away into your IV tube. The second dose will be given into your IV tube over the next 22 hours, using a pump device. Treatment Day 2: You will not get Oxaliplatin on Day 2. Leucovorin and fluorouracil will be given the same way as on Day 1. The fluorouracil will be given through your IV with a pump. If you have any problems with the pump or the tube, call your doctor, your nurse, or the person who is responsible for your pump. Do not let anyone other than a healthcare provider touch your infusion pump or tubing.
What should I avoid while receiving Oxaliplatin? • Avoid cold temperatures and cold objects. Cover your skin if you go outdoors in cold temperatures. • Do not drink cold drinks or use ice cubes in drinks. • Do not put ice or ice packs on your body. • Oxaliplatin can cause dizziness, vision problems, or vision loss that can affect your ability to drive or use machines. You should not drive or operate machinery if you develop these symptoms while receiving Oxaliplatin. See "How can I reduce the side effects caused by cold temperatures?" for more information. Talk with your doctor and nurse about your level of activity during treatment with Oxaliplatin. Follow their instructions.
What are the possible side effects of Oxaliplatin? Oxaliplatin can cause serious side effects, including: • See "What is the most important information I should know about Oxaliplatin?" • Nerve problems. Oxaliplatin can affect how your nerves work and make you feel. Nerve problems may happen with the first treatment or within two days after your treatment with Oxaliplatin. Nerve problems may last a short time (acute) or may become persistent. Symptoms may improve after stopping treatment with Oxaliplatin. Exposure to cold or cold objects may cause or worsen nerve problems. Tell your doctor right away if you get any signs of nerve problems, including: o very sensitive to cold temperatures and cold objects o trouble breathing, swallowing, or saying words, jaw tightness, odd feelings in your tongue, or chest pressure o pain, tingling, burning (pins and needles, numb feeling) in your hands, feet, or around your mouth or throat, which may cause problems walking, fall and fall-related injuries, or problems performing activities of daily living For information on ways to lessen or help with nerve problems, see the section "How can I reduce the side effects caused by cold temperatures?" below. • Severe low blood cell counts (myelosuppression). Oxaliplatin when used with fluorouracil and leucovorin can cause low blood cell counts. Low blood cell counts are common with Oxaliplatin when used with fluorouracil and leucovorin and can lead to serious infection and death. Your doctor will do blood tests to check your blood cell counts before starting Oxaliplatin and during treatment. Tell your doctor right away if you have a fever greater than 100.9°F (38.3°C) or a prolonged fever greater than 100.4°F (38°C) for more than one hour (febrile neutropenia). Call your doctor right away if you get any of the following signs of infection:
	o chills or shivering o pain on swallowing o sore throat o cough that brings up mucus		o burning or pain on urination o redness or swelling at intravenous site o persistent diarrhea
• Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a rare condition that affects the brain. Tell your doctor right away if you have any of the following signs and symptoms of PRES: o headache o confusion or a change in the way you think o seizures o vision problems, such as blurriness or vision loss
• Lung Problems. Oxaliplatin can cause lung problems that may lead to death. Tell your doctor right away if you get any of the following symptoms as these may be indicators of a serious lung disease:
	o shortness of breath o wheezing o cough
• Liver problems (hepatotoxicity). Your doctor will do blood tests to check your liver when you start receiving Oxaliplatin, and before each treatment course as needed. • Heart problems. Oxaliplatin can cause heart problems that have led to death. Your doctor may do blood and heart tests during treatment with Oxaliplatin if you have certain heart problems. If you faint (lose consciousness), or have an irregular heartbeat or chest pain during treatment with Oxaliplatin, get medical help right away as this may be a sign of a serious heart condition. • Muscle problems. Oxaliplatin can cause muscle damage (rhabdomyolysis) which can lead to death. Tell your doctor right away if you have muscle pain and swelling, along with weakness, fever, red-brown urine, decreased amount of urine or trouble urinating. • Bleeding problems (hemorrhage). Oxaliplatin when used with fluorouracil and leucovorin can cause bleeding problems (hemorrhage) that can lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs or symptoms of bleeding, including:
	o blood in your stools or black stools (looks like tar) o pink or brown urine o unexpected bleeding, or bleeding that is severe or you cannot control o vomit blood or vomit that looks like coffee grounds o cough up blood or blood clots o increased bruising o dizziness o weakness o confusion o changes in speech o headache that lasts a long time
The most common side effects of Oxaliplatin include:
• numbness, pain, tingling, and/or burning along the nerves • low white blood cells (blood cells important for fighting infection) • low platelet count (important for clotting and to control bleeding) • low red blood cells (blood cells that carry oxygen to the tissues) • nausea		• changes in liver function tests • diarrhea • vomiting • tiredness • mouth sores
Oxaliplatin may cause fertility problems in males and females. Talk to your doctor if this is a concern for you. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Oxaliplatin. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How can I reduce the side effects caused by cold temperatures? • Cover yourself with a blanket while you are getting your Oxaliplatin infusion. • Do not breathe deeply when exposed to cold air. • Wear warm clothing in cold weather at all times. Cover your mouth and nose with a scarf or a pull-down cap (ski cap) to warm the air that goes to your lungs. • Wear gloves when taking things from the freezer or refrigerator. • Drink fluids warm or at room temperature. • Always drink through a straw. • Do not use ice chips if you have nausea or mouth sores. Ask your doctor about what you can use. • Be aware that most metals are cold to touch, especially in the winter. These include your car door and mailbox. Wear gloves to touch cold objects. • Do not run the air conditioning at high levels in the house or in the car in hot weather. • If your body gets cold, warm-up the affected part. If your hands get cold, wash them with warm water. • Always let your doctor know before your next treatment how well you did since your last visit. Your doctor may have other useful tips for helping you with side effects.
General information about the safe and effective use of Oxaliplatin Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. You can ask your doctor or pharmacist for information about Oxaliplatin Injection, USP that is written for health professionals.
What are the ingredients in Oxaliplatin? Active ingredient: oxaliplatin Concentrate for solution for infusion inactive ingredients: water for injection, tartaric acid, sodium hydroxide Paraplatin® and Platinol® are registered trademarks of Bristol-Myers Squibb Company. Oxaliplatin Injection, USP (concentrate solution for infusion)

This Patient Information has been approved by the U.S. Food and Drug Administration.

Distributed by Hospira, Inc., Lake Forest, IL 60045

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Revised: 9/2024

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