NDC 16729-332 Oxaliplatin

Oxaliplatin

NDC Product Code 16729-332

NDC 16729-332-03

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 10 mL in 1 VIAL, SINGLE-DOSE

NDC 16729-332-05

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 20 mL in 1 VIAL, SINGLE-DOSE

NDC Product Information

Oxaliplatin with NDC 16729-332 is a a human prescription drug product labeled by Accord Healthcare Inc.. The generic name of Oxaliplatin is oxaliplatin. The product's dosage form is injection, solution, concentrate and is administered via intravenous form.

Labeler Name: Accord Healthcare Inc.

Dosage Form: Injection, Solution, Concentrate - A sterile preparation for parenteral use which, upon the addition of suitable solvents, yields a solution conforming in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Oxaliplatin Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • OXALIPLATIN 5 mg/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Platinum-based Drug - [EPC] (Established Pharmacologic Class)
  • Platinum-containing Compounds - [EXT]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Accord Healthcare Inc.
Labeler Code: 16729
FDA Application Number: ANDA207474 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 05-17-2018 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Oxaliplatin Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Anaphylactic Reactions

Anaphylactic reactions to oxaliplatin injection have been reported, and may occur within minutes of oxaliplatin injection administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms of anaphylaxis


[see


Warnings and Precautions (5.1)].

1 Indications And Usage

  • Oxaliplatin injection, used in combination with infusional 5-fluorouracil/leucovorin, is indicated for: adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor. treatment of advanced colorectal cancer.

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.

2.2 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 injection from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

Other

Dose Modifications in Therapy for Patients with Renal ImpairmentIn patients with normal renal function or mild to moderate renal impairment, the recommended dose of oxaliplatin injection is 85 mg/m


2. In patients with severe renal impairment, the initial recommended oxaliplatin injection dose should be reduced to 65 mg/m


2 [see


Use in Specific Populations (8.6) and


Clinical Pharmacology (12.3)]


.

NeuropathyOxaliplatin injection is associated with two types of neuropathy:An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing. The symptoms may 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 study patients who received oxaliplatin injection with 5-fluorouracil/leucovorin. In any individual cycle acute neurotoxicity was observed in approximately 30% of patients. In adjuvant patients the median cycle of onset for grade 3 peripheral sensory neuropathy was 9 in the previously treated patients the median number of cycles administered on the oxaliplatin injection with 5-fluorouracil/leucovorin combination arm was 6.


An acute syndrome of pharyngolaryngeal dysesthesia seen in 1 to 2% (grade 3/4) of patients previously untreated for advanced colorectal cancer, and the previously treated patients, is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of oxaliplatin injection because cold temperature can exacerbate acute neurological symptoms.A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, 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 the study patients receiving oxaliplatin injection with 5-fluorouracil/leucovorin. Persistent neuropathy can occur without any prior acute neuropathy event. The majority of the patients (80%) who developed grade 3 persistent neuropathy progressed from prior Grade 1 or 2 events. These symptoms may improve in some patients upon discontinuation of oxaliplatin injection.


In the adjuvant colon cancer trial, neuropathy was graded using a prelisted module derived from the Neuro-Sensory section of the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale, Version 1, as follows:Table 1 - NCI CTC Grading for Neuropathy in Adjuvant PatientsGradeDefinitionGrade 0No change or noneGrade 1Mild paresthesias, loss of deep tendon reflexesGrade 2Mild or moderate objective sensory loss, moderate paresthesiasGrade 3Severe objective sensory loss or paresthesias that interfere with functionGrade 4Not applicablePeripheral sensory neuropathy was reported in adjuvant patients treated with the oxaliplatin injection combination with a frequency of 92% (all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral sensory neuropathy decreasing to 39% at 6 months 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%).In the advanced colorectal cancer studies, neuropathy was graded using a study-specific neurotoxicity scale, which was different from the NCI CTC scale, Version 2.0 (see below).Table 2 - Grading Scale for Paresthesias/Dysesthesias in Advanced Colorectal Cancer PatientsGradeDefinitionGrade 1Resolved and did not interfere with functioningGrade 2Interfered with function but not daily activitiesGrade 3 Pain or functional impairment that interfered with daily activitiesGrade 4Persistent impairment that is disabling or life-threateningOverall, neuropathy was reported in patients previously untreated for advanced colorectal cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (grade 3/4) events. Information regarding reversibility of neuropathy was not available from the trial for patients who had not been previously treated for colorectal cancer.

