oxaliplatin injection Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in labeling:

•
Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
•
Peripheral Sensory Neuropathy [see Warnings and Precautions (5.2)]
•
Severe Myelosuppression [see Warnings and Precautions (5.3)]
•
Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.4)]
•
Pulmonary Toxicity [see Warnings and Precautions (5.5)]
•
Hepatotoxicity [see Warnings and Precautions (5.6)]
•
QT Interval Prolongation and Ventricular Arrhythmias [see Warnings and Precautions (5.7)]
•
Rhabdomyolysis [see Warnings and Precautions (5.8)]
•
Hemorrhage [see Warnings and Precautions (5.9)]

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 1,100 patients with stage II or III colon cancer and more than 4,000 patients with advanced colorectal cancer were treated in trials with Oxaliplatin. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant treatment 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 with advanced colorectal cancer were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea.

Adjuvant Treatment

The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor in the adjuvant treatment trial [see Clinical Studies (14.1)].

Fatal adverse reactions in patients who received Oxaliplatin in the combination arm included sepsis/neutropenic sepsis (n=3), intracerebral hemorrhage (n=2), and eosinophilic pneumonia (n=1).

Thromboembolic events occurred in 6% (grade 3–4, 1.2%) of patients in the Oxaliplatin arm.

Grade 3 or 4 adverse reactions occurred in 70% of patients in the Oxaliplatin arm. Grade 3–4 gastrointestinal bleeding occurred in 0.2% of patients. Febrile neutropenia occurred in 0.7% and documented infection with concomitant grade 3–4 neutropenia occurred in 1.1%.

Discontinuation due to an adverse reaction occurred in 15% of the patients in the Oxaliplatin arm.

Tables 5, 6, and 7 summarize the adverse reactions reported in patients with colon cancer receiving adjuvant treatment.

Table 5: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=1,108		FU/LV
N=1,111
All Grades
(%)		Grade 3–4
(%)		All Grades
(%)		Grade 3–4
(%)
*
Event coded in WHO-ART dictionary
†
Includes thrombosis related to the catheter

Neurology

Peripheral Sensory Neuropathy

92

12

16

<1

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

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†

11

3

10

3

Fever/Infection

Fever

27

1

12

1

Infection

25

4

25

3

Allergy/Immunology

Allergic Reaction

10

3

2

<1

Table 6: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (greater than or equal to 5% of all patients but with less than 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=1,108		FU/LV
N=1,111
All Grades
(%)		All Grades
(%)
*
Event coded in WHO-ART dictionary
†
No complete alopecia was reported

Dermatology/Skin

Alopecia†

30

28

Gastrointestinal

Constipation

22

19

Taste Perversion

12

8

Dyspepsia

8

5

Constitutional Symptoms/Pain/Ocular/Visual

Epistaxis

16

12

Weight Increase

10

10

Conjunctivitis

9

15

Headache

7

5

Dyspnea

5

3

Pain

5

5

Abnormal Lacrimation

4

12

Neurology

Sensory Disturbance

8

1

Allergy/Immunology

Rhinitis

6

8

In females, the following grade 3–4 adverse reactions were more frequent: diarrhea, fatigue, neutropenia, nausea, and vomiting.

In patients greater than or equal to 65 years old, the incidence of grade 3–4 diarrhea and neutropenia was higher than in younger adults.

Clinically relevant adverse reactions were reported in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin arm (listed in decreasing order of frequency) were pain, leukopenia, weight loss, and cough.

Table 7: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Colon Cancer Receiving Adjuvant Treatment
Laboratory-Related Adverse ReactionOxaliplatin with FU/LV
N=1,108		FU/LV N=1,111
All Grades
(%)		Grades
3–4
(%)		All Grades
(%)		Grades
3–4
(%)

Hematology

Neutropenia

79

41

40

5

Thrombocytopenia

77

2

19

<1

Anemia

76

1

67

<1

Hepatic

Increased Transaminases

57

2

34

1

Increased Alkaline Phosphatase

42

<1

20

<1

Hyperbilirubinemia

20

4

20

5

Previously Untreated Advanced Colorectal Cancer

The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a randomized trial of patients with previously untreated advanced colorectal cancer [see Clinical Studies (14.2)]. The adverse reaction profile in this trial was similar to that seen in other trials.

Tables 8, 9, and 10 summarize the adverse reactions reported in the previously untreated advanced colorectal cancer trial.

