oxaliplatin

APP Pharmaceuticals, LLC

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Oxaliplatin Injection, USP safely and effectively. See full prescribing information for Oxaliplatin Injection, USP.Oxaliplatin Injection, USP concentrate, for solution for intavenous use Initial U.S. Approval: 2002 RECENT MAJOR CHANGES2.25.15.2BOXED WARNING WARNING: ANAPHYLACTIC REACTIONS See full prescribing information for complete boxed warning. Anaphylactic reactions to Oxaliplatin have been reported, and may occur within minutes of Oxaliplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms. (5.1) INDICATIONS AND USAGE1DOSAGE AND ADMINISTRATION• Administer oxaliplatin in combination with 5-fluorouracil/leucovorin every 2 weeks. (2.1):- Day 1: Oxaliplatin 85 mg/m2 intravenous infusion in 250 to 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.• Reduce the dose of oxaliplatin to 75 mg/m2 (adjuvant setting) or 65 mg/m2 (advanced colorectal cancer) (2.2):- if there are persistent grade 2 neurosensory events that do not resolve.- after recovery from grade 3/4 gastrointestinal toxicities (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. Delay next dose until neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.• For patients with severe renal impairment (creatinine clearance

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: ANAPHYLACTIC REACTIONS
• 1 OXALIPLATIN INDICATIONS AND USAGE
• 2 OXALIPLATIN DOSAGE AND ADMINISTRATION
  • 2.1 Dosage
  • 2.2 Dose Modification Recommendations
  • 2.3 Preparation of Infusion Solution
• 3 DOSAGE FORMS AND STRENGTHS
• 4 OXALIPLATIN CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Allergic Reactions
  • 5.2 Neurologic Toxicity
  • 5.3 Pulmonary Toxicity
  • 5.4 Hepatotoxicity
  • 5.5 Use in Pregnancy
  • 5.6 Recommended Laboratory Tests
• 6 OXALIPLATIN ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Patients with Renal Impairment
• 10 OVERDOSAGE
• 11 OXALIPLATIN DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Combination Adjuvant Therapy with Oxaliplatin and Infusional 5-Fluorouracil /Leucovorin in Patients with Stage II or III Colon Cancer
  • 14.2 Combination Therapy with Oxaliplatin and 5-Fluorouracil/Leucovorin in Patients Previously Untreated for Advanced Colorectal Cancer
  • 14.3 Combination Therapy with Oxaliplatin and 5-Fluorouracil/Leucovorin in Previously Treated Patients with Advanced Colorectal Cancer
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage
  • 16.3 Handling and Disposal
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Information for Patients
  • 17.2 FDA-Approved Patient Labeling
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-Oxaliplatin Injection, USP

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

Oxaliplatin Injection 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.

2.1 Dosage

Figure 1

2.2 Dose Modification Recommendations

2.3 Preparation of Infusion Solution

3 DOSAGE FORMS AND STRENGTHS

Oxaliplatin Injection is supplied in single-use vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL.

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Allergic Reactions

5.2 Neurologic Toxicity

5.3 Pulmonary Toxicity

Oxaliplatin has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any grade) and <1% (grade 3) with no grade 4 events in the oxaliplatin plus infusional 5-fluorouracil/leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5-fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the oxaliplatin combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the oxaliplatin plus 5-fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-fluorouracil/leucovorin arm of unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

5.4 Hepatotoxicity

Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the oxaliplatin combination arm than in the control arm. 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. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases [see Clinical Trials Experience ( 6.1 )].

5.5 Use in Pregnancy

5.6 Recommended Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Thirteen percent of patients in the oxaliplatin and 5-fluorouracil/leucovorin combination arm and 18% in the 5-fluorouracil/leucovorin arm of the previously treated study had to discontinue treatment because of adverse effects related to gastrointestinal, or hematologic adverse reactions, or neuropathies. Both 5-fluorouracil and oxaliplatin are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin is administered in combination with 5-fluorouracil, the incidence of these events is increased.

The incidence of death within 30 days of treatment in the previously treated study, regardless of causality, was 5% with the oxaliplatin and 5-fluorouracil/leucovorin combination, 8% with oxaliplatin alone, and 7% with 5-fluorouracil/leucovorin. Of the 7 deaths that occurred on the oxaliplatin and 5-fluorouracil/leucovorin combination arm within 30 days of stopping treatment, 3 may have been treatment related, associated with gastrointestinal bleeding or dehydration.

The following table provides adverse reactions reported in the previously treated study [see Clinical Studies (14)] by body system and in decreasing order of frequency in the oxaliplatin and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥5% and for grade 3/4 events with incidences ≥1%. This table does not include hematologic and blood chemistry abnormalities; these are shown separately below.

