Download Managing Gleevec Side Effects

Managing Gleevec Side Effects
Presented by: The Life Raft Group
February 8, 2006
Special thanks to Jonathan Trent, M.D., Ph.D.,
Department of Sarcoma, MD Anderson Cancer
Center, for his helpful comments.
(Dr. Trents’ personal observations are noted in blue)
Gleevec Side Effects
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Despite publicity to the contrary, Gleevec can
have significant side effects
 But side effects do tend to get better over time
• Could be related to the theory of Gleevec drug levels
falling over time (levels can decrease 40% over 12
months)
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Being able to manage Gleevec side effects is a
key step that allows patients to take their Gleevec
as prescribed
Patient/Doctor Communications
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It is important for patients to report side effects
and discuss their management with their doctor
 The material presented here is for information
purposes only
• It is not a substitute for talking to your doctor
Common Side Effects
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Fatigue
Anemia
Nausea or vomiting
Diarrhea
Edema/fluid retention
Cramps
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Rash/skin problems
 Joint pain
 Eyes
• Itchy, watery eyes
• Bleeding (less often)
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Sensitive to sunlight
Less Common Side Effects
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Bleeding
Elevated liver function tests (detected on a blood test)
Kidney problems
Serious edema (fluid retention)
Hematological (blood counts) including
neutropenia (low neutrophil counts)
Hypothyroidism (low thyroid function)
Dose-related side effects
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Edema
 Fatigue
 Anemia
 Rash
• -however female gender may be a higher risk factor
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Bleeding
 Nausea
 Diarrhea
 Hematological effects (effects on blood counts)
 These are worse in patients started at 800mg compared to
patients started at 400mg. Starting at 400mg for 4 weeks
then increasing to 800 mg may help patients tolerate the
higher dose. It does in my experience and is supported by
a study at ASCO (Dileo et al, ASCO 2005)
Fatigue/anemia-the number 1 complaint
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KIT signaling is important to the formation of blood cells,
including red blood cells
• Suppression of normal blood cell formation is estimated to be
minor, in the range of 10% to 20%
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Sutent may suppress blood counts more as it also inhibits
FLT-3, another important growth factor for blood cells
Anemia can be caused by:
• Bleeding (which can be undetected)
• Iron deficiency and B12 deficiency- both common in patients who
have had stomach surgery. These can all be tested for by a doctor.
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Some report fatigue a few hours after taking Gleevec
Growth Factors affecting Hematopoiesis
AMGEN®
Fatigue/anemia solutions
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Some patients benefit from Procrit/Aranesp (EPO) shots
• These growth factors can stimulate red blood cell production
• Some patients require a higher dose
• EPO increases hemoglobin levels in most anemic GIST patients
who have not progressed under imatinib treatment, but not in
refractory GIST patients*
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We have anecdotal reports of benefit from iron
supplementation (in some patients?)
• Patients should talk to their doctor before taking iron on their own
• There are IV formulations if patients are nauseated. I use IV iron all
the time.
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Increased rest helps some patients
B12 may need to be given as an injection like EPO since
pills may not be absorbed if some of the stomach is
missing.
*ASCO 2004-abstract 9046
Nausea
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Likely caused by local irritant properties of the drug
 Take Gleevec with a meal and a large glass of water
 Spread out Gleevec during the meal, i.e., eat a little, take
a Gleevec, eat a little more, take another Gleevec, etc.
 In severe/continuing cases, your doctor might split your
dose. This has reduced nausea and other side effects in
some patients
 Anti-nausea medications may help (Compazine or Zofran)
 Patients with a history of esophagitis or hiatal hernia
should take Gleevec at least 2 hours before bedtime
 Patient-reported solutions
• “Medicinal chocolate”
• “Sweet potato”
Diarrhea solutions
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May be related to inhibition of KIT in ICC or due to
local irritant effect of the drug
 Usually manageable with antidiarrheal meds, i.e.,
Imodium
 Other “Patient solutions” (talk to your doctor first)
• Denatured tincture of opium (DTO) …10-12 drops in
water every four hours
• ½ pint of flavored or plain yogurt at bedtime
• Abnormal intestinal flora? Improved with Amoxicillin.
