Download Managing Treatment Related Side Effects - CML

Managing Treatment Related
Side Effects
Objectives
Review common side effects of tyrosine kinase
inhibitors used to treat CML
Provide practical suggestions for management of side
effects
Discuss drug-drug interactions
Discuss challenges of long-term treatment and
strategies to promote treatment adherence
TKI Side Effects
Side effects vary from person to person.
Individuals may tolerate one drug much
better than another.
Side effects generally increase as dose
increases.
Management of side effects essential to
encourage compliance or adherence.
Imatinib Blood Level Testing
Excessive side effects may occur if
person metabolizes imatinib slowly.
Inadequate response if person is a fast
metabolizer and imatinib levels low.
Can help evaluate potential drug
interactions that may increase or
decrease imatinib blood levels.
Imatinib Blood Levels
Imatinib blood levels reported in ng/ml.
Trough level, taken 22-24 hours after last
dose, lowest blood level of the day.
Based on data obtained thus far, the
minimum plasma trough concentration goal
for imatinib is approximately 1000 ng/mL,
somewhat higher acceptable if tolerated.
For more information, please refer to Peng B et al. J Clin Oncol. 2004;22:935942; Shmidli H et al. Br J Clin Pharmacol. 2005;60:35-44;Blasdel C et al.
imatinib (Glivec)® (imatinib mesylate)
Imatinib to Nilotinib, Change in
Dosing from with Food to Fasting
Imatinib (Glivec) is to be taken with food, once a day
unless on 800 mg when taken as 400 mg twice a
day.
Nilotinib (Tasigna) is to be taken FASTING, every 12
hours:
Dose #1: Morning, before breakfast.
Dose # 2 Evening, at least 2 hours after eating, then
wait at least one hour before eating again.
Evening dose more difficult timing for most, may
require lifestyle adjustment.
Nilotinib (Tasigna) Dosing
Example
Morning dose
Fasting overnight
Nilotinib 07.00
Breakfast after 08.00
Evening dose
NO food after 17.00
Nilotinib at 19.00
Dinner after 20.00
Myelosuppression-low blood counts
Ph-positive
Ph-negative
TKI
In untreated CML, the majority of
blood cells are
Ph+ cells.
TKI eliminates Ph+ cells.
Few normal cells left; this
therapeutic effect may
cause very low blood
counts.
Grade 3/4 Abnormalities in Clinical Studies
Imatinib
Dasatinib
Nilotinib
Neutropenia (low
neutrophils) Grade
3-4
17-36% CP
59% AP
Thrombocytopenia
(low platelets)
9-21% CP
44% AP
4-7% CP
41% AP
46% CP
68% AP
41% CP
71 %AP
18% CP
55% AP
28% CP
37% AP
28 % CP
37% AP
8% CP
23% AP
Anemia (low red
blood cells, low
hemoglobin)
CP=chronic phase; AP=accelerated phase.
Imatinib: CP=Gr 3/4 newly diagnosed and chronic phase Ifn (interferon) failure; Gleevec Prescribing
Information Nov 2007.
Sprycel Prescribing Information, Nov 2007; Tasigna, Prescribing Information, Oct 2007
Neutropenia
If absolute neutrophil count (ANC) is less than 500,
at higher risk for infections.
If ANC less than 1000, usually temporarily hold
therapy; in patients with advanced disease consider
growth factors, G-CSF (filgrastim) or the long acting
form, pegfilgrastim so can stay on TKI.
Infections not the problem they are with traditional
IV chemotherapy.
Monitor blood counts weekly or more if neutropenic.
Thrombocytopenia-low platelets
Can cause excessive bruising or bleeding.
No effective drug currently available.
With imatinib may take 3 weeks for full effect
on platelets, faster and more pronounced
drops with dasatinib.
If less than 50,000/mm3(50 x 10^9/L), hold
therapy and allow counts to recover.
With accelerated or blast crisis may allow
patients to go down to platelets 20,000/mm3
(20 x 10^9/L); transfusions often needed in
blast crisis.
Anemia-low red cell counts
Anemia can cause fatigue, headaches,
shortness of breath.
Can treat with ESA’s (erythropoietic
stimulating agents) such as erythropoietin or
darbepoetin.
May need ESA on an ongoing basis to keep
hemoglobin (Hgb) up; don’t exceed Hgb 12,
use less as counts improve.
