Cotellic (cobimetinib fumarate 20 mg) Dailymed

Review the Full Prescribing Information for vemurafenib for information on the serious risks of vemurafenib.

• New primary malignancies, cutaneous and non-cutaneous: Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and for up to 6 months following the last dose of COTELLIC. (5.1)
• Hemorrhage: Major hemorrhagic events can occur with COTELLIC. Monitor for signs and symptoms of bleeding. (5.2, 2.3)
• Cardiomyopathy: The risk of cardiomyopathy is increased in patients receiving COTELLIC with vemurafenib compared with vemurafenib as a single agent. The safety of COTELLIC has not been established in patients with decreased left ventricular ejection fraction (LVEF). Evaluate LVEF before treatment, after one month of treatment, then every 3 months thereafter during treatment with COTELLIC. (5.3, 2.3)
• Severe Dermatologic Reactions: Monitor for severe skin rashes. Interrupt, reduce, or discontinue COTELLIC. (5.4, 2.3)
• Serous Retinopathy and Retinal Vein Occlusion: Perform an ophthalmological evaluation at regular intervals and for any visual disturbances. Permanently discontinue COTELLIC for retinal vein occlusion (RVO). (5.5, 2.3)
• Hepatotoxicity: Monitor liver laboratory tests during treatment and as clinically indicated. (5.6, 2.3)
• Rhabdomyolysis: Monitor creatine phosphokinase periodically and as clinically indicated for signs and symptoms of rhabdomyolysis. (5.7, 2.3)
• Severe Photosensitivity: Advise patients to avoid sun exposure. (5.8, 2.3)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.9, 8.1, 8.3)

5.1New Primary Malignancies

New primary malignancies, cutaneous and non-cutaneous, can occur with COTELLIC.

Cutaneous Malignancies:

In Trial 1, the following cutaneous malignancies or premalignant conditions occurred in the COTELLIC with vemurafenib arm and the vemurafenib arm, respectively: cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA) (6% and 20%), basal cell carcinoma (4.5% and 2.4%), and second primary melanoma (0.8% and 2.4%). Among patients receiving COTELLIC with vemurafenib, the median time to detection of first cuSCC/KA was 4 months (range: 2 to 11 months), and the median time to detection of basal cell carcinoma was 4 months (range: 27 days to 13 months). The time to onset in the two patients with second primary melanoma was 9 months and 12 months.

Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. No dose modifications are recommended for COTELLIC [seeDosage and Administration (2.3)]. Conduct dermatologic monitoring for 6 months following discontinuation of COTELLIC when administered with vemurafenib.

Non-Cutaneous Malignancies:

Based on its mechanism of action, vemurafenib may promote growth and development of malignancies [refer to the Full Prescribing Information for vemurafenib]. In Trial 1, 0.8% of patients in the COTELLIC with vemurafenib arm and 1.2% of patients in the vemurafenib arm developed non-cutaneous malignancies.

Monitor patients receiving COTELLIC, when administered with vemurafenib, for signs or symptoms of non-cutaneous malignancies.

5.2Hemorrhage

Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with COTELLIC.

In Trial 1, the incidence of Grade 3–4 hemorrhages was 1.2% in patients receiving COTELLIC with vemurafenib and 0.8% in patients receiving vemurafenib. Hemorrhage (all grades) was 13% in patients receiving COTELLIC with vemurafenib and 7% in patients receiving vemurafenib. Cerebral hemorrhage occurred in 0.8% of patients receiving COTELLIC with vemurafenib and in none of the patients receiving vemurafenib. Gastrointestinal tract hemorrhage (3.6% vs 1.2%), reproductive system hemorrhage (2.0% vs 0.4%), and hematuria (2.4% vs 0.8%) also occurred at a higher incidence in patients receiving COTELLIC with vemurafenib compared with patients receiving vemurafenib.

In Trial 2, in patients with histiocytic neoplasms, 19% of patients experienced hemorrhage events (all were of grade 1 severity).

Withhold COTELLIC for Grade 3 hemorrhagic events. If improved to Grade 0 or 1 within 4 weeks, resume COTELLIC at a lower dose level. Discontinue COTELLIC for Grade 4 hemorrhagic events and any Grade 3 hemorrhagic events that do not improve [seeDosage and Administration (2.3)].

5.3Cardiomyopathy

Cardiomyopathy, defined as symptomatic and asymptomatic decline in left ventricular ejection fraction (LVEF), can occur with COTELLIC. The safety of COTELLIC has not been established in patients with a baseline LVEF that is either below institutional lower limit of normal (LLN) or below 50%.

