H ome M edication Deliverance Dr Julianna M Kula PharmD Pediatric HematologyOncologySCTInvestigational Clinical Pharmacist Lucile Packard Childrens Hospital at Stanford November 4 2014 ID: 736156
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Slide1
Medication Adherence – Improving Home Medication Deliverance
Dr. Julianna M Kula,
PharmD
Pediatric Hematology/Oncology/SCT/Investigational Clinical Pharmacist
Lucile Packard Children’s Hospital at Stanford
November 4, 2014Slide2
ObjectivesDiscuss the importance of drug adherence, specifically compliance in home regimensDefine orphan drug and explain how
mercaptopurine
is classified under the Orphan Drug Act
Address how the new
mercaptopurine
formulation effects caregivers both in the hospital and at home
Revisit important points to remember when administering
mercaptopurine
Evaluate other common home regimensSlide3
Patient Case RF is a 5 year old female with standard risk ALL currently being treated on COG protocol AALL0932 in Maintenance. She arrives in the clinic for her monthly chemotherapy and PE. While in clinic her mother mentions that her outpatient 6MP prescription that she just picked up from the pharmacy looks different. She also states that the pharmacy informed her that the drug was now commercially available. She would like to further discuss with you what the very helpful pharmacist counseled her on.Slide4
Definition: Drug AdherenceEarly definition: “the extent to which the patient’s behavior coincides with the medical or health advice”
More recent expansion:
“active, intentional, and responsible process of care, in which the individual works to maintain his or her health in close collaboration with health care personnel”
Those who take 80% to 109% of their prescribed regimen
Nonadherence
:
“when the failure to comply is sufficient to interfere appreciably with achieving the therapeutic goal”
Tebbi
, Cameron.
Treatment Compliance in Childhood and Adolescence
. Cancer. 1993; 71:3441-3449
.
Pritchard, Michelle T. et al.
Understanding medication adherence in pediatric acute lymphoblastic leukemia: a review
. Journal of Pediatric Hematology Oncology. 2006;28:816-823
.Slide5
Impacts: Non-adherenceMisjudgment of medication as ineffectiveOrdering of unnecessary diagnostic tests
Use of alternative treatments
Modification of medications
Bias assessment of a given experimental treatment regimen, resulting in an erroneous conclusion
Relapse in disease state
Tebbi
, Cameron et al.
Compliance of Pediatric and Adolescent Cancer Patients
. Cancer. 1986;58:1179-1184.Slide6
Non-adherence and RelapseMajority of children with ALL enter remission after induction20% relapse in 5 years
Low erythrocyte levels of 6MP metabolite (
thioguanine
nucleotide) correlate with relapse
Significant inter-patient
thioguanine
nucleotide variability has been observed
These results could be due to failure in adherence to home regimens
Bhatia,
Smita
et al.
Nonadherence
to oral
mercaptopurine
and risk of relapse in
hispanic
and non-
hispanic
white children with acute lymphoblastic leukemia: a report from the children’s oncology group.
Journal of clinical oncology. 2012;30:2094-2101. Slide7
Assessing AdherenceSelf-reportingDrug Assays
Microelectronic Monitoring (MEMS)
Tebbi
, Cameron et al.
Compliance of Pediatric and Adolescent Cancer Patients
. Cancer. 1986;58:1179-1184.Slide8
Self-Reporting
Noncompliance
by Chemotherapy Agents Over the Course of Therapy
2 Weeks
20 Weeks
50 Weeks
Noncompliance
Pred
(n)
6MP (n)
Other (n)
Pred
(n)
6MP (n)
Other (n)
Pred
(n)
6MP (n)
Other (n)
None931994355Occasional200342032Frequent100221011
2 week point: 81.2% reported complete compliance20 week point: 60.5% reported complete compliance50 week point: 65.0% reported complete compliance
Prednisone (pred), 6mercaptopurine (6MP)
Noncompliance in Various Age Groups2 weeks20 weeks50 weeksNoncompliance<10 (n)> 10 (n)<10 (n)> 10 (n)<10 (n)> 10 (n)None (mean age 9.5)9413894Occasional (mean age 10.5)026341Frequent (mean age 17.4)101402
Tebbi
, Cameron et al.
Compliance of Pediatric and Adolescent Cancer Patients
. Cancer. 1986;58:1179-1184.Slide9
Drug Assays
327 children in UK all on the same 6MP dose (75 mg/m
2
)
Intracellular metabolites assay of 6MP
Thioguanine
nucleotides
vs
methylmercaptopurine
metabolites (inverse relationship)
It appears that 10% or more of children in the study were non-compliant
Lennard
, L. et al.