Reversible Posterior Leukoencephalopathy SyndromeReversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension


[see


Adverse Reactions (6.2)]


. Diagnosis of RPLS is based upon confirmation by brain imaging.

2.3 Preparation Of Infusion Solution

Do not freeze and protect from light the concentrated solution.


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 to 500 mL of 5% Dextrose Injection, USP.



After dilution with 250 to 500 mL of 5% Dextrose Injection, USP, the shelf life is


6 hours at room temperature [20 to 25°C (68 to 77°F)] or up to 24 hours under refrigeration [2 to 8°C (36 to 46°F)]. After final dilution, protection from light is not required.


Oxaliplatin injection 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 should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

3 Dosage Forms And Strengths

Oxaliplatin injection, USP is supplied in single-dose vials containing 50 mg, 100 mg or 200 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL.

4 Contraindications

Oxaliplatin injection should not be administered to patients with a history of known allergy to oxaliplatin injection or other platinum compounds


[see


Warnings and Precautions (5.1)]


.

5.1 Allergic Reactions

See


boxed warningGrade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin injection has been observed in 2 to 3% of colon cancer patients. These allergic reactions which can be fatal, can occur within minutes of administration and at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy. Rechallenge is contraindicated in these patients


[see


Contraindications (4)]


. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.

5.3 Severe Neutropenia

Grade 3 or 4 neutropenia occurred in 41 to 44% of patients with colorectal cancer treated with oxaliplatin injection 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 injection, including fatal outcomes


[see


Adverse Reactions (6.1)]


.



Delay oxaliplatin injection until neutrophils are ≥ 1.5 x 10


9/L. Withhold oxaliplatin injection for sepsis or septic shock. Dose reduce oxaliplatin injection after recovery from Grade 4 neutropenia or febrile neutropenia


[see


Dosage and Administration (2.2)]


.

5.4 Pulmonary Toxicity

Oxaliplatin injection 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 injection 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 injection combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the oxaliplatin injection 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 injection should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

5.5 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 injection 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)]


.

5.6 Cardiovascular Toxicity

QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been reported in postmarketing experiences following oxaliplatin injection 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 injection and monitor these electrolytes periodically during therapy. Avoid oxaliplatin injection in patients with congenital long QT syndrome


[see


Adverse Reactions (6.2)]


.

5.7 Rhabdomyolysis

Rhabdomyolysis, including fatal cases, has been reported in patients treated with oxaliplatin injection. Discontinue oxaliplatin injection if any signs or symptoms of rhabdomyolysis occur.


[see


Adverse Reactions (6.2)]


.

5.8 Use In Pregnancy

Pregnancy Category DOxaliplatin injection may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of oxaliplatin injection in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with oxaliplatin injection.


[see


Use in Specific Populations (8.1)].

Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each oxaliplatin injection cycle


[see


Dosage and Administration (2)].


There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received oxaliplatin injection plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving oxaliplatin injection plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.

6 Adverse Reactions

  • The following serious adverse reactions are discussed in greater detail in other sections of the label:Anaphylaxis and Allergic reactions
  • [see
  • Boxed Warning,
  • Warnings and Precautions (5.1)
  • .]
  • Neuropathy
  • [see
  • Warnings and Precautions (5.2)
  • .]
  • Severe Neutropenia
  • [see
  • Warnings and Precautions (5.3)
  • .]
  • Pulmonary Toxicities
  • [see
  • Warnings and Precautions (5.4)
  • .]
  • Hepatotoxicity
  • [see
  • Warnings and Precautions (5.5)
  • .]
  • Cardiovascular Toxicities
  • [see
  • Warnings and Precautions (5.6)
  • .]
  • Rhabdomyolysis
  • [see
  • Warnings and Precautions (5.7)
  • .]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.More than 1100 patients with stage II or III colon cancer and more than 4,000 patients with advanced colorectal cancer have been treated in clinical studies with oxaliplatin injection. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. The most common adverse reactions in previously untreated and treated patients were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea


[see


Warnings and Precautions (5)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of oxaliplatin injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Body as a whole: angioedema, anaphylactic shock


Cardiovascular disorders: QT prolongation leading to ventricular arrhythmias including fatal Torsade de Pointes


Central and peripheral nervous system disorders:loss of deep tendon reflexes, dysarthria, Lhermitte’s sign, cranial nerve palsies, fasciculations, convulsion, Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES).


