Oxaliplatin Side Effects

Brand Names: Eloxatin

Please note - some side effects for Oxaliplatin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Oxaliplatin - for the Consumer

Oxaliplatin

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Oxaliplatin:

Constipation; decreased appetite; diarrhea; dizziness; fatigue; gas; hair loss; headache; heartburn; hiccups; increased tears; muscle or joint aches; nausea; pain, redness, or swelling at the injection site; runny nose; taste changes; trouble sleeping; vomiting; weight loss.

Seek medical attention right away if any of these SEVERE side effects occur when using Oxaliplatin:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blood in the urine; calf or groin pain, swelling, or redness; change in the amount of urine produced; chest pain or pressure; confusion, slurred speech, or one-sided weakness; coughing up blood; disorientation; excessive sweating; fainting; flushing; mouth sores or swelling; nosebleeds; red, swollen, blistered, or peeling skin; severe or persistent diarrhea or vomiting; severe or persistent dizziness; severe or persistent pain, swelling, or redness at the injection site; severe or persistent tiredness or weakness; shortness of breath; sudden, severe headache; swelling of the hands, ankles, or feet; symptoms of dehydration (eg, very dry eyes, mouth, or skin; unusual thirst); symptoms of infection (eg, fever, chills, or sore throat; painful urination; productive cough); symptoms of liver problems (eg, yellowing of the skin or eyes; dark urine; pale stools; persistent nausea, stomach pain, or loss of appetite); symptoms of low potassium levels (eg, irregular heartbeat, muscle pain or cramps); symptoms of stomach or bowel bleeding (eg, black, tarry stools; vomit that looks like coffee grounds); trouble walking, swallowing, speaking, or performing other daily tasks (eg, writing, buttoning); unusual bruising or bleeding; vision loss or other vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Oxaliplatin Side Effects - for the Professional

Oxaliplatin

Clinical Trials Experience

Serious adverse reactions including anaphylaxis and allergic reactions, neuropathy, pulmonary toxicities and hepatotoxicities can occur [See Warnings and Precautions (5.1)].

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 + 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 Reaction1	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
1Includes 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 Reactions (WHO/Pref)	Oxaliplatin + 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.

The incidence of death within 30 days of treatment in the previously untreated for advanced colorectal cancer study, regardless of causality, was 3% with the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination, 5% with irinotecan plus 5-fluorouracil/leucovorin, and 3% with Oxaliplatin for Injection plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination, 5.1% with irinotecan plus 5-fluorouracil/leucovorin, and 3.1% with Oxaliplatin for Injection plus irinotecan. The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study [see Clinical Studies (14)] by body system and decreasing order of frequency in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥ 5% and for grade 3/4 events with incidences ≥ 1%.

Table 5 – Adverse Reactions Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial (≥ 5% of all patients and with ≥ 1% NCI Grade 3/4 events)

