Advertisement

Topics

These highlights do not include all the information needed to use Gleevec   safely and effectively. See full prescribing information for Gleevec . GLEEVEC (imatinib mesylate) tablets for oral use Initial U.S. A | Gleevec

04:59 EDT 27th August 2014 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase.

Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia.

Adult patients with myelodysplastic/ myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements.

Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.

Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.

Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. Approval is based on recurrence-free survival with a median follow-up of 14 months. Clinical benefit has not been demonstrated by a long term effect on recurrence-free survival or survival.

Therapy should be initiated by a physician experienced in the treatment of patients with hematological malignancies or malignant sarcomas, as appropriate. The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.

In children, Gleevec treatment can be given as a once-daily dose or alternatively the daily dose may be split into two - once in the morning and once in the evening. There is no experience with Gleevec treatment in children under 2 years of age.

For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).

For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron.

Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

The recommended dose of Gleevec is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis.

In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.

The recommended dose of Gleevec for children with newly diagnosed Ph+ CML is 340 mg/m/day (not to exceed 600 mg).

The recommended dose of Gleevec is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.

The recommended dose of Gleevec is 400 mg/day for adult patients with MDS/MPD.

The recommended dose of Gleevec is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with Gleevec 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

The recommended dose of Gleevec is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 

The recommended dose of Gleevec is 800 mg/day for adult patients with DFSP.

The recommended dose of Gleevec is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions.

The recommended dose of Gleevec is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In the clinical study, Gleevec was administered for one year. The optimal treatment duration with Gleevec is not known.

Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of Gleevec should be increased by at least 50%, and clinical response should be carefully monitored [see Drug Interactions (7.1)].

Hepatic Impairment: Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment [see Use in Specific Populations (8.6)].

Renal Impairment: Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended.

Imatinib should be used with caution in patients with severe renal impairment. A dose of 100 mg/day was tolerated in two patients with severe renal impairment. [See Use in Specific Populations (8.7)]

If elevations in bilirubin >3 x institutional upper limit of normal (IULN) or in liver transaminases >5 x IULN occur, Gleevec should be withheld until bilirubin levels have returned to a <1.5 x IULN and transaminase levels to <2.5 x IULN. In adults, treatment with Gleevec may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg or 800 mg to 600 mg). In children, daily doses can be reduced under the same circumstances from 340 mg/m/day to 260 mg/m/day.

If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Gleevec should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1.

Table 1 Dose Adjustments for Neutropenia and Thrombocytopenia
ASM associated with eosinophilia
(starting dose 100 mg)
ANC <1.0 x 109/L
and/or
platelets <50 x 109/L
Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L
Resume treatment with Gleevec at previous dose (i.e., dose before severe adverse reaction)
HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg) ANC <1.0 x 109/L
and/or
platelets <50 x 109/L
Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L
Resume treatment with Gleevec at previous dose (i.e., dose before severe adverse reaction)
Chronic Phase CML (starting dose 400 mg)

MDS/MPD, ASM and HES/CEL (starting dose 400 mg)

GIST (starting dose
400 mg)
ANC <1.0 x 109/L
and/or
platelets <50 x 109/L
Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L
Resume treatment with Gleevec at the original starting dose of 400 mg
If recurrence of ANC <1.0 x 109/L and/or platelets <50 x 109/L, repeat step 1 and resume Gleevec at a reduced dose of 300 mg
Ph+ CML : Accelerated Phase and Blast Crisis (starting dose 600 mg)
Ph+ ALL
(starting dose 600 mg)
ANC <0.5 x 109/L
and/or
platelets <10 x 109/L
Check if cytopenia is related to leukemia (marrow aspirate or biopsy)
If cytopenia is unrelated to leukemia, reduce dose of Gleevec to 400 mg
If cytopenia persists 2 weeks, reduce further to 300 mg
If cytopenia persists 4 weeks and is still unrelated to leukemia, stop Gleevec until ANC ≥1 x 109/L and platelets ≥20 x 109/L and then resume treatment at 300 mg
DFSP
(starting dose 800 mg)
ANC <1.0 x 109/L
and/or
platelets <50 x 109/L
Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L
Resume treatment with Gleevec at 600 mg
In the event of recurrence of ANC <1.0 x 109/L and/or platelets <50 x 109/L, repeat step 1 and resume Gleevec at reduced dose of 400 mg
Pediatric newly diagnosed chronic phase CML
(starting dose 340 mg/m2)
ANC <1.0 x 109/L
and/or
platelets <50 x 109/L
Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 109/L
Resume treatment with Gleevec at previous dose (i.e., dose before severe adverse reaction)
In the event of recurrence of ANC <1.0 x 109/L and/or platelets <50 x 109/L, repeat step 1 and resume Gleevec at reduced dose of 260 mg/m2

100 mg film coated tablets

Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on one side, and “SA” with score on the other side

400 mg film coated tablets

Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “400” on one side with score on the other side, and “SL” on each side of the score

None

Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1)]. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Gleevec dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. Severe fluid retention was reported in 9% to 13.1% of patients taking Gleevec for GIST [see Adverse Reactions (6.11)].

Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy [see Dosage and Administration (2.11)].

Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients taking Gleevec. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.

Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.3)]. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Gleevec. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with Gleevec interruption and/or dose reduction [see Dosage and Administration (2.10)].

When Gleevec is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.

In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages.

Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation.

In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec should be considered at the initiation of therapy.

Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon re-challenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients.

It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.

Pregnancy Category D

Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec. Sexually active female patients taking Gleevec should use adequate contraception. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area.. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area. [ see Use in Specific Populations (8.1)]

Growth retardation has been reported in children and pre-adolescents receiving Gleevec. The long term effects of prolonged treatment with Gleevec on growth in children are unknown. Therefore, close monitoring of growth in children under Gleevec treatment is recommended. [see Postmarketing Experience (6.13)]

Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL and eosinophilic leukemia receiving Gleevec. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

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

The majority of Gleevec-treated patients experienced adverse reactions at some time. Most reactions were of mild-to-moderate grade, but drug was discontinued for drug-related adverse reactions in 2.4% of newly diagnosed patients, 4% of patients in chronic phase after failure of interferon-alpha therapy, 4% in accelerated phase and 5% in blast crisis.

The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 for newly diagnosed CML, Table 3 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec. [see Dosage and Administration (2.10)]. The frequency of severe superficial edema was 1.5%-6%.

A variety of adverse reactions represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting Gleevec treatment and using diuretics or other appropriate supportive care measures. A few of these reactions may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the Gleevec treated patients are shown in Tables 2 and 3.

Table 2 Adverse Reactions Reported in Newly Diagnosed CML Clinical Trial (≥10% of Gleevec Treated Patients)(1)
All Grades CTC Grades 3/4
Gleevec IFN+Ara−C Gleevec IFN+Ara−C
Preferred Term N=551 (%) N=533 (%) N=551 (%) N=533 (%)
Fluid Retention 61.7 11.1 2.5 0.9
− Superficial Edema 59.9 9.6 1.5 0.4
− Other Fluid Retention Reactions2 6.9 1.9 1.3 0.6
Nausea 49.5 61.5 1.3 5.1
Muscle Cramps 49.2 11.8 2.2 0.2
Musculoskeletal Pain 47.0 44.8 5.4 8.6
Diarrhea 45.4 43.3 3.3 3.2
Rash and Related Terms 40.1 26.1 2.9 2.4
Fatigue 38.8 67.0 1.8 25.1
Headache 37.0 43.3 0.5 3.8
Joint Pain 31.4 38.1 2.5 7.7
Abdominal Pain 36.5 25.9 4.2 3.9
Nasopharyngitis 30.5 8.8 0 0.4
Hemorrhage 28.9 21.2 1.8 1.7
- GI Hemorrhage 1.6 1.1 0.5 0.2
- CNS Hemorrhage 0.2 0.4 0 0.4
Myalgia 24.1 38.8 1.5 8.3
Vomiting 22.5 27.8 2.0 3.4
Dyspepsia 18.9 8.3 0 0.8
Cough 20.0 23.1 0.2 0.6
Pharyngolaryngeal Pain 18.1 11.4 0.2 0
Upper Respiratory Tract Infection 21.2 8.4 0.2 0.4
Dizziness 19.4 24.4 0.9 3.8
Pyrexia 17.8 42.6 0.9 3.0
Weight Increased 15.6 2.6 2.0 0.4
Insomnia 14.7 18.6 0 2.3
Depression 14.9 35.8 0.5 13.1
Influenza 13.8 6.2 0.2 0.2
Bone Pain 11.3 15.6 1.6 3.4
Constipation 11.4 14.4 0.7 0.2
Sinusitis 11.4 6.0 0.2 0.2
(1)All adverse reactions occurring in ≥10% of Gleevec treated patients are listed regardless of suspected relationship to treatment.
(2)Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

Manufacturer

Novartis Pharmaceuticals Corporation (NPC), a US subsidiary of Novartis AG

Active Ingredients

Source

Drugs and Medications [1 Associated Drugs and Medications listed on BioPortfolio]

Gleevec [Physicians Total Care, Inc.]