In Trial 1, patients were assessed for decreases in LVEF by echocardiograms or MUGA at baseline, Week 5, Week 17, Week 29, Week 43, and then every 4 to 6 months thereafter while receiving treatment. Grade 2 or 3 decrease in LVEF occurred in 26% of patients receiving COTELLIC with vemurafenib and 19% of patients receiving vemurafenib. The median time to first onset of LVEF decrease was 4 months (range 23 days to 13 months). Of the patients with decreased LVEF, 22% had dose interruption and/or reduction and 14% required permanent discontinuation. Decreased LVEF resolved to above the LLN or within 10% of baseline in 62% of patients receiving COTELLIC with a median time to resolution of 3 months (range: 4 days to 12 months).

In Trial 2, in patients with histiocytic neoplasms, 8% of patients experienced grade 2 ejection fraction decreased and 12% experienced grade 3-4 events. The median time to first onset of LVEF decrease was 29 days (range 22 days to 114 days). Of the patients with decreased LVEF, all had dose interruption and/or reduction and none required permanent discontinuation. Decreased LVEF resolved to above the LLN or within 10% of baseline in 60% of patients receiving COTELLIC with a median time to resolution of 31 days (range: 13 days to 126 days).

Evaluate LVEF prior to initiation, 1 month after initiation, and every 3 months thereafter until discontinuation of COTELLIC. Manage events of left ventricular dysfunction through treatment interruption, reduction, or discontinuation [seeDosage and Administration (2.3)]. In patients restarting COTELLIC after a dose reduction or interruption, evaluate LVEF at approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then as clinically indicated.

5.4Severe Dermatologic Reactions

Severe rash and other skin reactions can occur with COTELLIC.

In Trial 1, Grade 3 to 4 rash, occurred in 16% of patients receiving COTELLIC with vemurafenib and in 17% of patients receiving vemurafenib, including Grade 4 rash in 1.6% of patients receiving COTELLIC with vemurafenib and 0.8% of the patients receiving vemurafenib. The incidence of rash resulting in hospitalization was 3.2% in patients receiving COTELLIC with vemurafenib and 2.0% in patients receiving vemurafenib. In patients receiving COTELLIC, the median time to onset of Grade 3 or 4 rash events was 11 days (range: 3 days to 2.8 months). Among patients with Grade 3 or 4 rash events, 95% experienced complete resolution with the median time to resolution of 21 days (range 4 days to 17 months).

In Trial 2, in patients with histiocytic neoplasms, 81% of patients experienced rash events (all were of grade 1-2 severity).

Interrupt, reduce the dose, or discontinue COTELLIC [seeDosage and Administration (2.3)].

5.5Serous Retinopathy and Retinal Vein Occlusion

Ocular toxicities can occur with COTELLIC, including serous retinopathy (fluid accumulation under layers of the retina).

In Trial 1, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. Symptomatic and asymptomatic serous retinopathy was identified in 26% of patients receiving COTELLIC with vemurafenib. The majority of these events were reported as chorioretinopathy (13%) or retinal detachment (12%). The time to first onset of serous retinopathy events ranged between 2 days to 9 months. The reported duration of serous retinopathy ranged between 1 day to 15 months. One patient in each arm developed retinal vein occlusion.

In Trial 2, in patients with histiocytic neoplasms, 4% experienced grade 2 retinopathy and 4% experienced grade 3 retinal vascular disorder.

Perform an ophthalmological evaluation at regular intervals and any time a patient reports new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt COTELLIC until visual symptoms improve. Manage serous retinopathy with treatment interruption, dose reduction, or with treatment discontinuation [seeDosage and Administration (2.3)].

5.6Hepatotoxicity

Hepatotoxicity can occur with COTELLIC.

The incidences of Grade 3 or 4 liver laboratory abnormalities in Trial 1 among patients receiving COTELLIC with vemurafenib compared to patients receiving vemurafenib were: 11% vs. 5% for alanine aminotransferase, 8% vs. 2.1% for aspartate aminotransferase, 1.6% vs. 1.2% for total bilirubin, and 7% vs. 3.3% for alkaline phosphatase [see Adverse Drug Reactions (6.1)]. Concurrent elevation in ALT >3 times the upper limit of normal (ULN) and bilirubin >2 × ULN in the absence of significant alkaline phosphatase >2 × ULN occurred in one patient (0.4%) receiving COTELLIC with vemurafenib and no patients receiving single-agent vemurafenib.

In Trial 2, in patients with histiocytic neoplasms, 9% of the patients receiving COTELLIC experienced grade 3 or 4 aspartate aminotransferase increased and 5% of the patients experienced grade 3 or 4 alanine aminotransferase increased.