The following table provides adverse reactions reported in the previously treated study [see Clinical Studies (14)] by body system and in decreasing order of frequency in the oxaliplatin and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥5% but with incidences <1% NCI Grade 3/4 events.

Table 11 – Adverse Hematologic Reactions in Previously Treated Patients (≥5% of patients)

The incidence of Grade 3/4 thrombocytopenia was 2% in adjuvant patients with colon cancer. In patients treated for advanced colorectal cancer the incidence of Grade 3/4 thrombocytopenia was 3 to 5%, and the incidence of these events was greater for the combination of oxaliplatin and 5-fluorouracil/leucovorin over the irinotecan plus 5-fluorouracil/leucovorin or 5-fluorouracil/leucovorin control groups. Grade 3/4 gastrointestinal bleeding was reported in 0.2% of adjuvant patients receiving oxaliplatin and 5-fluorouracil/leucovorin. In the previously untreated patients, the incidence of epistaxis was 10% in the oxaliplatin and 5-fluorouracil/leucovorin arm, and 2% and 1%, respectively, in the irinotecan plus 5-fluorouracil/leucovorin or irinotecan plus oxaliplatin arms.

The incidence of gastrointestinal adverse reactions in the previously untreated and previously treated patients appears to be similar across cycles. Premedication with antiemetics, including 5-HT₃ blockers, is recommended. Diarrhea and mucositis may be exacerbated by the addition of oxaliplatin to 5-fluorouracil/leucovorin, and should be managed with appropriate supportive care. Since cold temperature can exacerbate acute neurological symptoms, ice (mucositis prophylaxis) should be avoided during the infusion of oxaliplatin.

Table 12 - Adverse Hepatic Reactions in Patients with Stage II or III Colon Cancer Receiving Adjuvant Therapy (≥5% of patients)

Table 13 – Adverse Hepatic – Clinical Chemistry Abnormalities in Patients Previously Untreated for Advanced Colorectal Cancer (≥5% of patients)

Table 14 – Adverse Hepatic – Clinical Chemistry Abnormalities in Previously Treated Patients (≥5% of patients)

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m² oxaliplatin and 5-fluorouracil/leucovorin has been observed in patients treated every 2 weeks. Increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m² oxaliplatin dosed every 3 weeks. Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds; although, this has not been specifically studied [see Clinical Pharmacology ( 12.3 )].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 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.

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Renal Impairment

The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients [see Pharmacokinetics ( 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 to 80 mL/min) or moderate (creatinine clearance=30 to 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 )].

10 OVERDOSAGE

11 DESCRIPTION

Oxaliplatin Injection, USP is an antineoplastic agent with the molecular formula C₈H₁₄N₂O₄Pt and the chemical name of cis-[(1 R,2 R)-1,2-cyclohexanediamine-N,N’] [oxalato(2-)-O,O’] platinum. Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane(DACH) and with an oxalate ligand as a leaving group.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

14 CLINICAL STUDIES

14.1 Combination Adjuvant Therapy with Oxaliplatin and Infusional 5-Fluorouracil /Leucovorin in Patients with Stage II or III Colon Cancer

The following tables show the baseline characteristics and dosing of the patient population entered into this study. The baseline characteristics were well balanced between arms.

The following table and figures summarize the disease-free survival (DFS) results in the overall randomized population and in patients with stage II and III disease based on an ITT analysis. The median duration of follow-up was approximately 77 months.

14.2 Combination Therapy with Oxaliplatin and 5-Fluorouracil/Leucovorin in Patients Previously Untreated for Advanced Colorectal Cancer

14.3 Combination Therapy with Oxaliplatin and 5-Fluorouracil/Leucovorin in Previously Treated Patients with Advanced Colorectal Cancer

Table 23 – Dosing Regimens in Refractory and Relapsed Colorectal Cancer Clinical Trial

Table 24 – Patient Demographics in Refractory and Relapsed Colorectal Cancer Clinical Trial

Table 25 - Response Rates (ITT Analysis)

15 REFERENCES

• 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.
• 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
• American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs.
• 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage

Store at 20°C to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not freeze and protect from light (keep in original outer carton).

16.3 Handling and Disposal

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from oxaliplatin injection. The use of gloves is recommended. If a solution of oxaliplatin injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If oxaliplatin injection contacts the mucous membranes, flush thoroughly with water.

Procedures for the handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published [see References ( 15 )]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATION

17.1 Information for Patients

17.2 FDA-Approved Patient Labeling

Patient Information

• Serious allergic reactions. Oxaliplatin injection can cause serious allergic reactions, including allergic reactions that may cause death. Oxaliplatin Injection is a platinum base medicine. Serious allergic reactions including death can occur 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 infusion or any time during your treatment with oxaliplatin injection.