Hearing and vestibular system disorders:deafness


Infections: septic shock, including fatal outcomes


Infusion reactions/hypersensitivity: laryngospasm


Liver and Gastrointestinal system disorders: severe diarrhea/vomiting resulting in hypokalemia, colitis (including


Clostridium difficile diarrhea), metabolic acidosis; ileus; intestinal obstruction, pancreatitis; veno-occlusive disease of liver also known as sinusoidal obstruction syndrome, and perisinusoidal fibrosis which rarely may progress.


Musculoskeletal and connective tissue disorders rhabdomyolysis, including fatal outcomes.


Platelet, bleeding, and clotting disorders:immuno-allergic thrombocytopenia


prolongation of prothrombin time and of INR in patients receiving anticoagulants


Red Blood Cell disorders:hemolytic uremic syndrome, immuno-allergic hemolytic anemia


Renal disorders:Acute tubular necrosis, acute interstitial nephritis and acute renal failure.


Respiratory system disorders:pulmonary fibrosis, and other interstitial lung diseases (sometimes fatal)


Vision disorders:decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following therapy discontinuation)

7 Drug Interactions

No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m


2 oxaliplatin injection 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/m


2 oxaliplatin injection 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)].

8.3 Nursing Mothers

It is not known whether oxaliplatin injection 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 injection, 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

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/m


2 with escalation to 110 mg/m


2. The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m


2 dose. Fifteen patients received oxaliplatin at a dose of 90 mg/m


2 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/m


2 with escalation to 160 mg/m


2, for a maximum of 6 cycles. In a separate cohort, oxaliplatin 85 mg/m


2 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/m


2 dose. Based on these studies, oxaliplatin 130 mg/m


2 as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) was used in subsequent Phase II studies. A dose of 85 mg/m


2 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/m


2 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/m


2 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 C


max of 0.75 ± 0.24 mcg/mL, AUC


0-48 of 7.52 ± 5.07 mcg∙h/mL and AUC


inf of 8.83 ± 1.57 mcg•h/mL at 85 mg/m


2 of oxaliplatin and C


max of 1.10 ± 0.43 mcg/mL, AUC


0-48 of 9.74 ± 2.52 mcg•h/mL and AUC


inf of 17.3 ± 5.34 mcg•h/mL at 130 mg/m


2 of oxaliplatin.

8.5 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 injection 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 injection combination arm compared to the infusional 5-fluorouracil/leucovorin alone arm appeared to be maintained across genders. The effect of oxaliplatin injection in patients ≥65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race.Patients ≥ 65 years of age receiving the oxaliplatin injection combination therapy experienced more grade 3 to 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 injection, 160 patients treated with oxaliplatin injection 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 injection, 95 patients treated with oxaliplatin injection 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.

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 injection is administered to patients with renal impairment. The starting oxaliplatin injection 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 injection should be reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min)


[see


Dosage and Administration (2.2)]


.

11 Description

Oxaliplatin injection, USP is an antineoplastic agent with the molecular formula C


8H


14N


2O


4Pt 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.


The molecular weight is 397.3. Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone.


Oxaliplatin injection, USP is supplied in vials containing 50 mg, 100 mg or 200 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. Water for Injection, USP is present as an inactive ingredient.

12.1 Mechanism Of Action

Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the


N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.


In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with 5-fluorouracil, oxaliplatin exhibits


in vitro and


in vivo antiproliferative activity greater than either compound alone in several tumor models [HT29 (colon), GR (mammary), and L1210 (leukemia)].

12.3 Pharmacokinetics

The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t


1/2α; 0.43 hours and t


1/2β; 16.8 hours) and a long terminal elimination phase (t


1/2γ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour intravenous infusion of oxaliplatin injection at a dose of 85 mg/m


2 expressed as ultrafilterable platinum were C


max of 0.814 mcg/mL and volume of distribution of 440 L.


Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC


0–48hr) assessed over 3 cycles was moderate to low (23% and 6%, respectively). A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells


in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both


in vitro (chromosome aberration in human lymphocytes) and


in vivo (mouse bone marrow micronucleus assay).


In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but caused developmental mortality (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day x 5 days every 28 days for three cycles. A no effect level was not identified. This daily dose is approximately one-sixth of the recommended human dose on a body surface area basis.