Monitor liver laboratory tests before initiation of COTELLIC and monthly during treatment, or more frequently as clinically indicated. Manage Grade 3 and 4 liver laboratory abnormalities with dose interruption, reduction, or discontinuation of COTELLIC [seeDosage and Administration (2.3)].

5.7 Rhabdomyolysis

Rhabdomyolysis can occur with COTELLIC.

In Trial 1, Grade 3 or 4 CPK elevations, including asymptomatic elevations over baseline, occurred in 14% of patients receiving COTELLIC with vemurafenib and 0.5% of patients receiving vemurafenib. The median time to first occurrence of Grade 3 or 4 CPK elevations was 16 days (range: 12 days to 11 months) in patients receiving COTELLIC with vemurafenib; the median time to complete resolution was 15 days (range: 9 days to 11 months). Elevation of serum CPK increase of more than 10 times the baseline value with a concurrent increase in serum creatinine of 1.5 times or greater compared to baseline occurred in 3.6% of patients receiving COTELLIC with vemurafenib and in 0.4% of patients receiving vemurafenib.

Obtain baseline serum CPK and creatinine levels prior to initiating COTELLIC, periodically during treatment, and as clinically indicated. If CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation, dose interruption or discontinuation of COTELLIC may be required [seeDosage and Administration (2.3)].

In Trial 2, in patients with histiocytic neoplasms, 27% of patients experienced grade 2 CPK elevation and 27% of patients experienced grade 3-4 CPK elevation.

5.8Severe Photosensitivity

Photosensitivity, including severe cases, can occur with COTELLIC.

In Trial 1, photosensitivity was reported in 47% of patients receiving COTELLIC with vemurafenib: 43% of patients with Grades 1 or 2 photosensitivity and the remaining 4% with Grade 3 photosensitivity. Median time to first onset of photosensitivity of any grade was 2 months (range: 1 day to 14 months) in patients receiving COTELLIC with vemurafenib, and the median duration of photosensitivity was 3 months (range: 2 days to 14 months). Among the 47% of patients with photosensitivity reactions on COTELLIC with vemurafenib, 63% experienced resolution of photosensitivity reactions.

Advise patients to avoid sun exposure, wear protective clothing and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. Manage intolerable Grade 2 or greater photosensitivity with dose modifications [seeDosage and Administration (2.3)].

5.9Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal reproduction studies, COTELLIC can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of cobimetinib in pregnant rats during the period of organogenesis was teratogenic and embryotoxic at doses resulting in exposures [area under the curves (AUCs)] that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with COTELLIC, and for 2 weeks following the final dose of COTELLIC [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

6 Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the label:

• New Primary Cutaneous Malignancies [see Warnings and Precautions (5.1)]
• Hemorrhage [see Warnings and Precautions (5.2)]
• Cardiomyopathy [see Warnings and Precautions (5.3)]
• Serious Dermatologic Reactions [see Warnings and Precautions (5.4)]
• Serous Retinopathy and Retinal Vein Occlusion [see Warnings and Precautions (5.5)]
• Hepatotoxicity [see Warnings and Precautions (5.6)]
• Rhabdomyolysis [see Warnings and Precautions (5.7)]
• Severe Photosensitivity [see Warnings and Precautions (5.8)]

Unresectable or Metastatic Melanoma: Most common adverse reactions for COTELLIC (≥20%) are diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting. The most common (≥5%) Grade 3-4 laboratory abnormalities are increased GGT, increased CPK, hypophosphatemia, increased ALT, lymphopenia, increased AST, increased alkaline phosphatase, hyponatremia. (6.1)

Histiocytic neoplasms: Most common adverse reactions (≥20%) are acneiform dermatitis, diarrhea, infection, fatigue, nausea, edema, dry skin, maculopapular rash, pruritus, dyspepsia, vomiting, dyspnea and urinary tract infections. The most common (≥5%) grade 3-4 lab abnormalities include: Hyponatremia, increased blood creatine phosphokinase, hypokalemia, increased blood creatinine, increased AST, hypocalcemia, lymphopenia, leukopenia, anemia (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Unresectable or Metastatic Melanoma

The safety of COTELLIC was evaluated in Trial 1, a randomized (1:1), double-blind, active-controlled trial in previously untreated patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma [see Clinical Studies (14)]. All patients received vemurafenib 960 mg twice daily on Days 1–28 and received either COTELLIC 60 mg once daily (n=247) or placebo (n=246) on Days 1–21 of each 28-day treatment cycle until disease progression or unacceptable toxicity. In the COTELLIC plus vemurafenib arm, 66% percent of patients were exposed for greater than 6 months and 24% of patients were exposed for greater than 1 year. Patients with abnormal liver function tests, history of acute coronary syndrome within 6 months, evidence of Class II or greater congestive heart failure (New York Heart Association), active central nervous system lesions, or evidence of retinal pathology were excluded from Trial 1. The demographics and baseline tumor characteristics of patients enrolled in Trial 1 are summarized in Clinical Studies [see Clinical Studies (14)].