Table 8: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=259		Irinotecan + FU/LV
N=256		Oxaliplatin + Irinotecan
N=258
All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)
*
Event coded in WHO-ART dictionary
†
Not otherwise specified
‡
Absolute neutrophil count

Neurology

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

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

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

Abnormal Vision

5

0

2

1

6

1

Neuralgia

5

0

0

0

2

1

Pulmonary

Cough

35

1

25

2

17

1

Dyspnea

18

7

14

3

11

2

Hiccups

5

1

2

0

3

2

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

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

Dermatology/Skin

Hand/Foot Syndrome

7

1

2

1

1

0

Injection Site Reaction

6

0

1

0

4

1

Cardiovascular

Thrombosis

6

5

6

6

3

3

Hypotension

5

3

6

3

4

3

Table 9: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients but with less than 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=259		Irinotecan + FU/LV
N=256		Oxaliplatin + Irinotecan
N=258
All Grades
(%)		All Grades
(%)		All Grades
(%)
*
Event coded in WHO-ART dictionary
†
No complete alopecia was reported
‡
Absolute neutrophil count

Dermatology/Skin

Alopecia†

38

44

67

Flushing

7

2

5

Pruritus

6

4

2

Dry Skin

6

2

5

Hematology/Infection

Fever Normal ANC‡

16

9

9

Cardiovascular

Edema

15

13

10

Gastrointestinal

Taste Perversion

14

6

8

Dyspepsia

12

7

5

Flatulence

9

6

5

Mouth Dryness

5

2

3

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

Neurology

Insomnia

13

9

11

Depression

9

5

7

Dizziness

8

6

10

Anxiety

5

2

6

Allergy/Immunology

Rash

11

4

7

Rhinitis Allergic

10

6

6

Hepatic/Metabolic/Laboratory/Renal

Hypocalcemia

7

5

4

Elevated Creatinine

4

4

5

Clinically relevant adverse reactions that occurred in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: 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.

Table 10: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients in the Previously Untreated Advanced Colorectal Cancer Trial
Laboratory-Related Adverse ReactionOxaliplatin and FU/LV N=259Irinotecan and FU/LV
N=256		Oxaliplatin and Irinotecan
N=258
All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)
*
Aspartate transaminase
†
Alanine transaminase

Hematology

Leukopenia

85

20

84

23

76

24

Neutropenia

81

53

77

44

71

36

Thrombocytopenia

71

5

26

2

44

4

Anemia

27

3

28

4

25

3

Hepatic

Increased AST*

17

1

2

1

11

1

Increased Alkaline Phosphatase

16

0

8

0

14

2

Hyperbilirubinemia

6

1

3

1

3

2

Increased ALT†

6

1

2

0

5

2

Previously Treated Advanced Colorectal Cancer

The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a randomized trial in patients with refractory and relapsed colorectal cancer [see Clinical Studies (14.3)]. The adverse reaction profile in this trial was similar to that seen in other trials.

Three patients who received Oxaliplatin in the combination arm experienced fatal adverse reactions: gastrointestinal bleeding and dehydration.

Grade 3 and 4 neutropenia were reported in 27% and 17% of patients, respectively, in the Oxaliplatin with fluorouracil/leucovorin combination arm. Grade 3–4 increased serum creatinine occurred in 1% of patients in the Oxaliplatin with combination fluorouracil/leucovorin arm.

Thirteen percent of patients in the Oxaliplatin with fluorouracil/leucovorin combination arm discontinued treatment; the most frequent reasons were gastrointestinal adverse reactions, hematologic adverse reactions and neuropathies.

Tables 11, 12, and 13 summarize the adverse reactions reported in the previously treated advanced colorectal cancer trial.

Table 11: Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Trial (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=150		Oxaliplatin
N=153		FU/LV
N=142
All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)
*
Event coded in WHO-ART dictionary