14.1 Combination Adjuvant Therapy With Oxaliplatin Injection And Infusional 5-Fluorouracil/Leucovorin In Patients With Colon Cancer

An international, multicenter, randomized study compared the efficacy and evaluated the safety of oxaliplatin injection in combination with an infusional schedule of 5-fluorouracil/leucovorin to infusional 5-fluorouracil/leucovorin alone, in patients with stage II (Dukes’ B2) or III (Dukes’ C) colon cancer who had undergone complete resection of the primary tumor. The primary objective of the study was to compare the 3-year disease-free survival (DFS) in patients receiving oxaliplatin injection and infusional 5-fluorouracil/leucovorin to those receiving 5-fluorouracil/leucovorin alone. Patients were to be treated for a total of 6 months (i.e., 12 cycles). A total of 2246 patients were randomized; 1123 patients per study arm. Patients in the study had to be between 18 and 75 years of age, have histologically proven stage II (T


3-T


4 N0 M0; Dukes’ B2) or III (any T N


1-2 M0; Dukes’ C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., ≥15 cm from the anal margin) and undergone (within 7 weeks prior to randomization) complete resection of the primary tumor without gross or microscopic evidence of residual disease. Patients had to have had no prior chemotherapy, immunotherapy or radiotherapy, and have an ECOG performance status of 0,1, or 2 (KPS ≥ 60%), absolute neutrophil count (ANC) > 1.5x 10


9/L, platelets ≥100x 10


9/L, serum creatinine ≤ 1.25 x ULN total bilirubin < 2 x ULN, AST/ALT < 2 x ULN and carcino-embyrogenic antigen (CEA) < 10 ng/mL. Patients with preexisting peripheral neuropathy (NCI grade ≥ 1) were ineligible for this trial.


The following table shows the dosing regimens for the two arms of the study.Table 15 - Dosing Regimens in Adjuvant Therapy StudyTreatment ArmDoseRegimenOxaliplatin Injection + 5-FU/LV


(FOLFOX4)


(N =1123)


Day 1: Oxaliplatin Injection: 85 mg/m


2 (2-hour infusion) + LV: 200 mg/m


2 (2-hour infusion), followed by


5-FU: 400 mg/m


2 (bolus), 600 mg/m


2 (22-hour infusion)



Day 2: LV: 200 mg/m


2 (2-hour infusion), followed by


5-FU: 400 mg/m


2 (bolus), 600 mg/m


2 (22-hour infusion)


every 2 weeks 12 cycles 5-FU/LV


(N=1123)


Day 1: LV: 200 mg/m


2 (2-hour infusion), followed by


5-FU: 400 mg/m


2 (bolus), 600 mg/m


2 (22-hour infusion)



Day 2: LV: 200 mg/m


2 (2-hour infusion), followed by


5-FU: 400 mg/m


2 (bolus), 600 mg/m


2 (22-hour infusion)


every 2 weeks 12 cyclesThe following tables show the baseline characteristics and dosing of the patient population entered into this study. The baseline characteristics were well balanced between arms.Table 16 - Patient Characteristics in Adjuvant Therapy StudyOxaliplatin Injection + infusional


5-FU/LV


N=1123


Infusional


5-FU/LV


N=1123


Sex: Male (%)56.152.4Female (%)43.947.6Median age (years)61.060.0<65 years of age (%)64.466.2≥65 years of age (%)35.633.8Karnofsky Performance Status (KPS) (%)10029.730.59052.253.9804.43.37013.211.9≤600.60.4Primary site (%)Colon including cecum54.654.4Sigmoid31.933.8Recto sigmoid12.910.9Other including rectum0.60.9Bowel obstruction (%)Yes17.919.3Perforation (%)Yes6.96.9Stage at Randomization (%)II (T=3,4 N=0, M=0)40.139.9III (T=any, N=1,2, M=0)59.659.3IV (T=any, N=any, M=1)0.40.8Staging – T (%)T10.50.7T24.54.8T376.075.9T419.018.5Staging – N (%)N040.239.9N139.439.4N220.420.7Staging – M (%)M10.40.8Table 17 - Dosing in Adjuvant Therapy StudyOxaliplatin Injection + infusional


5-FU/LV


N=1108


Infusional


5-FU/LV


N=1111


Median Relative Dose Intensity (%)  5-FU84.497.7Oxaliplatin Injection80.5N/AMedian Number of Cycles1212Median Number of cycles with Oxaliplatin Injection11N/AThe 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.Table 18 - Summary of DFS analysis – ITT analysis

Data cut off for disease free survival 1 June 2006 Oxaliplatin Injection + Infusional 5-FU/LVInfusional