In Trial 1, 15% of patients receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of COTELLIC. The most common adverse reactions resulting in permanent discontinuation were liver laboratory abnormalities defined as increased aspartate aminotransferase (AST) (2.4%), increased gamma glutamyltransferase (GGT) (1.6%) and increased alanine aminotransferase (ALT) (1.6%); rash (1.6%); pyrexia (1.2%); and retinal detachment (2%). Among the 247 patients receiving COTELLIC, adverse reactions led to dose interruption or reductions in 55%. The most common reasons for dose interruptions or reductions of COTELLIC were rash (11%), diarrhea (9%), chorioretinopathy (7%), pyrexia (6%), vomiting (6%), nausea (5%), and increased creatine phosphokinase (CPK) (4.9%). The most common (≥20%) adverse reactions with COTELLIC were diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting.

Table 3. Incidence of Adverse Drug Reactions Occurring in ≥10% (All Grades) of Unresectable or Metastatic Melanoma Patients Receiving COTELLIC with Vemurafenib and at a Higher Incidence≥5% for All Grades or ≥2% for Grades 3–4 incidence in patients receiving COTELLIC with vemurafenib compared with patients receiving vemurafenib as a single agent than Patients Receiving Vemurafenib in Trial 1

Adverse reactions	COTELLIC + Vemurafenib(n=247)		Placebo + Vemurafenib(n=246)
	All GradesNCI CTCAE, v4.0. (%)	Grades 3–4(%)	All Grades(%)	Grades 3–4(%)
GASTROINTESTINAL DISORDERS
  Diarrhea	60	6	31	1
  Nausea	41	1	25	1
  Vomiting	24	1	13	1
  StomatitisIncludes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation	14	1	8	0
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
  Photosensitivity reactionIncludes solar dermatitis, sunburn, photosensitivity reaction	46	4	35	0
  Acneiform dermatitis	16	2	11	1
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
  Pyrexia	28	2	23	0
  Chills	10	0	5	0
VASCULAR DISORDERS
  Hypertension	15	4	8	2
  Hemorrhage Includes hemorrhage, rectal hemorrhage, melena, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis, hematochezia, gingival bleeding, metrorrhagia, uterine hemorrhage, hemorrhagic ovarian cyst, menometrorrhagia, menorrhagia, vaginal hemorrhage, hemoptysis, pulmonary, cerebral, subarachnoid hemorrhage, subgaleal hematoma, hematuria, epistaxis, contusion, traumatic hematoma, ecchymosis, purpura, nail bed bleeding, ocular, eye, conjunctival, and retinal hemorrhage	13	1	7	<1
EYE DISORDERS
  Vision impairedIncludes vision blurred, visual acuity reduced, visual impairment	15	<1	4	0
  Chorioretinopathy	13	<1	<1	0
  Retinal detachmentIncludes retinal detachment, detachment of retinal pigment epithelium, detachment of macular retinal pigment epithelium	12	2	<1	0

The following clinically relevant adverse reactions (all grades) of COTELLIC were reported with <10% incidence in Trial 1:

Respiratory, thoracic and mediastinal disorders: Pneumonitis

Table 4. Incidence of Laboratory Abnormalities Occurring in ≥10% (All Grades) or ≥2% (Grades 3–4) of Patients with Unresectable or Metastatic Melanoma in Trial 1All the percentages are based on the number of patients who had a baseline result and at least one on-study laboratory test. The laboratory results are available for a total of 233~244 patients for COTELLIC, and 232~243 for vemurafenib, except where indicated.