Use of ESA’s now controversial due to
potential adverse effects and high cost.
Anemia continued
Adequate iron also necessary, check ferritin level,
erythropoietin prescribing information recommends
ferritin level of at least 100.
Oral iron supplements may be needed; iron also well
absorbed from red meat.
Recent study found intravenous iron can be helpful,
use if oral supplements not tolerated. (NCI Cancer Bulletin,
vol. 5/no. 8, April 15, 2008).
Check B12 and folic acid levels.
Transfusions used in extreme cases.
TKI dose decrease may be necessary.
Non-Hematological Side
Effects
Imatinib (Glivec) Common Side Effects
(all grades, newly diagnosed)
Edema (fluid retention)
61.7%
Nausea 49.5%
Muscle cramps 49.2%
Musculoskeletal pain
47%
Diarrhea 45.4%
Prescribing Information, Novartis
November 2007
Rash 40.1%
Fatigue 38.1%
Headache 37%
Abdominal pain 36.5%
Vomiting 22.5%
Imatinib Serious Side Effects
Severe edema, including pleural and pericardial
effusions 2-11%
Severe CHF (congestive heart failure) and left
ventricular dysfunction, <1%
Hepatotoxicity (liver) 5%, <1% discontinued
treatment
Hemorrhage 1.8 % in CP, 11% AP, 19% BC
Other severe rare events occur
Sprycel (dasatinib) Common Side
Effects (All Patients, All Grades)
Fluid retention
(edema) 37%
Diarrhea 31%
Headache 24%
Nausea 22%
Pleural effusion 22%
Rash 22%
Fatigue 21%
Hemorrhage 21%
Dyspnea 20%
Musculoskeletal pain
14%
Dasatinib Prescribing Information,
Bristol-Myers Squibb, November
2007.
Dasatinib Severe Effects
Bleeding and thrombocytopenia (platelet dysfunction in
vitro), platelets can drop very quickly, hemorrhage
possible, monitor carefully.
Fluid retention can be severe, including pleural or
pericardial effusion. If develop dyspnea (shortness of
breath), do chest x-ray. May occur months into therapy.
Side effects less severe at 100 mg once a day dose vs. 70
mg twice a day.
Possible prolongation of QTc interval (heart rhythm
change).
Nilotinib (Tasigna) Common Side Effects
Rash 33%
Pruritis (itching)
29%
Nausea 31%
Headache 31%
Fatigue 28%
Diarrhea 22%
Constipation 21%
Vomiting 21%
Arthralgias (joint
aches/pains) 18%
Cough 17%
Nilotinib Prescribing Information,
October 2007.
Nilotinib (Tasigna) Other
Tasigna can affect the electrical activity of
the heart by prolonging the QT interval, time
it takes for ventricle to repolarize.
Do not use in patients with long QT
syndrome.
Must correct low potassium, (hypokalemia),
low magnesium (hypomagnesemia).
Sudden deaths reported (0.6%), may have
been cardiac related.
Tasigna (nilotinib) Liver
Use with caution in patients with hepatic
(liver) impairment.
Liver enzyme and bilirubin elevations are
often transient, resolve with short treatment
break.
Elevated lipase and amylase may occur.
Pancreatitis has also occurred.
Hair
Hair loss, thinning hair, reported for all
three TKI’s; often has other causes.
Imatinib--other variable effects: Thicker
hair, darker hair, less gray.
Others report more gray but also
everyone on imatinib getting older!
Salon products as desired.
Eyes
Swelling around the eyes (periorbital edema),
usually worst in morning, very common on
imatinib.
Excessive tearing (imatinib) or dry eyes.
Bleeding in whites of eyes (subconjunctival
hemorrhages).
Blurry vision, particularly with imatinib,
probably related to tearing and changes in
fluid balance in lens.
Periorbital Edema
Periorbital Edema
Eyes--Management
Avoid high sodium (salt) foods.
Mild diuretic if necessary, e.g.
combination of hydrochlorothiazide and
triamterene which conserves potassium.
Plastic surgery in severe cases.
Eyes--Management
Artificial tears, plain
Prescription steroid eye drops
Subconjunctival hemorrhages (bleeding into
whites of eyes). No treatment needed
Prevention: Avoid straining, heavy lifting.