5-FU/LV


ParameterOverallN11231123Number of events – relapse or death (%)304 (27.1)360 (32.1)Disease-free survival % [95% CI]


Disease-free survival at 5 years73.3 [70.7, 76.0]67.4 [64.6, 70.2]Hazard ratio [95% CI]


A hazard ratio of less than 1.00 favors oxaliplatin injection + Infusional 5-fluorouracil/leucovorin0.80 [0.68, 0.93]Stratified Logrank testp=0.003Stage III (Dukes' C)N672675Number of events –relapse or death (%)226 (33.6)271 (40.1)Disease-free survival % [95% CI]


66.4 [62.7, 70.0]58.9 [55.2, 62.7]Hazard ratio [95% CI]


0.78 [0.65, 0.93]Logrank testp=0.005Stage II (Dukes' B2)N451448Number of events – relapse or death (%)78 (17.3)89 (19.9)Disease-free survival % [95% CI]


83.7 [80.2, 87.1]79.9 [76.2, 83.7]Hazard ratio [95% CI]


0.84 [0.62, 1.14]Logrank testp=0.258In the overall and stage III colon cancer populations DFS was statistically significantly improved in the oxaliplatin injection combination arm compared to infusional 5-fluorouracil/leucovorin alone. However, a statistically significant improvement in DFS was not noted in Stage II patients.Figure 2 shows the DFS Kaplan-Meier curves for the comparison of oxaliplatin injection and infusional 5-fluorouracil/leucovorin combination and infusional 5-fluorouracil/leucovorin alone for the overall population (ITT analysis). Figure 3 shows the DFS Kaplan-Meier curves for the comparison of oxaliplatin injection and infusional 5-fluorouracil/leucovorin combination and infusional 5-fluorouracil/leucovorin alone in Stage III patients.The following table summarizes the overall survival (OS) results in the overall randomized population and in patients with stage II and III disease, based on the ITT analysis.Table 19 - Summary of OS analysis - ITT analysis
ParameterOxaliplatin Injection + Infusional 5-FU/LVInfusional 5-FU/LVOverallN11231123Number of death events (%)245 (21.8)283 (25.2)Hazard ratio


A hazard ratio of less than 1.00 favors oxaliplatin injection + Infusional 5-fluorouracil/leucovorin
Data cut off for overall survival 16 January 2007
[95% CI]


0.84 [0.71 , 1.00]Stage III (Dukes’ C)N672675Number of death events (%)182 (27.1)220 (32.6)Hazard ratio


[95% CI]


0.80 [0.65 , 0.97]Stage II (Dukes’ B2)N451448Number of death events (%)63 (14.0)63 (14.1)Hazard ratio


[95% CI]


1.00 [0.70 , 1.41]

14.2 Combination Therapy With Oxaliplatin Injection And 5-Fluorouracil/Leucovorin In Patients Previously Untreated For Advanced Colorectal Cancer

A North American, multicenter, open-label, randomized controlled study was sponsored by the National Cancer Institute (NCI) as an intergroup study led by the North Central Cancer Treatment Group (NCCTG). The study had 7 arms at different times during its conduct, four of which were closed due to either changes in the standard of care, toxicity, or simplification. During the study, the control arm was changed to irinotecan plus 5-fluorouracil/leucovorin. The results reported below compared the efficacy and safety of two experimental regimens, oxaliplatin injection in combination with infusional 5-fluorouracil/leucovorin and a combination of oxaliplatin injection plus irinotecan, to an approved control regimen of irinotecan plus 5-fluorouracil/leucovorin in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. After completion of enrollment, the dose of irinotecan plus 5-fluorouracil/leucovorin was decreased due to toxicity. Patients had to be at least 18 years of age, have known locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy with curative intent, histologically proven colorectal adenocarcinoma, measurable or evaluable disease, with an ECOG performance status 0,1, or 2. Patients had to have granulocyte count ≥ 1.5 x 10


9/L, platelets ≥ 100 x 10


9/L, hemoglobin ≥9.0 gm/dL, creatinine ≤ 1.5 x ULN, total bilirubin ≤ 1.5 mg/dL, AST ≤ 5 x ULN, and alkaline phosphatase ≤ 5 x ULN. Patients may have received adjuvant therapy for resected Stage II or III disease without recurrence within 12 months. The patients were stratified for ECOG performance status (0, 1 vs. 2), prior adjuvant chemotherapy (yes vs. no), prior immunotherapy (yes vs. no), and age (<65 vs. ≥65 years). Although no post study treatment was specified in the protocol, 65 to 72% of patients received additional post study chemotherapy after study treatment discontinuation on all arms. Fifty-eight percent of patients on the oxaliplatin injection plus 5-fluorouracil/leucovorin arm received an irinotecan-containing regimen and 23% of patients on the irinotecan plus 5-fluorouracil/leucovorin arm received oxaliplatin-containing regimens. Oxaliplatin was not commercially available during the trial.


