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SUTENT (sunitinib)

Indications

SUTENT is indicated for the treatment of gastrointestinal stromal tumour (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance.

SUTENT is indicated for the treatment of treatment-naïve advanced and/or metastatic renal cell carcinoma.

SUTENT is also indicated for the treatment of metastatic renal cell carcinoma (MRCC) after failure of cytokine-based therapy (interferon α, interleukin-2).

Efficacy is based on time to tumour progression and an increase in survival in GIST and on objective response rates for MRCC.

Efficacy and safety has not been demonstrated for more than 12 months.

Contraindications

Use of SUTENT is contra-indicated in patients with hypersensitivity to sunitinib malate or to any other constituent of SUTENT capsules.

Warnings

QT Interval prolongation

Torsade de pointes has been observed in < 0.1 % of sunitinib-exposed patients. SUTENT should be used with caution in patients with a known history of QT interval prolongation, patients who are taking antidysrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances (see Special Precautions).

Thyroid dysfunction

Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical treatment prior to the start of SUTENT treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction on SUTENT treatment. Patients with signs and/or symptoms suggestive of thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice (see Special Precautions).

Side Effects and Special Precautions

Side-Effects:

The most important treatment-related serious adverse events associated with SUTENT treatment of solid tumour patients were pulmonary embolism (1 %), thrombocytopenia (1 %), tumour haemorrhage (0.9 %), febrile neutropenia (0.4 %), and hypertension (0.4 %).

The most common treatment-related adverse events (experienced by at least 20 % of the patients) of any grade included: fatigue; gastrointestinal disorders, such as diarrhoea, nausea, stomatitis, dyspepsia and vomiting; skin discolouration; dysgeusia and anorexia. Fatigue, hypertension and neutropenia were the most common treatment-related adverse events of Grade 3 maximum severity and increased lipase was the most frequently occurring treatment- related adverse event of Grade 4 maximum severity in patients with solid tumours.

Treatment related adverse reactions that were reported in >5 % of solid tumour patients are listed below, by system organ class, frequency and grade of severity. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1 which illustrates the “Treatment-related adverse events reported in ≥ 5 % of GIST patients”
 

GIST

System Organ Class

Frequency

Event

All Grades

n (%)

 

Grade 3

n (%)

Grade 4

n (%)

Blood and

lymphatic system

disorders

Very Common

Anaemia

33 (12.8%)

13 (5.1%)

1 (0.4%)

Common

Neutropenia

24 (9.3%)

15 (5.8%)

1 (0.4%)

Thrombocytopenia

23 (8.9%)

6 (2.3%)

1 (0.4%)

Endocrine

disorders

Common

Hypothyroidism

15(5.8%)

0(0.0%)

1(0.4%)

Metabolism and

nutrition

disorders

Very Common

Anorexia

44 (17.1%)

1 (0.4%)

0 (0.0%)

Nervous system

disorders

Very Common

Dysgeusia

48 (18.7%)

0 (0.0%)

0 (0.0%)

Headache

27 (10.5%)

2 (0.8%)

0 (0.0%)

Vascular

disorders

Very Common

Hypertention

43 (16.7%)

18 (7.0%)

0 (0.0%)

Respiratory,

thoracic and mediastinal

disorders

Common

Epistaxis

17 (6.6%)

0 (0.0%)

0 (0.0%)

Renal and urinary

Disorders

Common

Chromaturia

13 (5.1%)

0 (0.0%)

0 (0.0%)

 

GIST

System Organ

Class

Frequency

Event

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Gastrointestinal

disorders

Very Common

Diarrhoea

90 (35.0%)

13 (5.1%)

0 (0.0%)

Nausea

69 (26.8%)

2 (0.8%)

0 (0.0%)

Stomatitis

49 (19.1%)

2 (0.8%)

0 (0.0%)

Dyspepsia

32 (12.5%)

2 (0.8%)

0 (0.0%)

Vomiting

46 (17.9%)

1 (0.4%)

0 (0.0%)

Abdominal pain

30 (11.7%)

5 (1.9%)

1 (0.4%)

Common

Glossodynia

17 (6.6%)

0 (0.0%)

0 (0.0%)

Constipation

13 (5.1%)

1 (0.4%)

0 (0.0%)

Oral pain

16 (6.2%)

0 (0.0%)