Laboratory	COTELLIC + Vemurafenib		Placebo + Vemurafenib
	All GradesNCI CTCAE v4.0.	Grades 3–4	All Grades	Grades 3–4
	%	%	%	%
AST - aspartate aminotransferase, ALT - alanine aminotransferase, GGT - gamma-glutamyltransferase
Chemistry
  Increased creatinine	100	3.3	100	0.4
  Increased AST	73	8	44	2.1
  Increased ALT	68	11	55	5
  Increased alkaline phosphatase	71	7	56	3.3
  Increased creatine phosphokinaseIncrease creatine phosphokinase, n=213 for COTELLIC and 217 for vemurafenib.	79	14	16	0.5
  Hypophosphatemia	68	12	38	6
  Increased GGT	65	21	61	17
  Hyponatremia	38	6	33	2.1
  Hypoalbuminemia	42	0.8	20	0.4
  Hypokalemia	25	4.5	17	3.3
  Hyperkalemia	26	2.9	15	0.4
  Hypocalcemia	24	0.4	10	1.7
Hematology
  Anemia	69	2.5	57	3.3
  LymphopeniaLymphopenia, n=185 for COTELLIC, and 181 for vemurafenib.	73	10	55	8
  Thrombocytopenia	18	0	10	0

Histiocytic Neoplasms

The safety of COTELLIC was evaluated in Trial 2, a single-center single-arm trial in patients with histiocytic neoplasms [see Clinical Studies (14)]. In Trial 2, 26 patients with histiocytic neoplasms received COTELLIC 60 mg once daily for 21 days on, then 7 days off, in a 28-day treatment cycle. The median treatment duration was 10.7 months. Table 5 presents adverse reactions in at least 15% of patients reported with histiocytic neoplasms treated with COTELLIC. Table 6 presents laboratory abnormalities of grades ≥3 reported in patients with histiocytic neoplasms treated COTELLIC.

In Trial 2, 4 patients (15%) receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of COTELLIC. One patient discontinued due to worsening of underlying dyspnea and hypoxia; one patient discontinued due to retinal vascular disorder; one patient discontinued due to hyponatremia; and the other patient discontinued due to pneumonia.

Table 5 Incidence of Adverse Reactions Reported Occurring in ≥15% (All Grades) or Any Percentage (Grade ≥3) in Patients with Histiocytic Neoplasms Treated with COTELLIC in Trial 2

Body SystemsAdverse reactions	All GradesNCI CTCAE v4.0. (%)(n=26)	Grades ≥3 (%)(n=26)
GASTROINTESTINAL DISORDERS
  Diarrhea	62	8
  Nausea	46	0
  DyspepsiaGastritis, and gastroesophageal reflux disease.	27	0
  Vomiting	27	0
  Dry Mouth	15	0
  Oral painOral dysesthesia and oropharyngeal pain.	15	0
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
  FatigueMalaise	42	0
  EdemaFacial edema, edema genital, edema peripheral, periorbital edema, and lymphoedema.	42	4
  Pain	15	0
INFECTIONS AND INFESTATIONS
  InfectionsInfluenza like illness, mucosal infection, paronychia, pharyngitis, pneumonia, bronchitis, sepsis, sinusitis, skin infection, tooth infection, upper respiratory tract infection., and urinary tract infection.	62	23
    Urinary tract infection	23	8
    Pulmonary infectionsPneumonia and bronchitis.	19	12
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
  Fall	15	4
INVESTIGATIONS
  Decreased Ejection Fraction	19	12
RENAL AND URINARY
  Acute kidney injury	15	12
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
  Dyspnea	27	15
  Cough	15	0
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
  Acneiform dermatitis	65	0
  Dry skin	31	0
  Maculo-papular rash	31	0
  Pruritus	31	4
VASCULAR DISORDERS
  HemorrhageEpistaxis, contusion, purpura, hematoma, and rectal hemorrhage.	19	0
  Hypertension	15	4

The following clinically relevant adverse reactions (all grades) of COTELLIC were reported with <15% incidence in Trial 2:

Eye disorders: Vision blurred (12%), retinal vascular disorder (4%) and retinopathy (4%).

Gastrointestinal disorders: Stomatitis (12%)

Nervous system disorders: Headache (12%)

Respiratory, thoracic, and mediastinal disorders: Hypoxia (12%), pulmonary edema (4%), and respiratory failure (8%).

Table 6. Incidence of Grade ≥3 Laboratory Abnormalities Occurring in Patients with Histiocytic Neoplasms Treated with COTELLIC in Trial 2All the percentages are based on the number of patients who had a baseline result and at least one on-study laboratory test.

	Grades 3–4NCI CTCAE v4.0 %
AST - aspartate aminotransferase, ALT - alanine aminotransferase
Chemistry
  Increased blood creatine phosphokinase	27
  Hyponatremia	18
  Hypokalemia	12
  Increased blood creatinine	9
  Increased AST	9
  Hypocalcemia	9
  Increased ALT	5
Hematology
  Lymphopenia	27
  Leukopenia	9
  Anemia	8
  Neutropenia	5