Management of Side Effects

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Management of Side Effects

• Monica Davey, RN BSN MEd MBA
• Clinical Research Nurse Coordinator
• Sarcoma Program
• Fox Chase Cancer Center
• Philadelphia, PA

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Imatinib Mesylate(Gleevec, STI571, CGP57148B)

• Potent inhibitor of ABL, BCR-ABL, PDGFR and KIT
  tyrosine kinases

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S0033Percent with Maximum Toxicity at or above
Listed Grade by Dose
120
100
80
P lt.0001
60
40
20
0
1
2
3
4
5
5
S0033
Percent with Toxicity Grade 3
400 mg/day (n224)
800 mg/day (n234)
18.2 12.3 5.2 4.6 3.7 7.4 2.8 3.4 2.5 1.5
Hematologic Gastrointestinal Cardiovascular Hemorr
hage Flu-like Symptoms Pain Dermatologic Infection
Liver Lung
20.7 14.8 12.7 9.9 8.0 7.7 7.7 4.6 3.7 3.4
Any Toxicity
35.8
51.8
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Imatinib Mesylate Side Effects

• Medication is well tolerated
• Majority of patients (90-100) experience adverse
  effects at some time most being mild to moderate
  grade
• Grade 3 and 4 toxicity is seen in only one out of
  five patients

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Imatinib Mesylate Side Effects

• Fluid retention is the most common side effect.
• Superficial edema occurs in periorbital and
  extremity areas. Reported in about 60 of
  patients.
• Pleural effusion or ascites is uncommon occurring
  in about 2 of all patients.
• Grade 3 or 4 edema is uncommon reported in 5 of
  patients.

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Management of Fluid Retention

• Weigh yourself twice a week and notify your care
  provider if you gain more that five pounds from
  baseline.
• Management of edema may be accomplished with
  diuretic usage.
• Low salt diet is encouraged.

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Management of Fluid Retention

• With clinically significant grade 2 edema
  (symptomatic requiring therapy), you may need to
  hold Gleevec until the fluid retention resolves
  to grade 1 (asymptomatic).

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Gastrointestinal Side Effects

• Gleevec is known to be a GI irritant.
• This is less if you take the pills with meals, a
  large glass of water, and remain upright for
  about an hour.
• It should not be taken with grapefruit containing
  products or caffeine, as they may interfere with
  drug metabolism. Caffeine should also be avoided
  for one hour around ingestion.

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Gastrointestinal Side Effects

• Dyspepsia can be managed symptomatically with
  antacids or proton pump inhibitors.
• Flatulence occurs in about 23 of patients. Many
  patients use Simethicone.

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Imatinib Mesylate Side Effects

• Fatigue occurs in 38 of patients.
• May be self limiting.

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Myalgias

• Muscle cramps occurring in the hands, feet, and
  or legs occurs in 41 of patients.
• These are usually occasional in nature.
• May be increased with prolonged therapy.
• May be mitigated by increasing oral fluid intake
  on a regular basis.
• Quinine can be effective for treatment.

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Skin Rash

• Occurs in 38 of patients.
• Rash may be with or without pruritis or pustules.
• Usually resolves with topical or oral
  diphenhydramine hydrochloride (Benadryl).

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Pain

• Abdominal pain and cramping occurs in 37 of
  patients.
• Headache occurs in 35 of patients.
• Treatment is symptomatic.

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Hemorrhage

• Bleeding is noted in 17 of patients.
• This can be severe occurring as tumor hemorrhage,
  GI tract hemorrhage or one reported case of
  cerebral hemorrhage.
• Less severe bleeding has been reported such as
  subconjunctival or guaiac-positive stools.
• May be increased in CML patients with abnormal
  bone marrow function and decreased platelets.

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Hemorrhage Continued

• No therapeutic anticoagulation with warfarin
  (Coumadin) was permitted in patients that
  participated in the clinical trials since
  warfarin is metabolized through the CYP450 system
  and GI bleeding may occur with Gleevec.
  Low-molecular weight heparin (Lovenox) was
  utilized. Mini-dose Coumadin was permitted for
  prophylaxis of central venous catheter
  thrombosis. These patients were closely monitored.