0 (0.0%)

Flatulence

15 (5.8%)

0 (0.0%)

0 (0.0%)

Dry mouth

15 (5.8%)

0 0.0%)

0 (0.0%)

Gastro-oesophageal reflux disease

15 (5.8%)

0 (0.0%)

0 (0.0%)

Skin and

subcutaneous

tissue disorders

Very common

Skin discolouration

65 (25.3%)

0 (0.0%)

0 (0.0%)

Palmar-plantar erythrodysaesthesia syndrome

55 (21.4%)

14 (5.4%)

0 (0.0%)

Rash

39 (15.2%)

2 (0.8%)

0 (0.0%)

Common

Hair colour changes

22 (8.6%)

0 (0.0%)

0 (0.0%)

Dry skin

15 (5.8%)

0 (0.0%)

0 (0.0%)

Musculoskeletal,

connective tissue and bone

disorders

Common

Pain in extremity

21 (8.2%)

1 (0.4%)

0 (0.0%)

Arthralgia

15 (5.8%)

2 (0.8%)

0 (0.0%)

Myalgia

13 (5.1%)

0 (0.0%)

0 (0.0%)

 

GIST

System Organ Class

Frequency

Event

All Grades

n (%)

 

Grade 3

n (%)

Grade 4

n (%)

General disorders

and administration

site conditions

Very common

Fatigue/ Asthenia

135 (52.5%)

25 (9.7%)

0 (0.0%)

Mucosal inflammation

30 (11.7%)

0 (0.0%)

0 (0.0%)

Common

Oedema

21 (8.2%)

1 (0.4%)

0 (0.0%)

Investigations

Common

Haemoglobin decreased

16 (6.2%)

2 (0.8%)

0 (0.0%)

Blood creatine phosphokinase increase

14 (5.4%)

0 (0.0%)

0 (0.0%)

Ejection fraction decreased

13 (5.1%)

1 (0.4%)

0 (0.0%)

Lipase increase

13 (5.1%)

5 (1.9%)

4 (1.6%)

Platelet count decreased

13 (5.1%)

2 (0.8%)

1 (0.4%)

Any adverse event

222 (86.4%)

88 (34.2%)

24 (9.3%)

Table 2 which illustrates the “Treatment-related adverse events reported in ≥ 5 % of cytokine-refractory MRCC patients”
 

Cytokine-refractory MRCC

System Organ Class

Frequency

Event

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Blood and

lymphatic system

disorders

Very Common

Neutropenia

17 (10.1%)

8 (4.7%)

1 (0.6%)

Common

Anaemia

16 (9.5%)

6 (3.6%)

0 (0.0%)

Thrombocytopenia

15 (8.9%)

5 (3.0%)

2 (1.2%)

Leukopenia

14 (8.3%)

7 (4.1%)

0 (0.0%)

Eye

disorders

Common

Lacrimation increased

9 (5.3%)

0 (0.0%)

0 (0.0%)

Metabolism and

nutrition

disorders

Very Common

 

Anorexia

47 (27.8%)

1 (0.6%)

0 (0.0%)

Common

Dehydration

12 (7.1%)

4 (2.4%)

0 (0.0%)

Decreased appetite

11 (6.5%)

0 (0.0%)

0 (0.0%)

Nervous system

disorders

Very Common

 

Dysgeusia

71 (42%)

0 (0.0%)

0 (0.0%)

Headache

25 (14.8%)

1 (0.6%)

0 (0.0%)

Common

Dizziness

13 (7.7%)

2 (1.2%)

0 (0.0%)

Paraesthesia

9 (5.3%)

0 (0.0%)

0 (0.0%)

Vascular

disorders

Very Common

Hypertention

28 (16.6%)

7 (4.1%)

0 (0.0%)

Respiratory,

thoracic and mediastinal

disorders

 

Common

Epistaxis

16 (9.5%)

0 (0.0%)

0 (0.0%)

Dyspnoea

9 (5.3%)

0 (0.0%)

0 (0.0%)

 

Cytokine-refractory MRCC

System Organ

Class

Frequency

Event

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Gastrointestinal

disorders

Very Common

Diarrhoea

83 (49.1%)

5 (3.0%)

0 (0.0%)

Nausea

84 (49.7%)

2 (1.2%)

0 (0.0%)

Stomatitis

70 (41.4%)