• Bioflorin Giuliani capsules during antibiotic treatment
Rash/skin problems
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More common in females and at higher doses
Varies from mild to severe
Varies in cause and treatment:
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Shingles (treated with antiviral, steroids makes it worsen)
True Gleevec drug rash (most common)
Heat sensitivity
Fungal infection (ringworm, steroids may make it worsen)
Cellulitis (requires an antibiotic)
May require referral to a dermatologist
Rashes are the most common side effect requiring
permanent discontinuation of Gleevec
Rash/skin problems-2
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Most cases are mild and self-limiting
• Treatable with antihistamines or topical steroids
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Moderate cases
• Oral steroids (prednisone) (depending on cause)
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Severe cases (depending on cause)
• Immediate discontinuation of Gleevec and systemic
steroids
• Restart Gleevec with prednisone and taper off the
prednisone over several weeks
Mild rash/itching
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Patient reported remedies
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Neutrogena anti itch lotion
Florisone
Zyrtec
Sarna cream
Gold Bond medicated anti-itch cream
For neuropathy (nerve pain)
• Neurontin (provides pain relief, but does not prevent
nerve damage)
Edema/fluid retention
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Dose-related
Periorbital (around the eyes) edema is common
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Typically worse in the morning
Some patients report limiting salt intake may help
Topical phenylephrin 0.25% may help
Antihistamine like claritin or zyrtec
Lower-extremity edema is also seen
• Lasix with potassium supplements is a common treatment
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Generalized/severe fluid retention is rare
• Potentially life threating!
• Pulmonary, pleural or pericardial effusion, ascites, anasarca, and
cerebral edema.
Edema/fluid retention-2
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Risk factors
• Female
• Over 65
• History of cardiac or renal problems
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In older patients with a history of cardiac or renal
impairment, starting Gleevec at a lower dose may be
advisable
 Patients should be monitored for rapid weight gain
 Severe fluid retention is usually treated by:
• Stopping Gleevec
• Control edema with diuretics
• Restart Gleevec, possibly at a lower dose while maintaining or
increasing diuretic (may need to start at a very low dose, ie 50 mg
a day, and increase to 400 mg over 6-8 weeks. I’ve done this with
several patients)
Cramps/bone and joint pain
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Cramps in hands, feet, calves and thighs
Calcium and magnesium levels may drop over
time while taking Gleevec
Supplementation with calcium and magnesium
may improve symptoms. Vitamin D helps absorb
calcium.
Quinine or quinine water may also be helpful
Patient reported remedies
• Soma (carisoprodol) and quinine sulfate
• Gatorade/powerade
Eyes
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Bleeding in the eyes may occur several times a
year or more
• Usually looks worse than it is
• Usually affects only one eye at a time
• Usually clears up in a few days without any specific
treatment
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Itchy, teary eyes I treat with artificial tears 2 drops
each eye 4 times a day
Sensitivity to sunlight
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KIT signaling is important in melanocytes
 Melanocytes produce the pigment in the skin
 Gleevec may make skin more susceptible to
sunburn by inhibition of KIT signaling in
melanocytes
 Limit sun exposure, but no not completely avoid
the sun
• Sunlight is the best source of Vitamin D!
Bleeding
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An uncommon, but potentially serious side effect
 Observed in GIST patients in the pre-Gleevec era
 May bleed into the GI tract
• Liver tumors may also bleed
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Not observed in the adjuvant Gleevec trials
• Related more to GIST than to Gleevec?
AND/OR
• Related to Gleevec’s effects on some tumors?
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Dose related, some patients (on higher doses)
with bleeding may benefit from a dose reduction
 One theory is that tumors that are rapidly
shrinking (from Gleevec) may rip blood vessels
Elevated liver enzymes
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Rare side effect-may have several different
causes
 One CML patient died from liver failure
• Patient was taking a fairly high dose of Tylenol for a
month prior to starting Gleevec (but dose was below
the maximum dose)
• Patient was also taking Diflucan (which can cause liver
problems)
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Some LRG patients report that taking
pomegranate juice resulted in a reduction of liver
enzymes
Elevated liver enzymes- autoimmune
hepatitis
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At least three LRG patients (and others in the
literature) developed drug-induced autoimmune
hepatitis while taking Gleevec
• This was not always diagnosed promptly
• Responds to steroid therapy (prednisone) and imuran
(an immunosuppressive agent)
• Blood tests for ANA antibody may help detect this, but
this was only mildly elevated in some patients
– Liver biopsies might also be recommended
• Might it be reasonable to try a course of prednisone without the
biopsy?
• ALT (and to a lesser extent AST) may be most affected
enzymes
Kidney problems
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Reduced kidney function has been reported (rare)
 These cases have usually been related to
prolonged use of Gleevec
• A dose reduction may be needed
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Do multiple CT scans with contrast contribute to
this problem?
• Possibly, particularly in patients who are not drinking
adequate fluids and are dehydrated
Neutropenia
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Lowered count of neutrophils (below 1.0)
 A rare side effect of Gleevec
 Tends to decrease over time
 May require dose interruption and/or growth factor
support
• Growth factor support can be used to prevent dose
reduction or interruption. The growth factor support is
not always permanent.
Hypothyroidism
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Sutent may result in hypothyroidism
• Very rare with Gleevec
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Patients taking these drugs should have thyroid
function monitored especially if taking Sutent
 Can be corrected with thyroid hormone
supplementation
Gleevec or GIST?
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Although Gleevec causes side-effects, so does a
growing tumor
 Telling the difference between the effects of the
tumor and the side-effects of Gleevec is not
always easy