	Oxaliplatin + 5-FU/LV N=259		irinotecan + 5-FU/LV N=256		Oxaliplatin + irinotecan N=258
Adverse Reaction (WHO/Pref)	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
Any Event	99	82	98	70	99	76
Allergy/Immunology
Hypersensitivity	12	2	5	0	6	1
Cardiovascular
Thrombosis	6	5	6	6	3	3
Hypotension	5	3	6	3	4	3
Constitutional Symptoms/Pain/Ocular/Visual
Fatigue	70	7	58	11	66	16
Abdominal Pain	29	8	31	7	39	10
Myalgia	14	2	6	0	9	2
Pain	7	1	5	1	6	1
Vision abnormal	5	0	2	1	6	1
Neuralgia	5	0	0	0	2	1
Dermatology/Skin
Skin reaction – hand/foot	7	1	2	1	1	0
Injection site reaction	6	0	1	0	4	1
Gastrointestinal
Nausea	71	6	67	15	83	19
Diarrhea	56	12	65	29	76	25
Vomiting	41	4	43	13	64	23
Stomatitis	38	0	25	1	19	1
Anorexia	35	2	25	4	27	5
Constipation	32	4	27	2	21	2
Diarrhea-colostomy	13	2	16	7	16	3
Gastrointestinal NOS*	5	2	4	2	3	2
Hematology/Infection
Infection normal ANC**	10	4	5	1	7	2
Infection low ANC**	8	8	12	11	9	8
Lymphopenia	6	2	4	1	5	2
Febrile neutropenia	4	4	15	14	12	11
Hepatic/Metabolic/Laboratory/Renal
Hyperglycemia	14	2	11	3	12	3
Hypokalemia	11	3	7	4	6	2
Dehydration	9	5	16	11	14	7
Hypoalbuminemia	8	0	5	2	9	1
Hyponatremia	8	2	7	4	4	1
Urinary frequency	5	1	2	1	3	1
Neurology
Overall Neuropathy	82	19	18	2	69	7
Paresthesias	77	18	16	2	62	6
Pharyngo-laryngeal dysesthesias	38	2	1	0	28	1
Neuro-sensory	12	1	2	0	9	1
Neuro NOS*	1	0	1	0	1	0
Pulmonary
Cough	35	1	25	2	17	1
Dyspnea	18	7	14	3	11	2
Hiccups	5	1	2	0	3	2
* Not otherwise specified ** Absolute neutrophil count

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

Table 6 - Adverse Reactions Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial (≥ 5% of all patients but with < 1% NCI Grade 3/4 events)

	Oxaliplatin + 5-FU/LV N=259	irinotecan + 5-FU/LV N=256	Oxaliplatin + irinotecan N=258
Adverse Reaction (WHO/Pref)	All Grades (%)	All Grades (%)	All Grades (%)
Allergy/Immunology
Rash	11	4	7
Rhinitis allergic	10	6	6
Cardiovascular
Edema	15	13	10
Constitutional Symptoms/Pain/Ocular/Visual
Headache	13	6	9
Weight loss	11	9	11
Epistaxis	10	2	2
Tearing	9	1	2
Rigors	8	2	7
Dysphasia	5	3	3
Sweating	5	6	12
Arthralgia	5	5	8
Dermatology/Skin
Alopecia	38	44	67
Flushing	7	2	5
Pruritis	6	4	2
Dry Skin	6	2	5
Gastrointestinal
Taste perversion	14	6	8
Dyspepsia	12	7	5
Flatulence	9	6	5
Mouth Dryness	5	2	3
Hematology/Infection
Fever normal ANC*	16	9	9
Hepatic/Metabolic/Laboratory/Renal
Hypocalcemia	7	5	4
Elevated Creatinine	4	4	5
Neurology
Insomnia	13	9	11
Depression	9	5	7
Dizziness	8	6	10
Anxiety	5	2	6
* Absolute neutrophil count

Adverse reactions were similar in men and women and in patients <65 and ≥65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope. The following additional adverse reactions, at least possibly related to treatment and potentially important, were reported in ≥2% and <5% of the patients in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): metabolic, pneumonitis, catheter infection, vertigo, prothrombin time, pulmonary, rectal bleeding, dysuria, nail changes, chest pain, rectal pain, syncope, hypertension, hypoxia, unknown infection, bone pain, pigmentation changes, and urticaria.

Previously Treated Patients with Advanced Colorectal Cancer

Four hundred and fifty patients (about 150 receiving the combination of Oxaliplatin for Injection and 5-fluorouracil/leucovorin) were studied in a randomized trial in patients with refractory and relapsed 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. Thirteen percent of patients in the Oxaliplatin for Injection 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 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.

The incidence of death within 30 days of treatment in the previously treated study, regardless of causality, was 5% with the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination, 8% with Oxaliplatin for Injection alone, and 7% with 5-fluorouracil/leucovorin. Of the 7 deaths that occurred on the Oxaliplatin for Injection 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 for Injection 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.