6 (3.6%)

0 (0.0%)

Dyspepsia

69 (40.8%)

1 (0.6%)

0 (0.0%)

Vomiting

52 (30.8%)

2 (1.2%)

0 (0.0%)

Constipation

34 (20.1%)

0 (0.0%)

0 (0.0%)

Glossodynia

25 (14.8%)

0 (0.0%)

0 (0.0%)

Abdominal pain

17 (10.1%)

2 (1.2%)

0 (0.0%)

Common

Flatulence

16 (9.5%)

0 (0.0%)

0 (0.0%)

Abdominal distention

9 (5.3%)

0 (0.0%)

0 (0.0%)

Dry mouth

9 (5.3%)

0 0.0%)

0 (0.0%)

Skin and

subcutaneous

tissue disorders

 

 

Very common

Skin discolouration

54 (32.0%)

0 (0.0%)

0 (0.0%)

Rash

46 (27.2%)

0 (0.0%)

0 (0.0%)

Hair colour changes

24 (14.2%)

0 (0.0%)

0 (0.0%)

Dry skin

22 (13.0%)

0 (0.0%)

0 (0.0%)

Palmar-plantar erythrodysaesthesia syndrome

21 (12.4%)

6 (3.6%)

0 (0.0%)

Erythema

20 (11.8%)

0 (0.0%)

0 (0.0%)

Common

Alopecia

13 (7.7%)

0 (0.0%)

0 (0.0%)

Dermatitis exfoliative

10 (5.9%)

2 (1.2%)

0 (0.0%)

Periorbital oedema

9 (5.3%)

0 (0.0%)

0 (0.0%)

 

Cytokine-refractory MRCC

System Organ

Class

Frequency

Event

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Musculoskeletal,

connective tissue and bone

disorders

Very Common

Pain in extremity

21 (12.4%)

1 (0.6%)

0 (0.0%)

Common

Myalgia

15 (8.9%)

1 (0.6%)

0 (0.0%)

General disorders

and administration

site conditions

 

Very common

Fatigue/ Asthenia

108 (63.9%)

19 (11.2%)

0 (0.0%)

Mucosal inflammation

30 (17.8%)

1 (0.6%)

0 (0.0%)

Injury, poisoning,

and procedural

complications

Very Common

 

Blister

13 (7.7%)

4 (2.4%)

0 (0.0%)

Investigations

Very common

Lipase increased

17 (10.1%)

12 (7.1%)

3 (1.8%)

Common

Ejection fraction

abnormal

16 (9.5%)

1 (0.6%)

0 (0.0%)

Blood amylase

increased

9 (5.3%)

6 (3.6%)

0 (0.0%)

Weight decreases

11 (6.5%)

0 (0.0%)

0 (0.0%)

WBC decreased

10 (5.9%)

3 (1.8%)

0 (0.0%)

Platelet count

decreased

9 (5.3%)

3 (1.8%)

2 (1.2%)

Any adverse event

166 (98.2%)

77 (45.6%)

14 (8.3%)

Table 3 which illustrates the “Treatment-related adverse events reported in ≥ 5 % of patients with treatment-naïve MRCC who received SUTENT or IFN-α”
 

Treatment-naïve MRCC

Sunitinib (n=375)

IFN-α (n=360)

System Organ Class

Frequency

Event

All

Grades

n (%)

Grade 3/4

n (%)

All Grades

n(%)

Grade 3/4

n (%)

Infections and

infestations

Common

Influenza

5 (1.3%)

0

(0.0%)

28

(7.8%)

0

(0.0%)

Blood and lymphatic system disorders

Very Common

 

Thrombocytopenia

57 (15.2%)

25

(6.7%)

25

(6.9%)

9

(2.5%)

Neutropenia

51 (13.6%)

25

(6.7%)

25

(6.9%)

9

(2.5%)

Common

Leukopenia

31 (8.3%)

8

(2.1%)

13

(3.6%)

3

(0.8%)

Anaemia

25 (6.7%)

5

(1.3%)

28

(7.8%)

4

(1.1%)

Metabolism and

nutrition

disorders

Very Common

Anorexia

96 (25.6%)

4

(1.1%)

94

(26.1%)

5

(1.4%)

Common

Decreased appetite

29 (7.7%)

0 (0%)

37

(10.3%)

1 (0%)

Dehydration

19 (5.1%)

