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Indications
Oxaliplatin for injection USP, 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. Oxaliplatin for injection USP is a platinum-based drug used in combination with infusional 5-fluorouracil/leucovorin, which 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.
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Contraindications
Oxaliplatin for injection should not be administered to patients with a history of known allergy to oxaliplatin for injection or other platinum compounds [see Warnings and Precautions (5.1)] . - Known allergy to oxaliplatin for injection or other platinum compounds. (4, 5.1)
Warnings and precautions
- Allergic Reactions: Monitor for development of rash, urticaria, erythema, pruritis, bronchospasm, and hypotension. (5.1) - Neuropathy: Reduce the dose or discontinue oxaliplatin for injection if necessary. (5.2) - Severe Neutropenia: Delay oxaliplatin for injection until neutrophils are ≥1.5 x 10 9 /L. Withhold oxaliplatin for injection for sepsis. (5.3) - Pulmonary Toxicity: May need to discontinue oxaliplatin for injection until interstitial lung disease or pulmonary fibrosis are excluded.
(5.4) - Hepatotoxicity: Monitor liver function tests. (5.5) - Cardiovascular Toxicity: Correct hypokalemia or hypomagnesemia prior to initiating oxaliplatin for injection. (5.6) - Rhabdomyolysis: Discontinue oxaliplatin for injection if rhabdomyolysis occurs. (5.7) - Pregnancy. Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus. (5.8, 8.1)
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See boxed warning Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin for 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.
5.2Neurological Toxicity Neuropathy Oxaliplatin
for injection, USP 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 for 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 for 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 for 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 for 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 for 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 Patients Grade Definition Grade 0 No change or none Grade 1 Mild paresthesias, loss of deep tendon reflexes Grade 2 Mild or moderate objective sensory loss, moderate paresthesias Grade 3 Severe objective sensory loss or paresthesias that interfere with function Grade 4 Not applicable Peripheral sensory neuropathy was reported in adjuvant patients treated with the oxaliplatin for 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 Patients Grade Definition Grade 1 Resolved and did not interfere with functioning Grade 2 Interfered with function but not daily activities Grade 3 Pain or functional impairment that interfered with daily activities Grade 4 Persistent impairment that is disabling or life-threatening Overall, 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 syndrome Reversible Posterior Leukoencephalopathy syndrome (RPLS, also known as PRES, Posterior Revirsible 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)].
Dignosis of RPLS is based upon confirmation by brain imaging.
5.3 Severe Neutropenia Grade 3 or 4 neutropenia occurred in 41 to 44% of patients with colorectal cancer treated with oxaliplatin for 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 for injection, including fatal outcomes [see Adverse Reactions (6.1)]. Delay oxaliplatin for injection until neutrophils are ≥ 1.5 x 10 9 /L.
Withhold oxaliplatin for injection for sepsis or septic shock. Dose reduce oxaliplatin for injection after recovery from Grade 4 neutropenia or febrile neutropenia [see Dosage and Administration (2.2)].
5.4Pulmonary Toxicity Oxaliplatin
for 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 for injection plus infusional 5-fluorouracil/leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1%
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Interactions
No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 oxaliplatin for 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/m2 oxaliplatin for 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)].
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Category D Based
on direct interaction with DNA, oxaliplatin for injection may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of oxaliplatin for injection 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 for injection. Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days 1 to 5 (pre-implantation), 6 to 10, or 11 to 16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6 to 10 and 11 to 16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6 to 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.
Adverse reactions
The following serious adverse reactions are discussed in greaterdetail 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).] Most common adverse reactions (incidence ≥ 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, Fatigue and stomatitis.
Other adverse reactions, including serious adverse reactions, have been reported. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 864-879-994 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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 for 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)].
Combination Adjuvant Therapy with Oxaliplatin for Injection and Infusional 5-fluorouracil/leucovorin in Patients with Colon Cancer One thousand one hundred and eight patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, have been treated in a clinical study with oxaliplatin for injection in combination with infusional 5-fluorouracil/leucovorin [see Clinical Studies (14)].
The incidence of grade 3 or 4 adverse reactions was 70% on the oxaliplatin for injection combination arm, and 31% on the infusional 5-fluorouracil/leucovorin arm. The adverse reactions in this trial are shown in the tables below. Discontinuation of treatment due to adverse reactions occurred in 15% of the patients receiving oxaliplatin for injection and infusional 5-fluorouracil/leucovorin. Both 5-fluorouracil/leucovorin and oxaliplatin for injection are associated with gastrointestinal or hematologic adverse reactions.
When oxaliplatin for injection is administered in combination with infusional 5-fluorouracil/leucovorin, the incidence of these events is increased. The incidence of death within 28 days of last treatment, regardless of causality, was 0.5% (n=6) in both the oxaliplatin for injection combination and infusional 5-fluorouracil/leucovorin arms, respectively. Deaths within 60 days from initiation of therapy were 0.3% (n=3) in both the oxaliplatin for injection combination and infusional 5-fluorouracil/leucovorin arms, respectively.