The following table presents the dosing regimens of the three arms of the study.Table 20 – Dosing Regimens in Patients Previously Untreated for Advanced Colorectal Cancer Clinical TrialTreatment ArmDoseRegimenOxaliplatin Injection +


5-FU/LV


(FOLFOX4)


(N=267)


Day 1: Oxaliplatin Injection: 85 mg/m


2 (2-hour infusion) + LV 200 mg/m


2 (2-hour infusion), followed by 5-FU: 400 mg/m


2 (bolus), 600 mg/m


2 (22-hour infusion)


Day 2: LV 200 mg/m


2 (2-hour infusion), followed by


5-FU: 400 mg/m


2 (bolus), 600 mg/m


2 (22-hour infusion)


every 2 weeksIrinotecan +


5-FU/LV


(IFL)


(N=264)


Day 1: irinotecan 125 mg/m


2 as a 90–min infusion +


LV 20 mg/m


2 as a 15-min infusion or intravenous push, followed by


5-FU 500 mg/m


2 intravenous bolus weekly x 4


every 6 weeksOxaliplatin Injection +


Irinotecan


(IROX)


(N=264)


Day 1: Oxaliplatin Injection: 85 mg/m


2 intravenous (2¬ hour infusion) +


irinotecan 200 mg/m


2 intravenous over 30 minutes


every 3 weeksThe following table presents the demographics of the patient population entered into this study.Table 21 – Patient Demographics in Patients Previously Untreated for Advanced Colorectal Cancer Clinical TrialOxaliplatin Injection + 5-FU/LV


N=267


Irinotecan + 5-FU/LV


N=264


Oxaliplatin Injection + irinotecan


N=264


Sex: Male (%)58.865.261.0        Female (%)41.234.839.0Median age (years)61.061.061.0<65 years of age (%)616263≥65 years of age (%)393837ECOG (%)0-194.495.594.725.64.55.3Involved organs (%)  Colon only0.70.80.4  Liver only39.344.339.0  Liver + other41.238.640.9  Lung only6.43.85.3  Other (including lymph nodes)11.611.012.9  Not reported0.71.51.5Prior radiation (%)3.01.53.0Prior surgery (%)74.579.281.8Prior adjuvant (%)15.714.815.2The length of a treatment cycle was 2 weeks for the oxaliplatin injection and 5-fluorouracil/leucovorin regimen; 6 weeks for the irinotecan plus 5-fluorouracil/leucovorin regimen; and 3 weeks for the oxaliplatin injection plus irinotecan regimen. The median number of cycles administered per patient was 10 (23.9 weeks) for the oxaliplatin injection and 5-fluorouracil/leucovorin regimen, 4 (23.6 weeks) for the irinotecan plus 5-fluorouracil/leucovorin regimen, and 7 (21.0 weeks) for the oxaliplatin injection plus irinotecan regimen. Patients treated with the oxaliplatin injection and 5-fluorouracil/leucovorin combination had a significantly longer time to tumor progression based on investigator assessment, longer overall survival, and a significantly higher confirmed response rate based on investigator assessment compared to patients given irinotecan plus 5-fluorouracil/leucovorin. The following table summarizes the efficacy results.Table 22 – Summary of Efficacy


Compared to irinotecan plus 5-fluorouracil/leucovorin (IFL) arm Oxaliplatin Injection + 5-FU/LV


N=267


irinotecan + 5-FU/LV


N=264


Oxaliplatin Injection + irinotecan


N=264


Survival (ITT)Number of deaths N (%)155 (58.1)192 (72.7)175 (66.3)Median survival (months)19.414.617.6Hazard Ratio and (95% confidence interval)0.65 (0.53-0.80)


P-value<0.0001


--TTP (ITT, investigator assessment)Percentage of progressors82.881.889.4Median TTP (months)8.76.96.5Hazard Ratio and (95% confidence interval)


A hazard ratio of less than 1.00 favors oxaliplatin injection + Infusional 5-fluorouracil/leucovorin 0.74 (0.61-0.89)


P-value0.0014


-- Response Rate (investigator assessment)