These highlights do not include all the information needed to use Gleevec   safely and effectively.   See full prescribing information for Gleevec . GLEEVEC (imatinib mesylate) tablets for oral use

Clinical Trials [64 Associated Clinical Trials listed on BioPortfolio]

Effect of Antacids on Gleevec® in Healthy Volunteers

This is a research study that will investigate the effects of antacids (often used to treat stomach upset) on Gleevec® (a drug that is FDA-approved to treat some types of cancer) in healt...

Phase II Gleevec Idiopathic Hypereosinophilic Syndrome

The purpose of the trial is to determine the safety and efficacy of Gleevec" in idiopathic hypereosinophilic syndrome (HES) and to characterize the molecular basis for the therapeutic bene...

Homoharringtonine With Oral Gleevec in Chronic, Accelerated and Blast Phase Chronic Myeloid Leukemia (CML)

This will be an open label, multi-center study of up to 77 patients with CML in chronic, accelerated or blast phase who have developed resistance to or have failed previous treatment with ...

Effect of a Proton Pump Inhibitor on Gleevec® in Healthy Volunteers

This is a research study that will investigate the effects of proton pump inhibitors (often used to treat stomach upset) on Gleevec® (a drug that is FDA-approved to treat some types of ca...

A Short Course of Neoadjuvant Gleevec (Imatinib Mesylate) in Dermatofibrosarcoma Protuberans

This research study is for patients who have been diagnosed with a rare type of tissue tumor (DFSP). Surgery has been recommended to treat this cancer. Surgery cures most patients of ...

PubMed Articles [1 Associated PubMed Articles listed on BioPortfolio]

2'-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer.

Breast cancer (BC) is the most common cancer in women. Estrogen, epidermal growth factor receptor 2 (ERBB2, HER2), and oxidative stress represent critical mechanistic nodes associated with BC. RLIP76 ...

Advertisement
Quick Search
Advertisement
Advertisement

 

Relevant Topics

Pediatrics
Pediatrics is the general medicine of childhood. Because of the developmental processes (psychological and physical) of childhood, the involvement of parents, and the social management of conditions at home and at school, pediatrics is a specialty. With ...

Bioinformatics
Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...

Leukemia
Leukemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases. In turn, it is part of the even broader grou...


Drugs and Medication Quicklinks


Searches Linking to this Drug Record

Table 3 Adverse Reactions Reported in Other CML Clinical Trials (≥10% of All Patients in any Trial)(1)
Myeloid Blast Crisis
(n= 260)
Accelerated Phase
(n=235)
Chronic Phase, IFN Failure
(n=532)
% % %
Preferred Term All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4
Fluid Retention 72 11 76 6 69 4
-Superficial Edema 66 6 74 3 67 2
-Other Fluid Retention Reactions (2) 22 6 15 4 7 2
Nausea 71 5 73 5 63 3
Muscle Cramps 28 1 47 0.4 62 2
Vomiting 54 4 58 3 36 2
Diarrhea 43 4 57 5 48 3
Hemorrhage 53 19 49 11 30 2
- CNS Hemorrhage 9 7 3 3 2 1
- GI Hemorrhage 8 4 6 5 2 0.4
Musculoskeletal Pain 42 9 49 9 38 2
Fatigue 30 4 46 4 48 1
Skin Rash 36 5 47 5 47 3
Pyrexia 41 7 41 8 21 2
Arthralgia 25 5 34 6 40 1
Headache 27 5 32 2 36 0.6
Abdominal Pain 30 6 33 4 32 1
Weight Increased 5 1 17 5 32 7
Cough 14 0.8 27 0.9 20 0
Dyspepsia 12 0 22 0 27 0
Myalgia 9 0 24 2 27 0.2
Nasopharyngitis 10 0 17 0 22 0.2
Asthenia 18 5 21 5 15 0.2
Dyspnea 15 4 21 7 12 0.9
Upper Respiratory Tract Infection 3 0 12 0.4 19 0
Anorexia 14 2 17 2 7 0
Night Sweats 13 0.8 17 1 14 0.2
Constipation 16 2 16 0.9 9 0.4
Dizziness 12 0.4 13 0 16 0.2
Pharyngitis 10 0 12 0 15 0
Insomnia 10 0 14 0 14 0.2
Pruritus 8 1 14 0.9 14 0.8
Hypokalemia 13 4 9 2 6 0.8
Pneumonia 13 7 10 7 4 1