Table 7 – Adverse Reactions Reported In Previously Treated Colorectal Cancer Clinical Trial (≥ 5% of all patients and with ≥ 1% NCI Grade 3/4 events)

	5-FU/LV (N = 142)		Oxaliplatin (N = 153)		Oxaliplatin + 5-FU/LV (N = 150)
Adverse Reaction (WHO/Pref)	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
Any Event	98	41	100	46	99	73
Cardiovascular
Dyspnea	11	2	13	7	20	4
Coughing	9	0	11	0	19	1
Edema	13	1	10	1	15	1
Thromboembolism	4	2	2	1	9	8
Chest Pain	4	1	5	1	8	1
Constitutional Symptoms/Pain
Fatigue	52	6	61	9	68	7
Back Pain	16	4	11	0	19	3
Pain	9	3	14	3	15	2
Dermatology/Skin
Injection Site Reaction	5	1	9	0	10	3
Gastrointestinal
Diarrhea	44	3	46	4	67	11
Nausea	59	4	64	4	65	11
Vomiting	27	4	37	4	40	9
Stomatitis	32	3	14	0	37	3
Abdominal Pain	31	5	31	7	33	4
Anorexia	20	1	20	2	29	3
Gastroesophageal Reflux	3	0	1	0	5	2
Hematology/Infection
Fever	23	1	25	1	29	1
Febrile Neutropenia	1	1	0	0	6	6
Hepatic/Metabolic/Laboratory/Renal
Hypokalemia	3	1	3	2	9	4
Dehydration	6	4	5	3	8	3
Neurology
Neuropathy	17	0	76	7	74	7
Acute	10	0	65	5	56	2
Persistent	9	0	43	3	48	6

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 for Injection and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥5% but with incidences <1% NCI Grade 3/4 events.

Table 8 - Adverse Reactions Reported In Previously Treated Colorectal Cancer Clinical Trial (≥ 5% of all patients but with < 1% NCI Grade 3/4 events)

	5-FU/LV (N = 142)	Oxaliplatin (N = 153)	Oxaliplatin + 5-FU/LV (N = 150)
Adverse Reaction (WHO/Pref)	All Grades (%)	All Grades (%)	All Grades (%)
Allergy/Immunology
Rhinitis	4	6	15
Allergic Reaction	1	3	10
Rash	5	5	9
Cardiovascular
Peripheral Edema	11	5	10
Constitutional Symptoms/Pain/Ocular/Visual
Headache	8	13	17
Arthralgia	10	7	10
Epistaxis	1	2	9
Abnormal Lacrimation	6	1	7
Rigors	6	9	7
Dermatology/Skin
Hand-Foot Syndrome	13	1	11
Flushing	2	3	10
Alopecia	3	3	7
Gastrointestinal
Constipation	23	31	32
Dyspepsia	10	7	14
Taste Perversion	1	5	13
Mucositis	10	2	7
Flatulence	6	3	5
Hepatic/Metabolic/Laboratory/Renal
Hematuria	4	0	6
Dysuria	1	1	6
Neurology
Dizziness	8	7	13
Insomnia	4	11	9
Pulmonary
Upper Resp Tract Infection	4	7	10
Pharyngitis	10	2	9
Hiccup	0	2	5

Adverse reactions were similar in men and women and in patients <65 and ≥ 65 years, but older patients may have been more susceptible to dehydration, diarrhea, hypokalemia and fatigue. The following additional adverse reactions, at least possibly related to treatment and potentially important, were reported in ≥ 2% and <5% of the patients in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): anxiety, myalgia, erythematous rash, increased sweating, conjunctivitis, weight decrease, dry mouth, rectal hemorrhage, depression, ataxia, ascites, hemorrhoids, muscle weakness, nervousness, tachycardia, abnormal micturition frequency, dry skin, pruritus, hemoptysis, purpura, vaginal hemorrhage, melena, somnolence, pneumonia, proctitis, involuntary muscle contractions, intestinal obstruction, gingivitis, tenesmus, hot flashes, enlarged abdomen, urinary incontinence.