5

(1.3%)

11

(3.1%)

1

(0.3%)

Psychiatric disorders

 

Common

 

Insomnia

15 (4.0%)

0 (0.0%)

18

(5.0%)

0 (0.0%)

Depression

10 (2.7%)

0 (0%)

28

(7.8%)

4

(1.1%)

Nervous system disorders

Very Common

Dysgeusia

158 (42.1%)

0 (0%)

49

(13.6%)

0 (0%)

Headache

41 (10.9%)

2

(0.5%)

50

(13.9%)

0 (0%)

 

Treatment-naïve MRCC

Sunitinib (n=375)

IFN-α (n=360)

System Organ Class

Frequency

Event

All

Grades

n (%)

Grade 3/4

n (%)

All Grades

n(%)

Grade 3/4

n (%)

Nervous system disorders

Common

Paraesthesia

19 (5.1%)

0 (0%)

3

(0.8%)

0 (0%)

Dizziness

18 (4.8%)

0 (0%)

25

(6.9%)

1

(0.3%)

Vascular disorders

 

Very Common

Hypertention

89 (23.7%)

31

(8.3%)

4

(1.1%)

1

(0.3%)

Respiratory, thoracic and mediastinal disorders

Very common

Epistaxis

44 (11.7%)

3

(0.8%)

4

(1.1%)

0 (0%)

Common

Dyspnoea

21 (5.6%)

4

(1.1%)

27

(7.5%)

4

(1.1%)

Pharyngolaryngeal

pain

19 (5.1%)

1

(0.3%)

1

(0.3%)

0 (0%)

Gastrointestinal

disorders

Very Common

Diarrhoea

199 (53.1%)

18

(4.8%)

45

(12.5%)

0 (0.0%)

Nausea

166 (44.3%)

12

(3.2%)

120

(33.3%)

4

(1.1%)

Dyspepsia

96 (25.6%)

2

(0.5%)

11

(3.1%)

0 (0%)

Stomatitis

94 (25.1%)

3

(0.8%)

6

(1.7%)

1

(0.3%)

Vomiting

90 (24.0%)

13

(3.5%)

36

(10.0%)

2

(0.6%)

Abdominal pain

45 (12.0%)

4

(1.1%)

14

(3.9%)

0 (0%)

Dry mouth

40 (10.7%)

0 (0%)

23

(6.4%)

1

(0.3%)

 

Treatment-naïve MRCC

Sunitinib (n=375)

IFN-α (n=360)

System Organ Class

Frequency

Event

All

Grades

n (%)

Grade 3/4

n (%)

All Grades

n(%)

Grade 3/4

n (%)

Gastrointestinal

disorders

Common

Oral pain

35 (9.3%)

0 (0%)

1

(0.3%)

0 (0%)

Glossodynia

34 (9.1%)

0 (0%)

1

(0.3%)

0 (0%)

Flatulence

29 (7.7%)

0 (0%)

6

(1.7%)

0 (0%)

Constipation

29 (7.7%)

0 (0%)

13

(3.6%)

0 (0%)

Gastro-

oesophageal  reflux

disease

28 (7.5%)

0 (0%)

2

(0.6%)

0 (0%)

Skin and

subcutaneous

tissue disorders

Very common

Rash

85 (22.7%)

2

(0.5%)

26

(7.3%)

2

(0.6%)

Palmar-plantar erythrodysaesthesia syndrome

76 (20.3%)

19

(5.1%)

2

(0.6%)

0 (0%)

Dry skin

60 (16.0%)

1

(0.3%)

17

(4.7%)

0 (0%)

Skin discolouration

58 (15.5%)

0 (0%)

0 (0%)

0 (0%)

Hair colour changes

54 (14.4%)

0 (0%)

1

(0.3%)

0 (0%)

Common

Alopecia

29 (7.7%)

0 (0.0%)

27

(7.5%)

0 (0%)

Erythema

26 (6.9%)

1

(0.3%)

3

(0.8%)

0 (0%)

Skin exfoliation

25 (6.7%)

1

(0.3%)

3

(0.8%)

0 (0%)

 

Treatment-naïve MRCC

Sunitinib (n=375)

IFN-α (n=360)

System Organ Class

Frequency

Event

All

Grades

n (%)

Grade 3/4

n (%)

All Grades

n(%)