Based on all patients with measurable disease at baseline
The numbers in the response rate and TTP analysis are based on unblinded investigator assessment.
Patients with measurable disease210212215Complete response N (%)13 (6.2)5 (2.4)7 (3.3)Partial response N (%)82 (39.0)64 (30.2)67 (31.2)Complete and partial response N (%)95 (45.2)69 (32.5)74 (34.4)95% confidence interval(38.5 – 52.0)(26.2 – 38.9)(28.1 – 40.8)P-value0.0080


-- Figure 4 illustrates the Kaplan-Meier survival curves for the comparison of oxaliplatin injection and 5-fluorouracil/leucovorin combination and oxaliplatin injection plus irinotecan to irinotecan plus 5-fluorouracil/leucovorin.A descriptive subgroup analysis demonstrated that the improvement in survival for oxaliplatin injection plus 5-fluorouracil/leucovorin compared to irinotecan plus 5-fluorouracil/leucovorin appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved. An estimated survival advantage in oxaliplatin injection plus 5-fluorouracil/leucovorin versus irinotecan plus 5-fluorouracil/leucovorin was seen in both genders; however it was greater among women than men. Insufficient subgroup sizes prevented analysis by race.

14.3 Combination Therapy With Oxaliplatin Injection And 5-Fluorouracil/Leucovorin In Previously Treated Patients With Advanced Colorectal Cancer

A multicenter, open-label, randomized, three-arm controlled study was conducted in the US and Canada comparing the efficacy and safety of oxaliplatin injection in combination with an infusional schedule of 5-fluorouracil/leucovorin to the same dose and schedule of 5-fluorouracil/leucovorin alone and to single agent oxaliplatin in patients with advanced colorectal cancer who had relapsed/progressed during or within 6 months of first-line therapy with bolus 5-fluorouracil/leucovorin and irinotecan. The study was intended to be analyzed for response rate after 450 patients were enrolled. Survival will be subsequently assessed in all patients enrolled in the completed study. Accrual to this study is complete, with 821 patients enrolled. Patients in the study had to be at least 18 years of age, have unresectable, measurable, histologically proven colorectal adenocarcinoma, with a Karnofsky performance status >50%. Patients had to have SGOT(AST) and SGPT(ALT) ≤2x the institution’s upper limit of normal (ULN), unless liver metastases were present and documented at baseline by CT or MRI scan, in which case ≤5x ULN was permitted. Patients had to have alkaline phosphatase ≤2x the institution’s ULN, unless liver metastases were present and documented at baseline by CT or MRI scan, in which cases ≤5x ULN was permitted. Prior radiotherapy was permitted if it had been completed at least 3 weeks before randomization.


The dosing regimens of the three arms of the study are presented in the table below.


Table 23 – Dosing Regimens in Refractory and Relapsed Colorectal Cancer Clinical TrialTreatment ArmDoseRegimenOxaliplatin Injection +


5-FU/LV


(N =152)


Day 1: Oxaliplatin Injection: 85 mg/m


2 (2-hour infusion) + LV 200 mg/m


2 (2-hour infusion), followed by 5-FU: 400 mg/m


2 (bolus), 600 mg/m


2 (22-hour infusion)


Day 2: LV 200 mg/m


2 (2-hour infusion), followed by 5-FU: 400 mg/m


2 (bolus), 600 mg/m


2 (22-hour infusion)


every 2 weeks 5-FU/LV


(N=151)


Day 1: LV 200 mg/m


2 (2-hour infusion), followed by 5-FU: 400 mg/m


2 (bolus), 600 mg/m


2 (22-hour infusion)


Day 2: LV 200 mg/m


2 (2-hour infusion), followed by 5-FU: 400 mg/m


2 (bolus), 600 mg/m


2 (22-hour infusion)


every 2 weeksOxaliplatin Injection


(N=156)


Day 1: Oxaliplatin Injection 85 mg/m


2 (2-hour infusion)


every 2 weeksPatients entered into the study for evaluation of response must have had at least one unidimensional lesion measuring ≥20mm using conventional CT or MRI scans, or ≥10mm using a spiral CT scan. Tumor response and progression were assessed every 3 cycles (6 weeks) using the Response Evaluation Criteria in Solid Tumors (RECIST) until radiological documentation of progression or for 13 months following the first dose of study drug(s), whichever came first. Confirmed responses were based on two tumor assessments separated by at least 4 weeks.


The demographics of the patient population entered into this study are shown in the table below.