Hematologic Changes

The following tables list the hematologic changes occurring in ≥ 5% of patients, based on laboratory values and NCI grade, with the exception of those events occurring in adjuvant patients and anemia in the patients previously untreated for advanced colorectal cancer, respectively, which are based on AE reporting and NCI grade alone.

Table 9 - Adverse Hematologic Reactions in Patients with Colon Cancer Receiving Adjuvant Therapy (≥ 5% of patients)

Hematology Parameter	Oxaliplatin + 5–FU/LV (N=1108)		5–FU/LV (N=1111)
	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
Anemia	76	1	67	<1
Neutropenia	79	41	40	5
Thrombocytopenia	77	2	19	<1

Table 10 – Adverse Hematologic Reactions in Patients Previously Untreated for Advanced Colorectal Cancer (≥ 5% of patients)

Hematology Parameter	Oxaliplatin + 5–FU/LV N=259		irinotecan + 5–FU/LV N=256		Oxaliplatin + irinotecan N=258
	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
Anemia	27	3	28	4	25	3
Leukopenia	85	20	84	23	76	24
Neutropenia	81	53	77	44	71	36
Thrombocytopenia	71	5	26	2	44	4

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

Hematology Parameter	5–FU/LV (N=142)		Oxaliplatin (N=153)		Oxaliplatin + 5–FU/LV (N=150)
	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
Anemia	68	2	64	1	81	2
Leukopenia	34	1	13	0	76	19
Neutropenia	25	5	7	0	73	44
Thrombocytopenia	20	0	30	3	64	4

Thrombocytopenia and Bleeding

Thrombocytopenia was frequently reported with the combination of Oxaliplatin for Injection and infusional 5-fluorouracil/leucovorin. The incidence of all hemorrhagic events in the adjuvant and previously treated patients was higher on the Oxaliplatin for Injection combination arm compared to the infusional 5-fluorouracil/leucovorin arm. These events included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant trial, two patients died from intracerebral hemorrhages.

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 for Injection 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 for Injection and 5-fluorouracil/leucovorin. In the previously untreated patients, the incidence of epistaxis was 10% in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin arm, and 2% and 1%, respectively, in the irinotecan plus 5-fluorouracil/leucovorin or irinotecan plus Oxaliplatin for Injection arms.

Neutropenia

Neutropenia was frequently observed with the combination of Oxaliplatin for Injection and 5-fluorouracil/leucovorin, with Grade 3 and 4 events reported in 29% and 12% of adjuvant patients with colon cancer, respectively. In the adjuvant trial, 3 patients died from sepsis/neutropenic sepsis. Grade 3 and 4 events were reported in 35% and 18% of the patients previously untreated for advanced colorectal cancer, respectively. Grade 3 and 4 events were reported in 27% and 17% of previously treated patients, respectively. In adjuvant patients the incidence of either febrile neutropenia (0.7%) or documented infection with concomitant grade 3/4 neutropenia (1.1%) was 1.8% in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin arm. The incidence of febrile neutropenia in the patients previously untreated for advanced colorectal cancer was 15% (3% of cycles) in the irinotecan plus 5-fluorouracil/leucovorin arm and 4% (less than 1% of cycles) in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination arm. Additionally, in this same population, infection with grade 3 or 4 neutropenia was 12% in the irinotecan plus 5-fluorouracil/leucovorin, and 8% in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination. The incidence of febrile neutropenia in the previously treated patients was 1% in the 5-fluorouracil/leucovorin arm and 6% (less than 1% of cycles) in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination arm.

Gastrointestinal

In patients receiving the combination of Oxaliplatin for Injection plus infusional 5-fluorouracil/leucovorin for adjuvant treatment for colon cancer the incidence of Grade 3/4 nausea and vomiting was greater than those receiving infusional 5-fluorouracil/leucovorin alone. In patients previously untreated for advanced colorectal cancer receiving the combination of Oxaliplatin for Injection and 5-fluorouracil/leucovorin, the incidence of Grade 3 and 4 vomiting and diarrhea was less compared to irinotecan plus 5-fluorouracil/leucovorin controls. In previously treated patients receiving the combination of Oxaliplatin for Injection and 5-fluorouracil/leucovorin, the incidence of Grade 3 and 4 nausea, vomiting, diarrhea, and mucositis/stomatitis increased compared to 5-fluorouracil/leucovorin controls.

