Oxaliplatin Concentrate Injection

Oxaliplatin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

Dosage

Administer Oxaliplatin in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):

Day 1: Oxaliplatin 85 mg/m2 intravenous infusion in 250-500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

The administration of Oxaliplatin does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

For information on 5-fluorouracil and leucovorin, see the respective package inserts.

2.2 Dose Modification Recommendations

Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.9)]. Prolongation of infusion time for Oxaliplatin from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

Adjuvant Therapy in Patients with Stage III Colon Cancer

Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)].

For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.

A dose reduction of Oxaliplatin to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment), or grade 4 neutropenia, or febrile neutropenia, or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.

Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer

Neuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions (5.2)]. Other toxicities were graded by the NCI CTC, Version 2.0.

For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/leucovorin regimen need not be altered.

A dose reduction of Oxaliplatin to 65 mg/m2 and 5-fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment), or grade 4 neutropenia, or febrile neutropenia, or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.

Dose Modifications in Therapy for Patients with Renal Impairment

In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin is 85 mg/m2. In patients with severe renal impairment, the initial recommended Oxaliplatin dose should be reduced to 65 mg/m2 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Preparation of Infusion Solution

Do not freeze the concentrated solution. Protect from light (keep in outer carton until use).

A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.

The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP.

After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution, protection from light is not required.

Oxaliplatin Injection, USP is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.

Needles or intravenous administration sets containing aluminum parts that may come in contact with Oxaliplatin Injection, USP should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

Oxaliplatin should not be administered to patients with a history of known allergy to Oxaliplatin or other platinum compounds [see Warnings and Precautions (5.1)].

Pregnancy

Pregnancy Category D

Based on direct interaction with DNA, Oxaliplatin may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Oxaliplatin in pregnant women. Reproductive toxicity studies in rats demonstrated adverse effects on fertility and embryo-fetal development at maternal doses that were below the recommended human dose based on body surface area. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant and use effective contraception while receiving treatment with Oxaliplatin.

Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days 1-5 (pre-implantation), 6-10 or 11-16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6-10 and 11-16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6-10. Administration of oxaliplatin to male and female rats prior to mating resulted in 97% post-implantation loss in animals that received approximately one-seventh the recommended human dose based on the body surface area.

Nursing Mothers

It is not known whether Oxaliplatin or its derivatives are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Oxaliplatin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The effectiveness of oxaliplatin in children has not been established. Oxaliplatin has been tested in 2 Phase 1 and 2 Phase 2 trials in 235 patients ages 7 months to 22 years with solid tumors (see below) and no significant activity observed.

In a Phase 1/2 study, oxaliplatin was administered as a 2-hour intravenous infusion on days 1, 8 and 15 every 4 weeks (1 cycle), for a maximum of 6 cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty eight pediatric patients in the Phase 1 study received oxaliplatin at 6 dose levels starting at 40 mg/m2 with escalation to 110 mg/m2. The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m2 dose. Fifteen patients received oxaliplatin at a dose of 90 mg/m2 intravenous in the Phase 2 portion of the study. At this dose, paresthesia (60%, G3/4: 7%), fever (40%, G3/4: 7%) and thrombocytopenia (40%, G3/4: 27%) were the main adverse reactions. No responses were observed.

In a second Phase 1 study, oxaliplatin was administered to 26 pediatric patients as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) at 5 dose levels starting at 100 mg/m2 with escalation to 160 mg/m², for a maximum of 6 cycles. In a separate cohort, oxaliplatin 85 mg/m2 was administered on day 1 every 2 weeks, for a maximum of 9 doses. Patients had metastatic or unresectable solid tumors mainly neuroblastoma and ganglioneuroblastoma. No responses were observed. The DLT was sensory neuropathy at the 160 mg/m2 dose. Based on these studies, oxaliplatin 130 mg/m2 as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) was used in subsequent Phase 2 studies. A dose of 85 mg/m2 on day 1 every 2 weeks was also found to be tolerable.

In one Phase 2 study, 43 pediatric patients with recurrent or refractory embryonal CNS tumors received oxaliplatin 130 mg/m2 every 3 weeks for a maximum of 12 months in absence of progressive disease or unacceptable toxicity. In patients <10 kg the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were leukopenia (67%, G3/4: 12%), anemia (65%, G3/4: 5%), thrombocytopenia (65%, G3/4: 26%), vomiting (65%, G3/4: 7%), neutropenia (58%, G3/4: 16%) and sensory neuropathy (40%, G3/4: 5%). One partial response was observed.

In a second Phase 2 study, 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, Ewing sarcoma or peripheral PNET, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, Brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors of interest received oxaliplatin 130 mg/m2 every 3 weeks for a maximum of 12 months or 17 cycles. In patients ≤12 months old the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were sensory neuropathy (52%, G3/4: 12%), thrombocytopenia (37%, G3/4: 17%), anemia (37%, G3/4: 9%), vomiting (26%, G3/4: 4%), ALT increased (24%, G3/4: 6%), AST increased (24%, G3/4: 2%), and nausea (23%, G3/4: 3%). Two partial responses were observed.