Neurology

Neuropathy

74

7

76

7

17

0

    Acute

56

2

65

5

10

0

    Persistent

48

6

43

3

9

0

Constitutional Symptoms/Pain

Fatigue

68

7

61

9

52

6

Back Pain

19

3

11

0

16

4

Pain

15

2

14

3

9

3

Gastrointestinal

Diarrhea

67

11

46

4

44

3

Nausea

65

11

64

4

59

4

Vomiting

40

9

37

4

27

4

Stomatitis

37

3

14

0

32

3

Abdominal Pain

33

4

31

7

31

5

Anorexia

29

3

20

2

20

1

Gastroesophageal Reflux

5

2

1

0

3

0

Hematology/Infection

Fever

29

1

25

1

23

1

Febrile Neutropenia

6

6

0

0

1

1

Cardiovascular

Dyspnea

20

4

13

7

11

2

Coughing

19

1

11

0

9

0

Edema

15

1

10

1

13

1

Thromboembolism

9

8

2

1

4

2

Chest Pain

8

1

5

1

4

1

Dermatology/Skin

Injection Site Reaction

10

3

9

0

5

1

Hepatic/Metabolic/Laboratory/Renal

Hypokalemia

9

4

3

2

3

1

Dehydration

8

3

5

3

6

4

Table 12: Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients but with less than 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=150		Oxaliplatin
N=153		FU/LV
N=142
All Grades
(%)		All Grades
(%)		All Grades
(%)
*
Event coded in WHO-ART dictionary
†
No complete alopecia was reported

Gastrointestinal

Constipation

32

31

23

Dyspepsia

14

7

10

Taste Perversion

13

5

1

Mucositis

7

2

10

Flatulence

5

3

6

Constitutional Symptoms/Pain/Ocular/Visual

Headache

17

13

8

Arthralgia

10

7

10

Epistaxis

9

2

1

Abnormal Lacrimation

7

1

6

Rigors

7

9

6

Allergy/Immunology

Rhinitis

15

6

4

Allergic Reaction

10

3

1

Rash

9

5

5

Neurology

Dizziness

13

7

8

Insomnia

9

11

4

Dermatology/Skin

Hand-Foot Syndrome

11

1

13

Flushing

10

3

2

Alopecia†

7

3

3

Pulmonary

Upper Respiratory Tract Infection

10

7

4

Pharyngitis

9

2

10

Cardiovascular

Peripheral Edema

10

5

11

Hepatic/Metabolic/Laboratory/Renal

Hematuria

6

0

4

Dysuria

6

1

1

Clinically relevant adverse reactions in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: 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, and urinary incontinence.

Table 13: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Previously Treated Advanced Colorectal Cancer
Laboratory-Related Adverse ReactionOxaliplatin and FU/LV
N=150		Oxaliplatin
N=153		FU/LV
N=142
All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)
*
Alanine transaminase
†
Aspartate transaminase

Hematology

Anemia

81

2

64

1

68

2

Leukopenia

76

19

13

0

34

1

Neutropenia

73

44

7

0

25

5

Thrombocytopenia

64

4

30

3

20

0

Hepatic

Increased ALT*

31

0

36

1

28

3

Increased AST†

47

0

54

4

39

2

Increased Bilirubin

13

1

13

5

22

6

Additional Adverse Reactions

The following adverse reactions were observed across clinical trials.

Intravenous site reactions

Injection site reaction, including redness, swelling, and pain, can occur with Oxaliplatin. In some cases, skin necrosis has occurred with extravasation.

PRES

PRES occurred in less than 0.1% of patients.

Pulmonary fibrosis and interstitial lung disease

Pulmonary fibrosis, which may be fatal, occurred in less than 1% of patients.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Oxaliplatin. 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.

•
General: angioedema, anaphylactic shock
•
Cardiovascular: QT prolongation leading to ventricular arrhythmias, including fatal torsade de pointes; bradyarrhythmia
•
Neurological: loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsion
•
Hearing and vestibular system: deafness
•
Infections: septic shock, including fatal outcomes
•
Infusion-related reactions and hypersensitivity reactions: laryngospasm
•
Hepatic and gastrointestinal: severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis, ileus, intestinal obstruction, pancreatitis, sinusoidal obstruction syndrome, perisinusoidal fibrosis which rarely may progress, focal nodular hyperplasia, esophagitis
•
Musculoskeletal and connective tissue: rhabdomyolysis, including fatal outcomes
•
Platelet, bleeding, and clotting disorders: immuno-allergic thrombocytopenia, prolonged prothrombin time and INR in patients receiving anticoagulants
•
Blood disorders: secondary leukemia
•
Red blood cell: hemolytic uremic syndrome, immuno-allergic hemolytic anemia
•
Renal: acute tubular necrosis, acute interstitial nephritis, acute renal failure
•
Respiratory: interstitial lung diseases (sometimes fatal) and pneumonia (including fatal outcomes)
•
Vision: decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following treatment discontinuation)
•
Injury, poisoning, and procedural complications: fall-related injuries

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Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in labeling:

•
Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
•
Peripheral Sensory Neuropathy [see Warnings and Precautions (5.2)]
•
Severe Myelosuppression [see Warnings and Precautions (5.3)]
•
Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.4)]
•
Pulmonary Toxicity [see Warnings and Precautions (5.5)]
•
Hepatotoxicity [see Warnings and Precautions (5.6)]
•
QT Interval Prolongation and Ventricular Arrhythmias [see Warnings and Precautions (5.7)]
•
Rhabdomyolysis [see Warnings and Precautions (5.8)]
•
Hemorrhage [see Warnings and Precautions (5.9)]

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 1,100 patients with stage II or III colon cancer and more than 4,000 patients with advanced colorectal cancer were treated in trials with Oxaliplatin. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant treatment 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 with advanced colorectal cancer were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea.

Adjuvant Treatment

The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor in the adjuvant treatment trial [see Clinical Studies (14.1)].

Fatal adverse reactions in patients who received Oxaliplatin in the combination arm included sepsis/neutropenic sepsis (n=3), intracerebral hemorrhage (n=2), and eosinophilic pneumonia (n=1).

Thromboembolic events occurred in 6% (grade 3–4, 1.2%) of patients in the Oxaliplatin arm.

Grade 3 or 4 adverse reactions occurred in 70% of patients in the Oxaliplatin arm. Grade 3–4 gastrointestinal bleeding occurred in 0.2% of patients. Febrile neutropenia occurred in 0.7% and documented infection with concomitant grade 3–4 neutropenia occurred in 1.1%.

Discontinuation due to an adverse reaction occurred in 15% of the patients in the Oxaliplatin arm.

Tables 5, 6, and 7 summarize the adverse reactions reported in patients with colon cancer receiving adjuvant treatment.

Table 5: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=1,108		FU/LV
N=1,111
All Grades
(%)		Grade 3–4
(%)		All Grades
(%)		Grade 3–4
(%)
*
Event coded in WHO-ART dictionary
†
Includes thrombosis related to the catheter

Neurology

Peripheral Sensory Neuropathy

92

12

16

<1

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

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†

11

3

10

3

Fever/Infection

Fever

27

1

12

1

Infection

25

4

25

3

Allergy/Immunology

Allergic Reaction

10

3

2

<1

Table 6: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (greater than or equal to 5% of all patients but with less than 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=1,108		FU/LV
N=1,111
All Grades
(%)		All Grades
(%)
*
Event coded in WHO-ART dictionary
†
No complete alopecia was reported

Dermatology/Skin

Alopecia†

30

28

Gastrointestinal

Constipation

22

19

Taste Perversion

12

8

Dyspepsia

8

5

Constitutional Symptoms/Pain/Ocular/Visual

Epistaxis

16

12

Weight Increase

10

10

Conjunctivitis

9

15

Headache

7

5

Dyspnea

5

3

Pain

5

5

Abnormal Lacrimation

4

12

Neurology

Sensory Disturbance

8

1

Allergy/Immunology

Rhinitis

6

8

In females, the following grade 3–4 adverse reactions were more frequent: diarrhea, fatigue, neutropenia, nausea, and vomiting.

In patients greater than or equal to 65 years old, the incidence of grade 3–4 diarrhea and neutropenia was higher than in younger adults.

Clinically relevant adverse reactions were reported in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin arm (listed in decreasing order of frequency) were pain, leukopenia, weight loss, and cough.

Table 7: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Colon Cancer Receiving Adjuvant Treatment
Laboratory-Related Adverse ReactionOxaliplatin with FU/LV
N=1,108		FU/LV N=1,111
All Grades
(%)		Grades
3–4
(%)		All Grades
(%)		Grades
3–4
(%)

Hematology

Neutropenia

79

41

40

5

Thrombocytopenia

77

2

19

<1

Anemia

76

1

67

<1

Hepatic

Increased Transaminases

57

2

34

1

Increased Alkaline Phosphatase

42

<1

20

<1

Hyperbilirubinemia

20

4

20

5

Previously Untreated Advanced Colorectal Cancer

The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a randomized trial of patients with previously untreated advanced colorectal cancer [see Clinical Studies (14.2)]. The adverse reaction profile in this trial was similar to that seen in other trials.

Tables 8, 9, and 10 summarize the adverse reactions reported in the previously untreated advanced colorectal cancer trial.