Diet with plenty of fruits and vegetables
(bioflavonoids may decrease platelet fragility)
Fluid Retention (Edema)
Commonly in hands, feet, legs, hands,
occasionally around heart or lungs.
Dasatinib--pleural (lung) effusion 22%
incidence all grades, less common with 100
mg once daily, ~10%.
For pleural effusion may use diuretics,
steroids, drainage of fluid (thoracentesis) if
necessary, dose interruption and decrease.
Nausea and Vomiting
Important to take imatinib (Glivec) after a substantial
meal; nilotinib (Tasigna) on an empty stomach;
dasatinib with or without food.
Take imatinib with at least 240 mL of water; eat
additional bland food if mild nausea.
May help to divide the imatinib dose, e.g. 300 and
300 mg. taken twice a day.
Anti-nausea drugs available if necessary,
ondansetron, prochlorperazine. Take 1-2 hours
before taking TKI.
Heartburn
More common in patients with a history of
dyspepsia or gastroesophageal reflux (GERD).
Prevention: avoid overeating, spicy foods
Decrease caffeine and alcohol.
Elevate head of bed approximately 15 cm
using blocks under legs of bed, not pillows.
Remain upright sitting or standing 1-2 hours
after taking TKI.
Heartburn continued
Imatinib-consider H2 blockers e.g. famotidine, and
proton pump inhibitors (PPI’s), omeprazole or
esomeprazole, lowest dose possible.
Use of H2 blockers or proton pump inhibitors with
dasatinib not recommended. Use antacids instead.
Antacids should be given 2 hours prior to or 2 hours
after imatinib or dasatinib.
Antacids, H2 blockers, or proton pump inhibitors
NOT recommended with nilotinib.
Diarrhea
Increased volume and soft stools common
with imatinib.
Diarrhea may occur with all 3 TKI’s.
Avoid sorbitol, mannitol, maltitol (common
ingredients in “sugar-free” foods and gum).
Anti-diarrheal medication: loperamide. May
be helpful to take ½ or one tablet daily to
PREVENT diarrhea.
Diarrhea
Psyllium seed--increased fiber.
Lactase enzyme supplements with milk
products if sensitive. Lactose
intolerance may occur temporarily after
gastrointestinal illness. (Nilotinib and
dasatinib contain lactose).
Acidophilus to restore normal gut
bacteria, particularly after antibiotics.
Constipation
Extremely rare with imatinib, can occur
with dasatinib and nilotinib.
Increase fruits and vegetables in diet.
Drink adequate oral fluids since
dehydration worsens constipation.
Stool softeners.
Psyllium seed or other fiber.
Mild laxatives.
Muscle Cramps
Most common with imatinib, usually in
hands, feet, calves of legs but can occur
anywhere.
Often helped by calcium, take in divided
doses of 500 mg. two to three times a day.
Avoid taking at same time as TKI.
Calcium citrate more easily absorbed than
calcium carbonate which is also an antacid.
Potassium supplements as needed, especially
if on diuretics.
Muscle Cramps
Tonic water (quinine) very effective for
some.
Adequate hydration important in hot
weather.
Check electrolytes: calcium, potassium,
phosphorus and magnesium.
Muscle, Joint, Bone Pain
May be severe when patients first start
therapy, occurs with all 3 TKI’s.
Usually resolves within days to weeks,
but may persist.
May be relieved by non-steroidal antiinflammatory drugs.
Rarely short-term opioids are needed.
Muscle and Joint Pain
Can be difficult to treat when
persistent and require change to
different TKI because individuals vary in
their sensitivity to the individual TKI’s.
Check creatine kinase if severe.
Consider possible drug interactions, e.g.
simvastatin.
Bone Pain
Recent study used pregabalin 75-300
mg twice daily.
Patients reported significantly lower
pain scores, improved mood, reduced
sleep disturbance and improved qualityof-life.
F. Iuliano et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 18007).
Skin Problems--Rash
Occurs with all 3 TKI’s.
Topical hydrocortisone creams.
Stronger steroid creams, e.g. triamcinolone.
For severe cases, hold drug and use oral prednisone
to control rash, then reinstitute TKI gradually,
starting with lower dose. Sometimes rash is a onetime occurrence.
Antihistamines.
Keep skin moisturized.
Mild rashes may be intermittent.