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Hematologic Side Effects

• Anemia (94), Neutropenia (43), and
  thrombocytopenia (23) are common occurrences in
  GIST patients treated with Gleevec.
• Grade 3 or 4 hematological toxicities were
  observed infrequently. (1 7 )

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Hematologic Side Effects

• No neutropenic fever or septic complications were
  reported.
• Complete blood counts are usually performed
  weekly for the first month, biweekly for the
  second month, and then every three months
  thereafter as clinically indicated.

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Dose Adjustments for Neutropenia and
Thrombocytopenia

• Absolute neutrophil count (ANC) lt 1.0 and/or
  platelets lt50.

• Stop Imatinib Mesylate until ANC is gt 1.5 and
  platelets are gt 75.
• Resume treatment at ordered dose.
• If recurrence of ANC lt 1.0 and/or platelets lt 50,
  repeat first step, then resume treatment with a
  dose reduction.

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Hepatotoxicity

• Liver function studies are monitored before
  initiation of treatment and monthly or as
  clinically indicated.
• Elevation of AST and ALT was observed in 50 and
  34 of patients respectively.
• Grade 3 or 4 elevations in bilirubin occurred in
  about 3 of patients. Hepatic metastases were
  present in those patients observed.

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Hepatotoxicity continued

• It is suggested that Acetaminophen-containing
  products be avoided.
• Underlying liver dysfunction may increase the
  risk for liver toxicity.

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Drug-Drug Interactions

• Imatinib can increase exposure to co medications
  that are substrates of CYP3A4.
• Co administration of imatinib with inhibitors of
  CYP3A4 may increase imatinib exposure.
• Systemic exposure to substrates of CYP2D6 is
  expected to be increased when co-administered
  with Gleevec.
• Check with your care provider before beginning
  any new medications.

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Drug-Food Interactions

• Grapefruit and other foods may alter
  pharmacokinetics.
• Do not take eat Grapefruit or ingest grapefruit
  juice while taking Gleevec.
• Avoid Caffeinated beverages for one hour around
  Gleevec ingestion.

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Special Populations

• Reliable birth control is to be utilized.
• The efficacy of Gleevec was similar in older and
  younger patients.
• Safety and effectiveness in pediatric patients
  have not been established.

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Late Side Effects

• Thin skin
• Easy bruising
• Hair thinning with lack of texture
• Sub-conjunctival hemorrhages
• Fatigue
• Anemia

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Gleevec in Summary

• Medication is well tolerated
• Majority of patients (90-100) experience adverse
  effects at some time, most being mild to moderate
  grade
• Grade 3 and 4 toxicity are seen in only one out
  of five patients

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Sutent/SU011248
Multi-targeted tyrosine kinase inhibitor
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Sutent Side Effects

• Fatigue most common (56)
• Rash/dermatitis
• Discoloration of skin
• Hypertension
• Arthralgias
• Headache
• Edema

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Gastrointestinal Side Effects

• Nausea
• Vomiting
• Diarrhea
• Altered taste
• Anorexia
• Abdominal pain/distention
• Dyspepsia
• Stomatitis

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Hematological Side Effects

• Neutropenia
• Thrombocytopenia
• Anemia

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SU011248 Side Effects

• Generally acceptable and manageable on the 4/2
  schedule
• Mostly reversible upon discontinuation of
  treatment
• Degree of severity has been correlated with
  higher drug exposure

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AMN 107 Nilotinib

• A Synthetic Second Generation
• Multi-targeted Tyrosine kinase Inhibitor

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AMN 107 Side Effects

• Nausea/vomiting
• Thrombocytopenia
• Pyrexia
• Anemia
• Headache
• Cough

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AMN 107 Side Effects

• Diarrhea
• Fatigue
• Rash
• Dyspnea
• Peripheral edema
• Arthralgias
• Elevated transaminases

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RAD001 Side Effects

• Headache
• Hyperlipidemia
• Neutropenia
• Thrombocytopenia

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Summary

• SU011248 /Sutent is currently available for
  Gleevec resistant GIST
• Other drugs are currently in development RAD001,
  AMN 107

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New Set of Challenges With Oral Therapies

• Patient compliance
• Safe administration
• Side effect monitoring
• Drug and food interactions
• Medication costs\Insurance issues
• Availability

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Oral chemotherapy can be effective only if
patients adhere to its administration schedule
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Questions