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 for Injection 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 for Injection.

Dermatologic

Oxaliplatin for Injection did not increase the incidence of alopecia compared to 5-fluorouracil/leucovorin alone. No complete alopecia was reported. The incidence of Grade 3/4 skin disorders was 2% in both the Oxaliplatin for Injection plus infusional 5-fluorouracil/leucovorin and the infusional 5-fluorouracil/leucovorin alone arms in the adjuvant colon cancer patients. The incidence of hand-foot syndrome in patients previously untreated for advanced colorectal cancer was 2% in the irinotecan plus 5-fluorouracil/leucovorin arm and 7% in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination arm. The incidence of hand-foot syndrome in previously treated patients was 13% in the 5-fluorouracil/leucovorin arm and 11% in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination arm.

Intravenous Site Reactions

Extravasation, in some cases including necrosis, has been reported. Injection site reaction, including redness, swelling, and pain, has been reported.

Anticoagulation and Hemorrhage

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 for Injection plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin for Injection plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.

Renal

About 5 to 10% of patients in all groups had some degree of elevation of serum creatinine. The incidence of Grade 3/4 elevations in serum creatinine in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination arm was 1% in the previously treated patients. Serum creatinine measurements were not reported in the adjuvant trial.

Hepatic

Hepatotoxicity (defined as elevation of liver enzymes) appears to be related to Oxaliplatin for Injection combination therapy [see Warnings and Precautions (5.4)]. The following tables list the clinical chemistry changes associated with hepatic toxicity occurring in ≥ 5% of patients, based on adverse reactions reported and NCI CTC grade for adjuvant patients and patients previously untreated for advanced colorectal cancer, laboratory values and NCI CTC grade for previously treated patients.

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

Hepatic Parameter	Oxaliplatin + 5-FU/LV (N=1108)		5-FU/LV (N=1111)
	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
Increase in transaminases	57	2	34	1
ALP increased	42	<1	20	<1
Bilirubinaemia	20	4	20	5

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

Clinical Chemistry	Oxaliplatin + 5-FU/LV N=259		irinotecan + 5-FU/LV N=256		Oxaliplatin + irinotecan N=258
	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
ALT (SGPT-ALAT)	6	1	2	0	5	2
AST (SGOT-ASAT)	17	1	2	1	11	1
Alkaline Phosphatase	16	0	8	0	14	2
Total Bilirubin	6	1	3	1	3	2

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

Clinical Chemistry	5-FU/LV (N=142)		Oxaliplatin (N=153)		Oxaliplatin + 5-FU/LV (N=150)
	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)	All Grades (%)	Grade 3/4 (%)
ALT (SGPT-ALAT)	28	3	36	1	31	0
AST (SGOT-ASAT)	39	2	54	4	47	0
Total Bilirubin	22	6	13	5	13	1

Thromboembolism

The incidence of thromboembolic events in adjuvant patients with colon cancer was 6% (1.8% grade 3/4) in the infusional 5-fluorouracil/leucovorin arm and 6% (1.2% grade 3/4) in the Oxaliplatin for Injection and infusional 5-fluorouracil/leucovorin combined arm, respectively. The incidence was 6 and 9% of the patients previously untreated for advanced colorectal cancer and previously treated patients in the Oxaliplatin for Injection and 5-fluorouracil/leucovorin combination arm, respectively.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Oxaliplatin for 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

Central and peripheral nervous system disorders:

loss of deep tendon reflexes, dysarthria, Lhermitte’s sign, cranial nerve palsies, fasciculations, convulsion

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.

Hearing and vestibular system disorders:

deafness

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)

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Side Effects by Body System - for Healthcare Professionals

General

In general, side effects have been reported in 98% of patients, with 73% of those characterized as NCI CTC Grade 3/4 severity. The incidence of side effects given in the following sections refers to oxaliplatin/fluorouracil/leucovorin combination therapy.