Table 24 – Patient Demographics in Refractory and Relapsed Colorectal Cancer Clinical Trial5-FU/LV


(N = 151)


Oxaliplatin Injection


(N = 156)


Oxaliplatin Injection + 5-FU/LV


(N = 152)


Sex: Male (%)54.360.957.2        Female (%)45.739.142.8Median age (years)60.061.059.0  Range21-8027-7922-88Race (%)  Caucasian87.484.688.8  Black7.97.15.9  Asian1.32.62.6  Other3.35.82.6KPS (%)  70 – 10094.792.395.4  50 – 602.64.52.0  Not reported2.63.22.6Prior radiotherapy (%)25.219.225.0Prior pelvic radiation (%)18.513.521.1Number of metastatic sites (%)  127.231.425.7  ≥272.267.974.3Liver involvement (%)  Liver only22.525.618.4  Liver + other60.359.053.3The median number of cycles administered per patient was 6 for the oxaliplatin injection and 5-fluorouracil/leucovorin combination and 3 each for 5-fluorouracil/leucovorin alone and oxaliplatin injection alone.Patients treated with the combination of oxaliplatin injection and 5-fluorouracil/leucovorin had an increased response rate compared to patients given 5-fluorouracil/leucovorin or oxaliplatin alone. The efficacy results are summarized in the tables below.Table 25 - Response Rates (ITT Analysis)Best Response5-FU/LV


(N=151)


Oxaliplatin Injection


(N=156)


Oxaliplatin Injection + 5-FU/LV


(N=152)


CR000PR02 (1%)13 (9%)p-value0.0002 for 5-FU/LV vs. Oxaliplatin Injection + 5-FU/LV95%CI0-2.4%0.2-4.6%4.6-14.2%Table 26 - Summary of Radiographic Time to Progression


This is not an ITT analysis. Events were limited to radiographic disease progression documented by independent review of radiographs. Clinical progression was not included in this analysis, and 18% of patients were excluded from the analysis based on unavailability of the radiographs for independent review. Arm5-FU/LV


(N=151)


Oxaliplatin Injection


(N=156)


Oxaliplatin Injection + 5-FU/LV


(N=152)


No. of Progressors7410150No. of patients with no radiological evaluation beyond baseline22


(15%)


16


(10%)


17


(11%)


Median TTP (months)2.71.64.695% CI1.8-3.01.4-2.74.2-6.1At the time of the interim analysis 49% of the radiographic progression events had occurred. In this interim analysis an estimated 2-month increase in median time to radiographic progression was observed compared to 5-fluorouracil/leucovorin alone. Of the 13 patients who had tumor response to the combination of oxaliplatin injection and 5-fluorouracil/leucovorin, 5 were female and 8 were male, and responders included patients <65 years old and ≥65 years old. The small number of non-Caucasian participants made efficacy analyses in these populations uninterpretable.

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. https://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.

16.1  How Supplied

Oxaliplatin Injection, USP is supplied in clear, glass, single-dose vials with gray elastomeric stoppers and aluminum flip-off seals containing 50 mg/10 mL, 100 mg/20 mL or 200 mg/40 mL of oxaliplatin USP as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. Water for Injection, USP is present as an inactive ingredient.NDC 16729-332-03: 50 mg/10 mL single-dose vial with green flip-off seal individually packaged in a carton.NDC 16729-332-05: 100 mg/20 mL single-dose vial with dark blue flip-off seal individually packaged in a carton.NDC 16729-332-35: 200 mg/40 mL single-dose vial with orange flip-off seal individually packaged in a carton.

16.2  Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°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

  • Advise patients:To expect side effects of oxaliplatin injection, particularly its neurologic effects, both the acute, reversible effects and the persistent neurosensory toxicity. Patients should be informed that the acute neurosensory toxicity may be precipitated or exacerbated by exposure to cold or cold objects.To avoid cold drinks, use of ice, and should cover exposed skin prior to exposure to cold temperature or cold objects.Of the risk of low blood cell counts and to contact their physician immediately should fever, particularly if associated with persistent diarrhea, or evidence of infection develop.To contact their physician if persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties occur, or signs of allergic reaction appear.To exercise caution when driving and using machines. No studies on the effects of the ability to operate cars and machines have been performed; however, oxaliplatin treatment resulting in an increase risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to a minor or moderate influence on the ability to drive and use machines.Of the potential effects of vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), which may affect patients' ability to drive and use machines.

* Please review the disclaimer below.