Grade 3/4

n (%)

Skin and

subcutaneous

tissue disorders

Common

Pruritus

21 (5.6%)

1

(0.3%)

10

(2.8%)

0 (0%)

Musculoskeletal,

connective tissue and bone

disorders

Very Common

Pain in extremity

42 (11.2%)

2

(0.5%)

11

(3.1%)

0 (0%)

Common

Arthralgia

33 (8.8%)

1

(0.3%)

45

(12.5%)

0 (0%)

Myalgia

20 (5.3%)

1

(0.3%)

56

(15.6%)

1

(0.3%)

General disorders

and administration

site conditions

 

Very common

Fatigue

191 (50.9%)

27

(7.2%)

184

(51.1%)

42

(11.7%)

Mucosal inflammation

75 (20.0%)

6

(1.6%)

4

(1.1%)

1

(0.3%)

Asthenia

63 (16.8%)

17

(4.5%)

71

(19.7%)

13

(3.6%)

General disorders

and administration site conditions

Common

 

Oedema

29 (7.7%)

0 (0%)

4

(1.1%)

0 (0%)

Pyrexia

27 (7.2%)

3

(0.8%)

121

(33.6%)

0 (0%)

Chills

24 (6.4%)

2

(0.5%)

103

(28.6%)

0 (0%)

Uncommon

Influenza-like illness

2 (0.5%)

0 (0%)

25

(6.9%)

1

(0.3%)

 

Treatment-naïve MRCC

Sunitinib (n=375)

IFN-α (n=360)

System Organ Class

Frequency

Event

All

Grades

n (%)

Grade 3/4

n (%)

All Grades

n(%)

Grade 3/4

n (%)

Investigations

Very common

Ejection fraction

decreased

38 (10.1%)

8

(2.1%)

10

(2.8%)

2

(0.6%)

Common

Weight decreases

34 (9.1%)

0 (0%)

43

(11.9%)

0 (0%)

Platelet count

decreased

25 (6.7%)

9

(2.4%)

3

(0.8%)

0 (0%)

Any adverse event

357 (95.2%)

206

(54.9%)

329

(91.4%)

113

(31.4%)

The following adverse events have been reported in SUTENT clinical trials:

System Organ ClassFrequencyAdverse Events
Cardiac disordersUncommonCardiac failure, cardiac failure congestive, left ventricular failure
RareProlonged QT interval, torsade de pointes
Gastrointestinal disordersUncommonPancreatitis
RareGastrointestinal perforation
Hepatobiliary disordersUncommonHepatic failure
InvestigationsCommonElevated thyroid stimulating hormone (TSH)

 

Post-marketing experience: The following adverse events have been identified during post-approval use of SUTENT.

Infection and infestations: Cases of serious infection (with or without neutropenia) in some cases with fatal outcome have been reported.

Musculoskeletal and connective tissue disorders: Cases of myopathy and/or rhabdomyolysis, some with acute renal failure have been reported. Most of these patients had pre-existing risk factors and/or were receiving concomitant medications known to be associated with these adverse reactions.

Blood and lymphatic system disorders: Cases of thrombotic microangiopathy and haemolytic uraemic syndrome have been reported. Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

Renal and urinary disorders: Cases of proteinuria and cases of nephrotic syndrome have been reported. Baseline urinalysis is reported, and patients should be monitored for the development or worsening of proteinuria. The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue patients with nephrotic syndrome.

Special Precautions:

In-vitro studies indicate that SUTENT neither induces nor inhibits major CYP enzymes, including CYP3A4.
The dose of SUTENT may need to be reduced based on tolerability when co-administered with CYP3A4 inhibitors.
The dose of SUTENT may need to be increased when it is co-administered with potent CYP3A4 inducers.

Skin and tissues
Skin discolouration due to drug colour (yellow) is a common treatment-related adverse event occurring in approximately 30 % of patients. Patients should be advised that depigmentation of the hair or skin may also occur during treatment with SUTENT. Other possible dermatologic effects may include dryness, thickness or cracking of the skin, blisters or occasional rash on the palms of the hands and soles of the feet.

Mouth pain/irritation was reported in approximately 14 % of patients. Dysgeusia (taste disturbance) was reported in approximately 28 % of patients.

The above events were not cumulative, were typically reversible and generally did not result in treatment discontinuation.