The most common side effects include peripheral sensory neuropathies, neutropenia, nausea, emesis, and diarrhea. Thirteen percent of patients in the combination therapy group and 18% in the fluorouracil/leucovorin group discontinued treatment due to neuropathies, or gastrointestinal or hematologic side effects.

The incidence of death was 5% in the combination therapy group, 8% in the oxaliplatin monotherapy group, and 7% in the fluorouracil/leucovorin group within 30 days of treatment (regardless of causality).

Gastrointestinal

Gastrointestinal side effects have included diarrhea (68% overall, 11% NCI CTC Grade 3/4), nausea (65% overall, 11% Grade 3/4), vomiting (40% overall, 9% Grade 3/4), stomatitis (37% overall, 3% Grade 3/4), abdominal pain (33% overall, 4% Grade 3/4), anorexia (29% overall, 3% Grade 3/4), and gastroesophageal reflux (5% overall, 2% Grade 3/4). Side effects with less than 1% incidence of Grade 3/4 severity have included constipation (32%), dyspepsia (14%), taste perversion (13%), mucositis (7%), and flatulence (5%). Additional side effects possibly related to treatment have been reported in 2% to 5% of patients and include dry mouth, melena, gingivitis, rectal hemorrhage, hemorrhoids, hemoptysis, proctitis, tenesmus, intestinal obstruction, and enlarged abdomen. Ileus, pancreatitis, and colitis (including Clostridium difficile diarrhea) have also been reported.

Nervous system

Acute neuropathy is reversible and primarily of a peripheral sensory nature. The onset occurs within hours to 2 days of dosing. It generally resolves within 2 weeks and frequently recurs with repeat doses. Exposure to cold temperature or cold objects may precipitate or exacerbate symptoms. Symptoms may include transient paresthesia, dysesthesia, and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and chest pressure have also been reported. Ice should be avoided for mucositis prophylaxis. Acute pharyngolaryngeal dysesthesia with sensations of dysphagia and dyspnea but no laryngospasm or bronchospasm has been reported in 1% to 2% of patients.

Persistent neuropathy generally lasts for more than 2 weeks and is also primarily of a peripheral sensory nature. Symptoms included paresthesias, dysesthesias, hypoesthesias, and deficits in proprioception that may interfere with daily activities (e.g., writing, buttoning, swallowing, or walking). Persistent neuropathy may occur with no prior neuropathy event. Eighty percent of patients who developed Grade 3 persistent neuropathy progressed from Grade 1 or 2. The symptoms may improve in some patients when oxaliplatin is discontinued.

Preventive measures include calcium and magnesium solutions, gabapentin, carbamazepine, amifostine, and glutathione. Treatment measures include calcium and magnesium solutions, gabapentin, and alpha-lipoic acid.

Nervous system side effects which have been most frequently reported include two types of neuropathy (74%) - acute and persistent, with an incidence of 56% and 48%, respectively. Six percent of patients experienced NCI CTC Grade 3/4 persistent neuropathy.

Side effects with less than 1% incidence of Grade 3/4 severity have included headache, dizziness, and insomnia. Additional side effects possibly related to treatment have been reported in 2% to 5% of patients and include anxiety, depression, ataxia, nervousness, and somnolence. Deafness, loss of deep tendon reflexes, dysarthria, Lhermitte sign, cranial nerve palsies, and fasciculations have also been reported.

Hematologic

Hematologic side effects have included thrombocytopenia (68% all grades; 4% NCI CTC Grade 3/4), neutropenia (73% all grades; 44% Grade 3/4), leukopenia (76% all grades; 19% Grade 3/4), anemia (81% all grades, 2% Grade 3/4), thromboembolism (9% overall, 8% Grade 3/4), and febrile neutropenia (6% overall, 6% Grade 3/4). Immunoallergic thrombocytopenia, immunoallergic hemolytic anemia, and hemolytic uremic syndrome have also been reported. One case of fatal hemolytic anemia has been reported.

