Transcript Side Effects Management

Management of
Side Effects
Monica Davey, RN BSN MEd MBA
Clinical Research Nurse Coordinator
Sarcoma Program
Fox Chase Cancer Center
Philadelphia, PA
Imatinib Mesylate
(Gleevec, STI571, CGP57148B)
• Potent inhibitor of ABL, BCR-ABL, PDGFR and KIT tyrosine kinases
S0033
Percent with Maximum Toxicity at or above
Listed Grade by Dose
120
100
80
400 mg
800 mg
P <.0001
60
40
20
0
1
2
3
4
5
S0033
Percent with Toxicity ≥ Grade 3
400 mg/day
(n=224)
800 mg/day
(n=234)
Hematologic
Gastrointestinal
Cardiovascular
Hemorrhage
Flu-like Symptoms
Pain
Dermatologic
Infection
Liver
Lung
18.2
12.3
5.2
4.6
3.7
7.4
2.8
3.4
2.5
1.5
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
Imatinib Mesylate Side Effects
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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
Imatinib Mesylate Side Effects
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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.
Management of Fluid Retention
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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.
Management of Fluid Retention
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With clinically significant grade 2 edema
(symptomatic requiring therapy), you may need
to hold Gleevec until the fluid retention resolves
to grade 1 (asymptomatic).
Gastrointestinal Side Effects
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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.
Gastrointestinal Side Effects
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Dyspepsia can be managed symptomatically
with antacids or proton pump inhibitors.
Flatulence occurs in about 23% of patients.
Many patients use Simethicone.
Imatinib Mesylate Side Effects
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Fatigue occurs in 38% of patients.
May be self limiting.
Myalgias
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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.
Skin Rash
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Occurs in 38% of patients.
Rash may be with or without pruritis or
pustules.
Usually resolves with topical or oral
diphenhydramine hydrochloride (Benadryl).
Pain
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Abdominal pain and cramping occurs in 37% of
patients.
Headache occurs in 35% of patients.
Treatment is symptomatic.
Hemorrhage
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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.
Hemorrhage Continued
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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.
Hematologic Side Effects
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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 %)
Hematologic Side Effects
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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.
Dose Adjustments for Neutropenia
and Thrombocytopenia
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Absolute neutrophil
count (ANC) < 1.0
and/or platelets <50.
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Stop Imatinib Mesylate until
ANC is > 1.5 and platelets
are > 75.
Resume treatment at ordered
dose.
If recurrence of ANC < 1.0
and/or platelets < 50, repeat
first step, then resume
treatment with a dose
reduction.
Hepatotoxicity
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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.
Hepatotoxicity continued
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It is suggested that Acetaminophen-containing
products be avoided.
Underlying liver dysfunction may increase the
risk for liver toxicity.
Drug-Drug Interactions
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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.
Drug-Food Interactions
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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.
Special Populations
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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.
Late Side Effects
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Thin skin
Easy bruising
Hair thinning with lack of texture
Sub-conjunctival hemorrhages
Fatigue
Anemia
Gleevec in Summary
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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
Sutent/SU011248
Multi-targeted tyrosine kinase inhibitor
Sutent Side Effects
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Fatigue most common (56%)
Rash/dermatitis
Discoloration of skin
Hypertension
Arthralgias
Headache
Edema
Gastrointestinal Side Effects
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Nausea
Vomiting
Diarrhea
Altered taste
Anorexia
Abdominal pain/distention
Dyspepsia
Stomatitis
Hematological Side Effects
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Neutropenia
Thrombocytopenia
Anemia
SU011248 Side Effects
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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
AMN 107 Nilotinib
A Synthetic Second Generation
Multi-targeted Tyrosine kinase
Inhibitor
AMN 107 Side Effects
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Nausea/vomiting
Thrombocytopenia
Pyrexia
Anemia
Headache
Cough
AMN 107 Side Effects
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Diarrhea
Fatigue
Rash
Dyspnea
Peripheral edema
Arthralgias
Elevated transaminases
RAD001 Side Effects
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Headache
Hyperlipidemia
Neutropenia
Thrombocytopenia
Summary
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SU011248 /Sutent is currently available for
Gleevec resistant GIST
Other drugs are currently in development
RAD001, AMN 107
New Set of Challenges With
Oral Therapies
Patient compliance
 Safe administration
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 Side
effect monitoring
 Drug and food interactions
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Medication costs\Insurance issues
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Availability
Oral chemotherapy can be
effective only if patients adhere
to its administration schedule
Questions