On the oxaliplatin for injection combination arm, 3 deaths were due to sepsis/neutropenic sepsis, 2 from intracerebral bleeding and one from eosinophilic pneumonia. On the 5-fluorouracil/leucovorin arm, one death was due to suicide, 2 from Steven-Johnson Syndrome (1 patient also had sepsis), 1 unknown cause, 1 anoxic cerebral infarction and 1 probable abdominal aorta rupture. The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial [see Clinical Studies (14)] by body system and decreasing order of frequency in the oxaliplatin for injection and infusional 5-fluorouracil/leucovorin arm for events with overall incidences ≥ 5% and for NCI grade 3/4 events with incidences ≥ 1%.
Table 3 – Adverse Reactions Reported in Patients with Colon Cancer receiving Adjuvant Treatment (≥5% of all patients and with ≥1% NCI Grade 3/4 events) Oxaliplatin for Injection + 5-FU/LV N=1108 5-FU/LV N=1111 Adverse reaction (WHO/Pref) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Any Event 100 70 99 31 Allergy/Immunology Allergic Reaction 10 3 2 <1 Constitutional Symptoms/Pain Fatigue 44 4 38 1 Abdominal Pain 18 1 17 2 Dermatology/Skin Skin Disorder 32 2 36 2 Injection Site Reaction 1 11 3 10 3 Gastrointestinal Nausea 74 5 61 2 Diarrhea 56 11 48 7 Vomiting 47 6 24 1 Stomatitis 42 3 40 2 Anorexia 13 1 8 <1 Fever/Infection Fever 27 1 12 1 Infection 25 4 25 3 Neurology Overall Peripheral Sensory Neuropathy 92 12 16 <1 1 Includes thrombosis related to the catheter The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial [see Clinical Studies (14)] by body system and decreasing order of frequency in the oxaliplatin for injection and infusional 5-fluorouracil/leucovorin arm for events with overall incidences ≥ 5% but with incidences <1% NCI grade 3/4 events.
Table 4 - Adverse Reactions Reported in Patients with Colon Cancer receiving Adjuvant Treatment (≥ 5% of all patients, but with <1% NCI Grade 3/4 events) Adverse reaction (WHO/Pref) Oxaliplatin for Injection + 5-FU/LV N=1108 5-FU/LV N=1111 All Grades (%) All Grades (%) Allergy/Immunology Rhinitis 6 8 Constitutional Symptoms /Pain/Ocular/Visual Epistaxis 16 12 Weight Increase 10 10 Conjunctivitis 9 15 Headache 7 5 Dyspnea 5 3 Pain 5 5 Lacrimation Abnormal 4 12 Dermatology/Skin Alopecia 30 28 Gastrointestinal Constipation 22 19 Taste Perversion 12 8 Dyspepsia 8 5 Metabolic Phosphate Alkaline increased 42 20 Neurology Sensory Disturbance 8 1 Although specific events can vary, the overall frequency of adverse reactions was similar in men and women and in patients <65 and ≥65 years.
However, the following grade 3/4 events were more common in females: diarrhea, fatigue, granulocytopenia, nausea and vomiting. In patients ≥65 years old, the incidence of grade 3/4 diarrhea and granulocytopenia was higher than in younger patients. Insufficient subgroup sizes prevented analysis of safety by race. The following additional adverse reactions, were reported in ≥2% and <5% of the patients in the oxaliplatin for injection and infusional 5-fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): pain, leukopenia, weight decrease, coughing.
The number of patients who developed secondary malignancies was similar; 62 in the oxaliplatin for injection combination arm and 68 in the infusional 5-fluorouracil/leucovorin arm. An exploratory analysis showed that the number of deaths due to secondary malignancies was 1.96% in the oxaliplatin for injection combination arm and 0.98% in infusional 5-fluorouracil/leucovorin arm. In addition, the number of cardiovascular deaths was 1.4% in the oxaliplatin for injection combination arm as compared to 0.7% in the infusional 5-fluorouracil/leucovorin arm.
Clinical significance of these findings is unknown. Patients Previously Untreated for Advanced Colorectal Cancer Two hundred and fifty-nine patients were treated in the oxaliplatin for injection and 5- fluorouracil/leucovorin combination arm of the randomized trial in patients previously untreated for advanced colorectal cancer [see Clinical Studies (14)]. The adverse reaction profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below.
Both 5-fluorouracil and oxaliplatin for injection are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin for injection is administered in combination with 5-fluorouracil, the incidence of these events is increased.
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
OXALIPLATIN 100MG/VIAL
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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