• have trouble breathing.
• feel like your throat is closing up.

• rash
• flushed face
• hives
• itching
• swelling of your lips or tongue
• sudden cough
• dizziness or feel faint
• sweating
• chest pain

• stage III colon cancer after surgery to remove the tumor.
• advanced colon or rectal cancer (colorectal cancer).

Oxaliplatin injection with infusional 5-fluorouracil and leucovorin was shown to lower the chance of colon cancer returning when given to patients with stage III colon cancer after surgery to remove the tumor. Oxaliplatin injection also increases survival in patients with stage III colon cancer. Oxaliplatin injection with infusional 5-fluorouracil and leucovorin was also shown to increase survival, shrink tumors and delay growth of tumors in some patients with advanced colorectal cancer.

• Do not use oxaliplatin injection if you are allergic to any of the ingredients in oxaliplatin injection or other medicines that contain platinum. Cisplatin and carboplatin are other chemotherapy medicines that also contain platinum. See the end of this leaflet for a complete list of the ingredients in oxaliplatin injection.

• have kidney problems
• have any other medical conditions
• have had any allergic reactions to any medicines
• are pregnant or plan to become pregnant. Oxaliplatin may harm your unborn child. You should avoid becoming pregnant while taking oxaliplatin injection. Talk with your doctor about how to avoid pregnancy.
• are breastfeeding or plan to breastfeed. It is not known if oxaliplatin injection passes into your breast milk. You and your doctor should decide whether you will stop breastfeeding or not take oxaliplatin injection.

• Your doctor will prescribe oxaliplatin injection in an amount that is right for you.
• Your doctor will treat you with several medicines for your cancer.
• It is very important that you do exactly what your doctor and nurse have taught you to do.
• Some medicines may be given to you before oxaliplatin injection to help prevent nausea and vomiting.
• Oxaliplatin injection is given with 2 other chemotherapy medicines, leucovorin and 5-fluorouracil.
• Each treatment course is given to you over 2 days. You will receive oxaliplatin injection on the first day only.
• There are usually 14 days between each chemotherapy treatment course.

Treatment Day 1:
Oxaliplatin injection and leucovorin are given through a thin plastic tube put into a vein (intravenous infusion or IV) and given for 2 hours. You will be watched by a healthcare provider during this time.

• It is important for you to keep all appointments. Call your doctor if you must miss an appointment. There may be special instructions for you.
• Your doctor may change how often you get oxaliplatin injection, how much you get, or how long the infusion will take.
• You and your doctor will discuss how many times you will get oxaliplatin injection.

• Avoid cold temperatures and cold objects. Cover your skin if you must go outside in cold temperatures.
• Do not drink cold drinks or use ice cubes in drinks.
• Do not put ice or ice packs on your body.

• Serious allergic reactions. See “What is the most important information I should know about oxaliplatin injection?”
• Nerve problems. Oxaliplatin injection can affect how your nerves work and make you feel. Tell your doctor right away if you get any signs of nerve problems listed below:
• very sensitive to cold temperatures and cold objects.
• trouble breathing, swallowing, or saying words, jaw tightness, odd feelings in your tongue, or chest pressure.
• 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.
• 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:
  • headache
  • confusion or a change in the way you think
  • seizures
  • vision problems, such as blurriness or vision loss. You should not drive, operate heavy machines, or engage in dangerous activities if you have vision problems while receiving oxaliplatin injection.

• Lung problems (interstitial fibrosis). 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. 
• Harm to an unborn baby. Oxaliplatin injection may cause harm to your unborn baby. See “What should I tell my doctor before treatment with oxaliplatin injection?”

• Decreased blood counts: Oxaliplatin injection can cause a decrease in neutrophils (a type of white blood cell important in fighting bacterial infections), red blood cells (blood cells that carry oxygen to the tissues), and platelets (important for clotting and to control bleeding).
• High blood pressure (hypertension)
• Infection. Call your doctor right away if you get any of the following signs of infection:
   

  fever (temperature of 100.5o F or greater) chills or shivering pain on swallowing sore throat

  cough that brings up mucus burning or pain on urination redness or swelling at intravenous site

• Bleeding or bruising. Tell your doctor about any signs or symptoms of bleeding or bruising.
• Diarrhea
• Nausea
• Vomiting
• Constipation
• Mouth sores
• Stomach pain
• Decreased appetite
• Tiredness
• Injection site reactions. Reactions may include redness, swelling, pain, tissue damage at the site of injection.
• Hair loss (alopecia)
• 
  Dehydration (too much water loss). Call you doctor if you have signs of dehydration including:

• Cover yourself with a blanket while you are getting your oxaliplatin injection 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 healthcare provider or doctor know before your next treatment how well you did since your last visit.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-Oxaliplatin Injection, USP