Table 8: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=259		Irinotecan + FU/LV
N=256		Oxaliplatin + Irinotecan
N=258
All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)
*
Event coded in WHO-ART dictionary
†
Not otherwise specified
‡
Absolute neutrophil count

Neurology

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

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

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

Abnormal Vision

5

0

2

1

6

1

Neuralgia

5

0

0

0

2

1

Pulmonary

Cough

35

1

25

2

17

1

Dyspnea

18

7

14

3

11

2

Hiccups

5

1

2

0

3

2

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

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

Dermatology/Skin

Hand/Foot Syndrome

7

1

2

1

1

0

Injection Site Reaction

6

0

1

0

4

1

Cardiovascular

Thrombosis

6

5

6

6

3

3

Hypotension

5

3

6

3

4

3

Table 9: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients but with less than 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=259		Irinotecan + FU/LV
N=256		Oxaliplatin + Irinotecan
N=258
All Grades
(%)		All Grades
(%)		All Grades
(%)
*
Event coded in WHO-ART dictionary
†
No complete alopecia was reported
‡
Absolute neutrophil count

Dermatology/Skin

Alopecia†

38

44

67

Flushing

7

2

5

Pruritus

6

4

2

Dry Skin

6

2

5

Hematology/Infection

Fever Normal ANC‡

16

9

9

Cardiovascular

Edema

15

13

10

Gastrointestinal

Taste Perversion

14

6

8

Dyspepsia

12

7

5

Flatulence

9

6

5

Mouth Dryness

5

2

3

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

Neurology

Insomnia

13

9

11

Depression

9

5

7

Dizziness

8

6

10

Anxiety

5

2

6

Allergy/Immunology

Rash

11

4

7

Rhinitis Allergic

10

6

6

Hepatic/Metabolic/Laboratory/Renal

Hypocalcemia

7

5

4

Elevated Creatinine

4

4

5

Clinically relevant adverse reactions that occurred in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: 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.

Table 10: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients in the Previously Untreated Advanced Colorectal Cancer Trial
Laboratory-Related Adverse ReactionOxaliplatin and FU/LV N=259Irinotecan and FU/LV
N=256		Oxaliplatin and Irinotecan
N=258
All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)
*
Aspartate transaminase
†
Alanine transaminase

Hematology

Leukopenia

85

20

84

23

76

24

Neutropenia

81

53

77

44

71

36

Thrombocytopenia

71

5

26

2

44

4

Anemia

27

3

28

4

25

3

Hepatic

Increased AST*

17

1

2

1

11

1

Increased Alkaline Phosphatase

16

0

8

0

14

2

Hyperbilirubinemia

6

1

3

1

3

2

Increased ALT†

6

1

2

0

5

2

Previously Treated Advanced Colorectal Cancer

The safety of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a randomized trial in patients with refractory and relapsed colorectal cancer [see Clinical Studies (14.3)]. The adverse reaction profile in this trial was similar to that seen in other trials.

Three patients who received Oxaliplatin in the combination arm experienced fatal adverse reactions: gastrointestinal bleeding and dehydration.

Grade 3 and 4 neutropenia were reported in 27% and 17% of patients, respectively, in the Oxaliplatin with fluorouracil/leucovorin combination arm. Grade 3–4 increased serum creatinine occurred in 1% of patients in the Oxaliplatin with combination fluorouracil/leucovorin arm.

Thirteen percent of patients in the Oxaliplatin with fluorouracil/leucovorin combination arm discontinued treatment; the most frequent reasons were gastrointestinal adverse reactions, hematologic adverse reactions and neuropathies.

Tables 11, 12, and 13 summarize the adverse reactions reported in the previously treated advanced colorectal cancer trial.

Table 11: Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Trial (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=150		Oxaliplatin
N=153		FU/LV
N=142
All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)
*
Event coded in WHO-ART dictionary