Gastrointestinal Events
Nausea, diarrhoea, stomatitis, dyspepsia and vomiting were the most commonly reported treatment-related gastrointestinal events.

Supportive care for gastrointestinal adverse events requiring treatment may include medication with an anti-emetic or anti-diarrhoeal medication.

Gastrointestinal tract
Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation have occurred in patients with intra-abdominal malignancies treated with SUTENT.

Haemorrhage
Treatment-related tumour haemorrhage occurred in approximately 2 % of patients with GIST. Tumour haemorrhage has not been observed in patients with MRCC or other solid tumours. Routine assessment of this event should include complete blood counts and physical examination.

In patients receiving SUTENT for treatment-naïve MRCC, 28 % had bleeding events. Of patients receiving SUTENT for cytokine-refractory MRCC, 26 % experienced bleeding. Routine assessment of this event should include complete blood counts and physical examination.

Treatment-related epistaxis was reported in 8 % of patients with solid tumours. Epistaxis was the most common treatment-related haemorrhagic adverse event, having been reported for approximately half of the patients with solid tumours who experienced haemorrhagic events.

Hypertension
Treatment-related hypertension was reported in approximately 16 % of patients with solid tumours. SUTENT dosing was reduced or temporarily delayed in approximately 2.7 % of this patient population. None of these patients were discontinued from treatment with SUTENT.

Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 4.7 % of this patient population. Patients should be screened for hypertension and controlled as appropriate. Treatment-related hypertension was reported in approximately 24 % of patients receiving SUTENT for treatment-naïve MRCC. Severe hypertension occurred in 5 % of treatment-naïve patients on SUTENT.

Temporary suspension is recommended in patients with severe hypertension that is not controlled with medical management. Treatment may be resumed once hypertension is appropriately controlled.

Haematological
Decreased absolute neutrophil counts of Grade 3 and 4 severity were reported in 13.1 % and 0.9 % patients, respectively. Decreased platelet counts of Grade 3 and 4 severity were reported in 4 % and 0.5 % patients respectively. The above events were not cumulative, were typically reversible and generally did not result in treatment discontinuation.
Complete blood counts should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT.

Cardiovascular
Decreases in left ventricular ejection fraction (LVEF) of ≥20 % and below the lower limit of normal occurred in approximately 2 % of SUTENT-treated GIST patients and of 4 % MRCC patients and 2 % of placebo-treated patients.
In the treatment-naïve MRCC STUDY, 21 % patients on SUTENT had an LVEF value below the lower limit of normal. One (<1 %) patient who received SUTENT was diagnosed with congestive heart failure.
These LVEF declines do not appear to have been progressive and often improved as treatment continued. Treatment-related adverse events of ‘cardiac failure’, ‘cardiac failure congestive’ or ‘left ventricular failure’ were reported in 0.7 % of patients with solid tumours and 1% of patients treated with placebo. All patients had GIST. The relationship, if any, between receptor tyrosinase kinase (RTK) inhibition and cardiac function remains unclear. Data from non-clinical (in vitro and in vivo) studies, at doses higher than the recommended human dose, indicate that SUTENT has the potential to inhibit the cardiac action potential repolarization process (e.g. prolongation of QT interval). Increases in the QTc interval to over 500 msec occurred in 0.5 % and changes from baseline in excess of 60 msec occurred in 1.1 % of the 450 solid tumour patients; both these parameters are recognized as potentially significant changes.
These observed changes in QT interval have not been associated with any adverse clinical events such as dysrhythmia.

Pulmonary Embolism
Treatment-related pulmonary embolism was reported in approximately 1.1 % patients with solid tumours who received SUTENT. None of these events resulted in a patient discontinuing treatment with SUTENT; however a dose reduction or temporary delay in treatment occurred in a few cases. There were no further occurrences of pulmonary embolism in these patients after treatment was resumed.

Pancreatic Function
Increases in serum lipase and amylase were observed in patients with various solid tumours who received SUTENT. Increases in lipase levels were transient and were generally not accompanied by signs or symptoms of pancreatitis in subjects with various solid tumours. Pancreatitis was observed in 0.4 % of patients with solid tumours. Hepatic failure was observed in <1 % of solid tumour patients treated with SUTENT. If symptoms of pancreatitis or hepatic failure are present, patients should have proper medical follow-up.