Other

Side effects affecting the body as a whole have included fatigue (68% overall, 7% NCI CTC Grade 3/4), fever (29% overall, 1% Grade 3/4), back pain (19% overall, 3% Grade 3/4), edema (15% overall, 1% Grade 3/4), pain (15% overall, 2% Grade 3/4), chest pain (8% overall, 1% Grade 3/4), flushing (10%), peripheral edema (10%), rigors (10%), hot flashes (2% to 5%), and angioedema.

Respiratory

Respiratory side effects have included dyspnea (20% overall, 4% NCI CTC Grade 3/4) and coughing (19% overall, 1% Grade 3/4). Side effects with a less than 1% incidence of Grade 3/4 severity have included rhinitis (15%), upper respiratory tract infection (10%), pharyngitis (9%), epistaxis (9%), and hiccup (5%). Pulmonary fibrosis and other interstitial lung diseases (sometimes fatal) have also been reported (0.7%). A case of cryptogenic organizing pneumonitis has been reported.

Hypersensitivity

Patients who develop mild to moderate hypersensitivity to oxaliplatin may be pretreated with steroids as well as type 1 and type 2 histamine receptor antagonists. However, patients who develop severe reactions are unlikely to tolerate further therapy.

Hypersensitivity reactions of an anaphylactoid and anaphylactic nature with symptoms of rash, urticaria, erythema, pruritus, and rarely, bronchospasm, and hypotension have been reported. Anaphylactic shock has also been reported. Less than 1% of hypersensitivity reactions were characterized as NCI CTC Grade 3/4. Other platinum compounds have been associated with fatal hypersensitivity reactions. Epinephrine, corticosteroids, and antihistamines have been used to manage symptoms.

Hepatic

Hepatic side effects have included elevations in ALT (31% overall, 0% NCI CTC Grade 3/4), AST (47% overall, 0% Grade 3/4), and total bilirubin (13% overall, 1% Grade 3/4). Veno-occlusive disease of the liver (also known as sinusoidal obstruction syndrome) and perisinusoidal fibrosis (which rarely may progress) have also been reported.

Dermatologic

Dermatologic side effects with a less than 1% incidence of NCI CTC Grade 3/4 severity have included hand-foot syndrome (11%), rash (9%), and alopecia (7%). Erythematous rash and purpura have been reported in 2% to 5% of patients.

Local

Local side effects (injection site reactions) have been reported in 10% of patients (3%, NCI CTC Grade 3/4), including redness, swelling, and pain. Extravasation may result in severe pain and inflammation and cause complications such as necrosis.

Renal

Renal side effects have included serum creatinine elevations (10% overall, 1% NCI CTC Grade 3/4).

Musculoskeletal

Musculoskeletal side effects have included arthralgia (10% overall, less than 1% Grade 3/4). Involuntary muscle contractions and muscle weakness have been reported in 2% to 5% of patients. Six cases of involuntary masticatory spasms induced by continuous infusion of oxaliplatin have also been reported.

Metabolic

Metabolic side effects have included hypokalemia (9% overall, 4% NCI CTC Grade 3/4) and dehydration (8% overall, 3% Grade 3/4). Weight decrease (2% to 5%) and metabolic acidosis have also been reported.

Ocular

Ocular side effects have included abnormal lacrimation (7% overall, less than 1% NCI CTC Grade 3/4), conjunctivitis (2% to 5%), decrease of visual acuity, visual field disturbance, transient vision loss (reversible following therapy discontinuation), and optic neuritis. A case of acute bilateral abducens paralysis due to oxaliplatin has also been reported.

Genitourinary

Genitourinary side effects that have been reported with a less than 1% incidence of NCI CTC Grade 3/4 severity include hematuria (6%) and dysuria (6%). Additional side effects possibly related to treatment have been reported in 2% to 5% of patients and include abnormal micturition frequency, vaginal hemorrhage, and urinary incontinence.

Cardiovascular

Cardiovascular side effects have included tachycardia (2% to 5%).

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