Neurology

Neuropathy

74

7

76

7

17

0

    Acute

56

2

65

5

10

0

    Persistent

48

6

43

3

9

0

Constitutional Symptoms/Pain

Fatigue

68

7

61

9

52

6

Back Pain

19

3

11

0

16

4

Pain

15

2

14

3

9

3

Gastrointestinal

Diarrhea

67

11

46

4

44

3

Nausea

65

11

64

4

59

4

Vomiting

40

9

37

4

27

4

Stomatitis

37

3

14

0

32

3

Abdominal Pain

33

4

31

7

31

5

Anorexia

29

3

20

2

20

1

Gastroesophageal Reflux

5

2

1

0

3

0

Hematology/Infection

Fever

29

1

25

1

23

1

Febrile Neutropenia

6

6

0

0

1

1

Cardiovascular

Dyspnea

20

4

13

7

11

2

Coughing

19

1

11

0

9

0

Edema

15

1

10

1

13

1

Thromboembolism

9

8

2

1

4

2

Chest Pain

8

1

5

1

4

1

Dermatology/Skin

Injection Site Reaction

10

3

9

0

5

1

Hepatic/Metabolic/Laboratory/Renal

Hypokalemia

9

4

3

2

3

1

Dehydration

8

3

5

3

6

4

Table 12: Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients but with less than 1% grade 3–4)
Adverse Reaction*Oxaliplatin + FU/LV
N=150		Oxaliplatin
N=153		FU/LV
N=142
All Grades
(%)		All Grades
(%)		All Grades
(%)
*
Event coded in WHO-ART dictionary
†
No complete alopecia was reported

Gastrointestinal

Constipation

32

31

23

Dyspepsia

14

7

10

Taste Perversion

13

5

1

Mucositis

7

2

10

Flatulence

5

3

6

Constitutional Symptoms/Pain/Ocular/Visual

Headache

17

13

8

Arthralgia

10

7

10

Epistaxis

9

2

1

Abnormal Lacrimation

7

1

6

Rigors

7

9

6

Allergy/Immunology

Rhinitis

15

6

4

Allergic Reaction

10

3

1

Rash

9

5

5

Neurology

Dizziness

13

7

8

Insomnia

9

11

4

Dermatology/Skin

Hand-Foot Syndrome

11

1

13

Flushing

10

3

2

Alopecia†

7

3

3

Pulmonary

Upper Respiratory Tract Infection

10

7

4

Pharyngitis

9

2

10

Cardiovascular

Peripheral Edema

10

5

11

Hepatic/Metabolic/Laboratory/Renal

Hematuria

6

0

4

Dysuria

6

1

1

Clinically relevant adverse reactions in greater than or equal to 2% and less than 5% of the patients in the Oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: 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, and urinary incontinence.

Table 13: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Previously Treated Advanced Colorectal Cancer
Laboratory-Related Adverse ReactionOxaliplatin and FU/LV
N=150		Oxaliplatin
N=153		FU/LV
N=142
All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)		All Grades
(%)		Grades 3–4
(%)
*
Alanine transaminase
†
Aspartate transaminase

Hematology

Anemia

81

2

64

1

68

2

Leukopenia

76

19

13

0

34

1

Neutropenia

73

44

7

0

25

5

Thrombocytopenia

64

4

30

3

20

0

Hepatic

Increased ALT*

31

0

36

1

28

3

Increased AST†

47

0

54

4

39

2

Increased Bilirubin

13

1

13

5

22

6

Additional Adverse Reactions

The following adverse reactions were observed across clinical trials.

Intravenous site reactions

Injection site reaction, including redness, swelling, and pain, can occur with Oxaliplatin. In some cases, skin necrosis has occurred with extravasation.

PRES

PRES occurred in less than 0.1% of patients.

Pulmonary fibrosis and interstitial lung disease

Pulmonary fibrosis, which may be fatal, occurred in less than 1% of patients.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Oxaliplatin. 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.

•
General: angioedema, anaphylactic shock
•
Cardiovascular: QT prolongation leading to ventricular arrhythmias, including fatal torsade de pointes; bradyarrhythmia
•
Neurological: loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsion
•
Hearing and vestibular system: deafness
•
Infections: septic shock, including fatal outcomes
•
Infusion-related reactions and hypersensitivity reactions: laryngospasm
•
Hepatic and gastrointestinal: severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis, ileus, intestinal obstruction, pancreatitis, sinusoidal obstruction syndrome, perisinusoidal fibrosis which rarely may progress, focal nodular hyperplasia, esophagitis
•
Musculoskeletal and connective tissue: rhabdomyolysis, including fatal outcomes
•
Platelet, bleeding, and clotting disorders: immuno-allergic thrombocytopenia, prolonged prothrombin time and INR in patients receiving anticoagulants
•
Blood disorders: secondary leukemia
•
Red blood cell: hemolytic uremic syndrome, immuno-allergic hemolytic anemia
•
Renal: acute tubular necrosis, acute interstitial nephritis, acute renal failure
•
Respiratory: interstitial lung diseases (sometimes fatal) and pneumonia (including fatal outcomes)
•
Vision: decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following treatment discontinuation)
•
Injury, poisoning, and procedural complications: fall-related injuries
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