Imatinib
Associated Skin
Rash
Other Skin Problems
Dry skin, itching—apply moisturizing lotion after
bathing; baking soda in bath water, hydrocortisone.
Imatinib-Fragile skin that tears easily, usually after
long-term use. Protect skin with clothing.
Imatinib-Changes in skin pigmentation, lighter, more
noticeable in dark skinned people.
Sun sensitivity-use sunscreen and protective clothing,
hats. Sunburn with imatinib can be severe.
Fatigue
Occurs with all 3 drugs.
Correct anemia if present.
Check thyroid function.
Moderate regular exercise, starting very gradually,
often helpful.
Rest before exhaustion, otherwise takes a long time
to recover. May need daily nap.
Fatigue continued
Pace and prioritize activities. Counseling,
stress management, meditation, yoga can be
helpful.
Fatigue often improves but may persist.
Treat depression and anxiety which can
contribute to fatigue.
May be associated with memory loss,
difficulty concentrating.
Weight Gain
Weight loss common before CML diagnosis.
Metabolic rate drops once out of control
white cell production stopped, weight gain
then likely.
Some patients report increased appetite on
imatinib.
To avoid weight gain, decrease calorie intake
and get more exercise.
Decrease sodium (salt) intake to minimize
fluid retention.
Drug Interactions
Imatinib, dasatinib, and nilotinib metabolized via
CYP3A4 pathway, inhibitors.
CYP3A4 inhibitors may INCREASE TKI plasma
concentration (blood level), Cmax and AUC.
CYP3A4 inducers may DECREASE TKI plasma
concentration (blood level), Cmax and AUC.
If one of these drugs must be used, can increase or
decrease dose of TKI accordingly, but usually
possible to instead substitute another drug.
Drug Interactions Examples
Imatinib, Dasatinib, Nilotinib
Increase Plasma
Concentrations TKI’s
Ketoconazole
Itraconazole
Erythromycin
Clarithromycin
Decrease Plasma
Concentrations TKI’s
Dexamethasone
Phenytoin
Carbamazepine
Phenobarbital
Rifampin
Rifapentine
St. John’s Wort
Plasma Concentrations
Altered by TKI’s
Simvastatin
Cyclosporine
Pimozide
Triazolobenzodiazepines
Dihydropyridine calcium
channel blockers
Warfarin
Acetaminophen
Drug Interactions continued
For list of CYP3A4 substrates, inhibitors and
inducers, by entering “CYP3A4” at
wikipedia.com.
Prescribing information recommends NOT using
warfarin with imatinib, avoid with nilotinib, and use
caution with dasatinib.
Patients requiring long-term anti-coagulation may not
be able to use low molecular weight heparin as a
practical matter. Monitor INR carefully if on warfarin.
Drug Interactions
Acetaminophen (paracetamol) should be
limited to 2000 mg. per day, and avoid
completely if liver enzymes elevated.
Use caution with drugs that irritate the
stomach or increase bleeding risk, e.g.
ibuprofen.
Herbals
St. John’s Wort (hypericum) decreases TKI
levels unpredictably—patients may think it
is safe because it is “natural.”
Many herbs have interactions with TKI’s,
local usage and names vary, vital to check
with doctor or pharmacist before taking
these.
Food Interactions
Do not take TKI’s with grapefruit juice
as may unpredictably increase blood
levels.
Avoid star fruit, Seville oranges.
Black mulberry, wild grape,
pomegranate, black raspberry juice may
also affect metabolism.
Surgery--General Considerations
For imatinib, consider holding it 72 hours
prior to surgery to prevent any possible
interactions with anesthesia, drugs needed in
emergencies. Dasatinib and nilotinib hold 48
hours prior.
Generally can resume TKI as soon as able to
eat and drink normally and recovery going
well.
QTc Prolongation
Nilotinib--avoid drugs that cause a
prolonged QTc interval. Monitor EKG’s if
dose changed or new drugs added.
Dasatinib--use caution.
List of drugs causing QTc prolongation
is extensive: anti-arrhythmics,
haloperidol, erythromycin etc.
List available at www.torsades.org.
Summary
All 3 TKI’s well-tolerated compared to
traditional chemotherapy and interferon.
With aggressive side-effect management,
most patients have good quality of life.
Side effects generally decrease over time.
Long-term effects --Due to animal studies
with imatinib, long term monitoring of liver,
urinary tract function recommended. Longterm effects of dasatinib and nilotinib
unknown.