The pharmacokinetic parameters of ultrafiltrable platinum have been evaluated in 105 pediatric patients during the first cycle. The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h. The inter-patient variability of platinum clearance in pediatric cancer patients was 41%. Mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 ± 0.24 mcg/mL, AUC0-48 of 7.52 ± 5.07 mcg∙h/mL and AUCinf of 8.83 ± 1.57 mcg∙h/mL at 85 mg/m2 of oxaliplatin and Cmax of 1.10 ± 0.43 mcg/mL, AUC0-48 of 9.74 ± 2.52 mcg∙h/mL and AUCinf of 17.3 ± 5.34 mcg∙h/mL at 130 mg/m2 of oxaliplatin.

Geriatric Use

No significant effect of age on the clearance of ultrafilterable platinum has been observed. In the adjuvant therapy colon cancer randomized clinical trial, [see Clinical Studies (14)] 723 patients treated with Oxaliplatin and infusional 5-fluorouracil/leucovorin were <65 years and 400 patients were ≥65 years. A descriptive subgroup analysis demonstrated that the improvement in DFS for the Oxaliplatin combination arm compared to the infusional 5-fluorouracil/leucovorin alone arm appeared to be maintained across genders. The effect of Oxaliplatin in patients ≥65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race. Patients ≥65 years of age receiving the Oxaliplatin combination therapy experienced more grade 3-4 granulocytopenia than patients <65 years of age (45% versus 39%).

In the previously untreated for advanced colorectal cancer randomized clinical trial [see Clinical Studies (14)] of Oxaliplatin, 160 patients treated with Oxaliplatin and 5-fluorouracil/leucovorin were <65 years and 99 patients were ≥65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the ≥65 year old patients as in the overall study population. In the previously treated for advanced colorectal cancer randomized clinical trial [see Clinical Studies (14)] of Oxaliplatin, 95 patients treated with Oxaliplatin and 5-fluorouracil/leucovorin were <65 years and 55 patients were ≥65 years. The rates of overall adverse reactions, including grade 3 and 4 events, were similar across and within arms in the different age groups in all studies. The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope were higher in patients ≥65 years old. No adjustment to starting dose was required in patients ≥65 years old.

Patients with Renal Impairment

The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients [see Clinical Pharmacology (12.3)]. Caution and close monitoring should be exercised when Oxaliplatin is administered to patients with renal impairment. The starting Oxaliplatin dose does not need to be reduced in patients with mild (creatinine clearance=50-80 mL/min) or moderate (creatinine clearance=30-49 mL/min) renal impairment. However, the starting dose of Oxaliplatin should be reduced in patients with severe renal impairment (creatinine clearance <30 mL/min) [see Dosage and Administration (2.2)].

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. 4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Patient Information

Oxaliplatin

(ox-Al-ah-platin)

Injection for intravenous use

Read this Patient Information leaflet carefully before you start receiving Oxaliplatin. There may be new information. It will help you learn more about Oxaliplatin. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment. Ask your doctor about any questions you have.

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 base medicine. Serious allergic reactions including death can happen in people who take Oxaliplatin and who have had previous allergic reactions to platinum 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

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 • 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 5-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 works in children.

Who should not receive Oxaliplatin?

Do not receive Oxaliplatin if you are allergic to any of the ingredients in Oxaliplatin or other medicines that contain platinum. 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 take a medicine that contains platinum.

What should I tell my doctor before receiving Oxaliplatin?

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 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 may harm your unborn baby. Females who are able to become pregnant should avoid becoming pregnant and should use effective birth control during treatment with Oxaliplatin. • are breastfeeding or plan to breastfeed. It is not known if Oxaliplatin passes into your breast milk. You and your doctor should decide if you will receive Oxaliplatin or breastfeed. You should not do both.

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 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 5-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 5-fluorouracil will be given the same way as on Day 1.

The 5-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 of 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 or performing activities of daily living.

For information on ways to lessen or help with the nerve problems, see the end of this leaflet, "How can I reduce the side effects caused by cold temperatures?"

• Reversible Posterior Leukoencephalopathy (RPLS). RPLS is a rare condition that affects the brain. Tell your doctor right away if you have any of the following signs and symptoms of RPLS: o headache o confusion or a change in the way you think o seizures o vision problems, such as blurriness or vision loss • Low white blood cell counts (neutropenia). Oxaliplatin can cause low white blood cell counts. Low blood cell counts are common with Oxaliplatin and can lead to serious infection and death. 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 • Lung problems (interstitial fibrosis). Oxaliplatin can cause lung problems that may lead to death. Tell your doctor right away if you get a dry cough and have trouble breathing (shortness of breath) before your next treatment. These may be signs of a serious lung disease. • Liver problems (hepatotoxicity). Your doctor will do blood tests to check your liver. • 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, tell your doctor 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, or red-brown urine. • Harm to an unborn baby. See "What should I tell my doctor before receiving Oxaliplatin?"

The most common side effects of Oxaliplatin include:

• Numbness, pain, tingling, and/or burning along the nerves • Low white blood cells (neutropenia) • 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

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 healthcare provider or 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.
This Patient Information leaflet summarizes the most important information about Oxaliplatin. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Oxaliplatin Injection, USP that is written for health professionals.
For more information go to www.hospira.com or call 1-800-615-0187.

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.

Revised: 11/2015

Oxaliplatin Injection, USP (concentrate solution for infusion)
Manufactured by:
Zydus Hospira Oncology Pvt Ltd
District Ahmedabad 382-213
Gujarat India

                                                                                EN-4132
Manufactured for:                                                                                                                             
Hospira, Inc.
Lake Forest, IL 60045