QT Interval Prolongation
At approximately twice the therapeutic concentrations, SUTENT has been shown to prolong the QTcF (Fredericia’s correction) interval. QT interval prolongation may lead to an increased risk for ventricular dysrhythmias including torsade de pointes.

Thyroid Dysfunction
Treatment-emergent acquired hypothyroidism was noted in 4 % of GIST patients. Hypothyroidism was reported as an adverse event in 2 % of patients on SUTENT in the treatment-naïve MRCC study.
Overall 7 % of the cytokine-refractory MRCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism.
Rare cases of hyperthyroidism, have been reported in clinical trials and through post-marketing surveillance.

Venous Thromboembolic Events
Seven patients (3 %) on SUTENT in a GIST study experienced venous thromboembolic events; five of the seven were Grade 3 deep vein thrombosis (DVT). Seven (2 %) patients receiving SUTENT for treatment-naïve MRCC had venous thrombolic events reported such as pulmonary embolism.

Interaction with Other Medicinal Products and other Forms of Interaction

When SUTENT is co-administered with other medications, there is a potential for medicine interaction.

Medicines that may increase SUTENT plasma concentrations:

Concurrent administration of SUTENT with the CYP3A4 inhibitor, ketoconazole, resulted in 59 % and 74 % increases in sunitinib Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Administration of SUTENT with other inhibitors of the CYP3A4 family (e.g., itraconazole, erythromycin, clarithromycin) may increase SUTENT concentrations.

Medicines that may decrease SUTENT plasma concentrations:

Concomitant use of SUTENT with the CYP3A4 inducer, rifampin, resulted in a more than 56 % and 78 % reduction in sunitinib Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers.

Administration of SUTENT with other inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital or Hypericum perforatum known also as St. John’s Wort) may decrease SUTENT concentrations.

To maintain SUTENT target concentrations, dose adjustment of SUTENT, or selection of co- medications with less enzyme induction potential, should be considered.

The calculated in vitro Ki values for all CYP isoforms tested (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 AND CYP4A9/11) indicated that SUTENT and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.

Dosage and Directions for Use

Therapy should be initiated by a physician experienced in the treatment of renal cell carcinoma or GIST.

The recommended dose of SUTENT is one 50 mg dose orally, taken daily for 4 consecutive weeks, followed by a 2-week rest period (Schedule 4/2) to comprise a complete cycle of 6 weeks.

In patients receiving SUTENT with a potent CYP3A4 inducer such as rifampin, the dosage of SUTENT may need to be increased in 12.5 mg increments (up to 75 mg per day). Clinical response and tolerability should be carefully monitored.

In patients receiving SUTENT with a CYP3A4 inhibitor such as ketoconazole, the doses of SUTENT may need to be reduced, based on tolerability and/or clinical response. Selection of an alternate concomitant medication with no, or minimal potential to induce or inhibit CYP34 should be considered.

Dose modifications in 12.5 mg increments may be applied based on individual safety and tolerability. Daily doses should not exceed 75 mg nor be decreased below 25 mg.

Population pharmacokinetic analyses of demographic data indicate that no dose adjustments are necessary for age, body weight, creatinine clearance, race, gender or ECOG (Eastern Cooperative Oncology Group) score.

Paediatric use: The safety and efficacy of SUTENT in paediatric patients have not been established.

Elderly patients use: No significant differences in safety or effectiveness were observed between younger and older patients.

Hepatic Insufficiency: No dosage adjustment is necessary when administering sunitinib to patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. SUTENT was not studied in patients with severe (Child-Pugh Class B).

Renal Insufficiency: No clinical studies have been performed in patients with impaired renal function. Studies excluded patients with serum creatinine > 2.0 x ULN. Population pharmacokinetic analyses have shown that SUTENT pharmacokinetics were unaltered in the range of renal function evaluated, as measured by creatinine clearance (42-347 ml/min).

SUTENT may be taken with or without food.

If a dose is missed, the patient should not be given an additional dose. The patient should take the usual prescribed dose on the following day.

Known Symptoms of Overdosage and Particulars of its Treatment

There is no experience of acute overdosage with SUTENT. There is no specific antidote for overdosage with SUTENT and treatment of overdose should consist of general supportive measures. If indicated, elimination of unabsorbed drug may be achieved by emesis or gastric lavage.