Oral Therapy Considerations
Compliance or adherence and persistency
are issues with all three TKI’s.
CML is a chronic disease that requires
ongoing daily therapy.
Limited opportunities and mechanisms to
counsel patients on oral therapy, not in
clinic as much as if on intravenous
therapies.
Source: Novartis Oncology, 2004.
Oral Therapy Considerations
Reasons for non-adherence included drug
cost (full dose too costly), feeling treatment
was unnecessary because patients felt well,
psychosocial factors, and using a different
dosage than prescribed in an attempt to
manage side effects.
Aoki E, et al. J Clin Oncol. Proceedings of the 42nd Annual Meeting of the American Society
for Clinical Oncology (ASCO), June 2-6, 2006, Atlanta, GA; Part 1, Vol. 24, No. 18S (June 20
Suppl):6506.
Cortez JE, et al. Hematol Oncol Clin N Am. 2004;18:619-639.
Novartis Survey, 2004.
Dosing imatinib (Glivec)® for Optimal Results in Chronic Myeloid Leukemia, Novartis
Oncology, 2004.
Pharmacy Record Analysis of 4043 Patients Prescribed
imatinib (Glivec)
Patient adherence with imatinib (Glivec) therapy estimated at
75%.
Dramatic decline in persistency over time(looking at individual
patients):
• Month 4: near 100%.
• Month 5: 94%.
• Month 14: 23%.
Nonadherence can compromise therapeutic outcomes; this
data in line with studies done with other drugs used to treat
serious chronic diseases.
1. Tsang J-P, Rudychev I, Pescatgore SL. Poster presented at: The American Society of Clinical Oncology Meeting. 2006.
2. Partridge AH, Avorn J, Wang PS, Winer EP. J Natl Cancer Inst. 2002;94:652-661.
Adherence Imatinib
3,500
2,921 2,913 2,908 2,883
Patients
3,000
2,742
2,617
2,448
2,269
2,500
2,126
1,997
1,866
1,671
2,000
1,368
1,500
685
1,000
500
0
0-1
1-2
2-3
3-4
4-5
5-6
6-7
7-8
8-9
9-10 10-11 11-12 12-13 13+
Months
Based
The
typical
on 14
persistency
months of curve
data, Tsang,
drops off
J-P,
at 1-2
Rudychev
months.
I, Pescatore SL. J Clin Onc. 2006;
24:330s. Abstract 6119.
Adherence by Gender-Age
92%
90%
90%
89%
87%
88%
Avg. Compliance
89%
88%
87%
86%
86%
85%
84%
87%
84%
84%
81%
82%
80%
78%
76%
<25 F
<25 M
25-35 F
25-35 M
35-45 F
35-45 M
45-55 F
Gender-Age
45-55 M
55-70 F
55-70 M
>70 F
>70 M
Non-adherence and costs
Retrospective analysis of claims of 267 patients with CML in US,
analyzed imatinib refill data.
Medication possession ratio (MPR) for imatinib 77.7%. 20%
had MPR of <50%.
31% had treatment interruption of at least 30 days.
Lower MPR levels in women, those with multiple concomitant
medications, higher starting dose of imatinib, high disease
complexity.
Lower MPR resulted in higher annual healthcare costs.
Darkow T et al. Treatment interruptions and non-adherence with imatinib
and associated healthcare costs. Pharmacoeconomics 2007, 25(6): 481496.
Strategies to Improve Adherence
• Encourage patientphysician
communication
• Multidisciplinary
team approach
that includes the
patient
• Encourage
establishing a
routine way to
take doses
• Educate patients to
take medications as
prescribed and why
this is important
• Use routine
monitoring to engage
patients, review
progress,
and monitor
compliance
• Manage side effects
proactively
Promoting Adherence
Most patients do best if they take their
CML medication in conjunction with
something they habitually do every day.
Helpful to use pill container, calendar or
chart to mark doses taken.
Carry extra doses especially when
traveling.
Trust
Trust between health care provider and
patient is crucial.
Studies show adherence to treatment
depends on whether health professional was
viewed as an ally in cooperation with patient.
Dimateo MR. Variations in patients’ adherence to medical
recommendations: a quantitative review of 50 years of research. Med
care. 2004; 42:200-208.
Please check with your physician before
taking any medications suggested in
this guide.