Pharmacological Action

Pharmacodynamic properties

Sunitinib malate is a small molecule that simultaneously inhibits multiple receptor tyrosine kinases (RTKs) that are implicated in tumour growth, pathologic angiogenesis, and metastatic progression of cancer.

Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as a potent inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Inhibition of the tyrosine kinase activity of these RTKs by sunitinib has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays.

The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.

Sunitinib malate demonstrated inhibition of activity of target RTKs (PDGFRβ, VEGFR2, KIT) in tumours in vivo and demonstrated the ability to inhibit tumour growth, cause tumour regression, and/or inhibit metastatic progression in a variety of rodent cancer models.

Consistent with its multi-targeted profile, sunitinib malate demonstrated the ability to directly inhibit growth of tumour cells expressing dysregulated RTK targets (PDGFR, RET, or KIT) and to inhibit PDGFRβ- and VEGFR2-dependent tumour angiogenesis.

Pharmacokinetic properties

Absorption
Sunitinib is absorbed after oral administration with maximum concentrations (Cmax) generally observed from 6 – 12 hours (Tmax) post-dose. Food has no effect on the bioavailability of sunitinib.

Distribution
Binding of sunitinib and its primary active metabolite to human plasma protein in in vitro assays was 95 % and 90 %, respectively, with no apparent concentration dependence.

Biotransformation
Sunitinib is metabolized primarily by CYP3A4, the cytochrome P450 enzyme, which produces its primary active metabolite, which is then further metabolized by CYP3A4.

Elimination
Excretion is primarily via faeces (61 %) with renal elimination of drug and metabolites accounting for 16 % of the administered dose. Sunitinib and its primary active metabolite were the major drug-related compounds identified in plasma, urine and faeces, representing 91.5 %, 86.4 % and 73.8 % of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and faeces, but generally were not found in plasma. Total oral clearance (CL/F) was 34-62 l/hr.

Plasma Pharmacokinetics
Following oral administration in healthy volunteers, the elimination half-lives of sunitinib and its primary active desethyl metabolite are approximately 40 - 60 hours, and 80 - 110 hours, respectively.

In the dosing ranges of 25 to 100 mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionally with dose.
With repeated daily administration, sunitinib accumulates 3- to 4-fold and its primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days.
By day 14, combined plasma concentrations of sunitinib and is active metabolite are 62.9 – 101 ng/ml which are target concentrations predicted from preclinical data to inhibit receptor phosphorylation in vitro and result in tumour stasis/growth reduction in vivo. The primary active metabolite comprises 23 to 37 % of the total exposure.

No significant changes in the pharmacokinetics of sunitinib or the primary, active metabolite are observed with repeated daily administration or with repeated cycles in the dosing regimens tested. The pharmacokinetics were similar in all solid tumour populations tested and in healthy volunteers.

Population pharmacokinetic analyses of demographic data indicate that no dose adjustments are necessary for weight, creatinine clearance, gender, race or ECOG score.

Storage Instructions

Store at or below 30 ºC.

Keep out of reach and sight of children.

Proprietary Name and Dosage Form

SUTENT® 12,5 mg Capsules

SUTENT® 25 mg Capsules

SUTENT® 50 mg Capsules

Pregnancy and Lactation

SUTENT use in pregnancy and lactation has not been established.

Identification and Presentation

Identification:

SUTENT 12,5 mg Capsules: Hard gelatin capsules with orange cap and orange body, printed with white ink “Pfizer” on the cap, “STN 12,5 mg” on the body, containing yellow to orange granules.

SUTENT 25 mg Capsules: Hard gelatin capsules with caramel cap and orange body, printed with white ink “Pfizer” on the cap, “STN 25 mg” on the body, containing yellow to orange granules.

SUTENT 50 mg Capsules: Hard gelatin capsules with caramel cap and caramel body, printed with white ink “Pfizer” on the cap, “STN 50 mg” on the body, containing yellow to orange granules.

Presentation:

Opaque blue-white high density polyethylene bottles with a white child resistant polypropylene closure and a heat induction seal liner containing 28 or 30 hard gelatine capsules. SUTENT capsules are available in blister strips of 28 capsules.

References

SUTENT® 12.5mg 25mg 50 mg package insert – effective date 26 November 2010

Other

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE:
Pfizer Laboratories (Pty) Ltd
85 Bute Lane
Sandton 2196
South Africa

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