Intracellular metabolites of
mercaptopurine
in children with lymphoblastic
leukaemia
: a possible indicator of non-compliance
. British journal of cancer. 1995;72:1004-1006. Slide10
Drug Assays
120 children in remission
Median RBC-TGN concentration
Left: relapse free survival (%)
Right: event free survival (%)
Lennard
, Lynne et al.
Variable
mercaptopurine
metabolism and treatment outcome in childhood lymphoblastic leukemia
. Journal of clinical oncology. 1989;7:1816-1823.
Black line: patients with higher than median RBC-TGN concentrations
Grey/dotted line: patients with lower than median RBC-TGN concentrationsSlide11
Microelectronic Monitoring (MEMS)
Bhatia,
Smita
et al.
Nonadherence
to oral
mercaptopurine
and risk of relapse in
hispanic
and non-
hispanic
white children with acute lymphoblastic leukemia: a report from the children’s oncology group.
Journal of clinical oncology. 2012;30:2094-2101.
Entire cohort
Hispanics (blue)
vs
non-
hispanic
whites (dotted)
older age (> 12 years) (blue) vs younger age (< 12 years) (dotted)single mother (blue) vs multiple caregiver (dotted)Median adherence rate over 6 months: Relapse 88.2%; Continuous Remission 96.2% p=0.001Slide12
Microelectronic Monitoring (MEMS)
Bhatia,
Smita
et al.
Nonadherence
to oral
mercaptopurine
and risk of relapse in
hispanic
and non-
hispanic
white children with acute lymphoblastic leukemia: a report from the children’s oncology group.
Journal of clinical oncology. 2012;30:2094-2101.
Cumulative incidence of relapse: 11.0%
+
2.1%
>
95% adherence
<95% adherence
HispanicsNon-Hispanics WhitesAdherence rate < 95% associated with increase risk of relapseSlide13
Microelectronic Monitoring (MEMS)
Bhatia,
Smita
et al.
6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a children’s oncology group study
. Blood. 2014;124(15):2345-2353.
Entire cohort
Whites
Asian-Americans
African-American
Annual income
>
$50G
Annual income <$50G
Singe parent/single child
Nuclear family
Single parent/multiple children
mother full time caregiver
other caregiver configurationSlide14
Difficulties with Drug AdherenceMercaptopurine (6MP)
Methotrexate
Thioguanine
SteroidsSlide15
Mercaptopurine (6MP)Past: 50 mg tablet
Pros:
One dosage form (less chance for error in dispensing)
Easy for providers to change dosing
Size of tablet is reasonable and reasonably easy for patients to take
Long expiration date
Cons:
Patients too young to take tabletTotal weekly dose instead of daily dose causes difficulty of regimen Difficult for providers to alter dose
Difficult for patients to remember appropriate dose
Difficulty/safety for family members to alter tablets Slide16
6MP Compounded LiquidCompounding pharmacyDifficult to locate
Insurance coverage
Not all compounding pharmacies bill to insurance
Prior authorizations from insurance companies can be cumbersome
Inconsistent absorption
SHAKE WELL
Settles to bottom of bottleSlide17
Orphan Drug ActOrphan Drug Act
(Public Law 97-414, as amended) CONGRESSIONAL FINDINGS FOR THE ORPHAN DRUG ACT The Congress finds that--- (1) there are many diseases and conditions, such as Huntington's disease, myoclonus, ALS (Lou Gehrig's disease), Tourette syndrome, and muscular dystrophy which affect such small numbers of individuals residing in the United States that the diseases and conditions are considered rare in the United States; (2) adequate drugs for many of such diseases and conditions have not been developed; (3) drugs for these diseases and conditions are commonly referred to as "orphan drugs"; (4) because so few individuals are affected by any one rare disease or condition, a pharmaceutical company which develops an orphan drug may reasonably expect the drug to generate relatively small sales in comparison to the cost of developing the drug and consequently to incur a financial loss; (5) there is reason to believe that some promising orphan drugs will not be developed unless changes are made in the applicable Federal laws to reduce the costs of developing such drugs and to provide financial incentives to develop such drugs; and (6) it is in the public interest to provide such changes and incentives for the development of orphan drugs.Slide18
6MP and the Orphan Drug ActI, Dr Anthony Gill, Delegate of the Secretary for the purposes of 16J of the Therapeutic Goods Regulations 1990 (“the Regulations”), acting under
subregulation
16J (2) of the Regulations, designate
Mercaptopurine
as an orphan drug on the 14 December 2012 for the treatment of Acute Lymphoblastic
Leukaemia
in Children. The dose form of
Mercaptopurine for this indication is oral suspension. The sponsor of Mercaptopurine is Ballia
Holdings Pty Ltd
(Signed by) Dr Anthony
GillDelegate
of the Secretary 14 December 2012Slide19
Purixan
60 adult volunteers from South Africa (18-50yo)
Cross over design
1
x
50 mg dose of liquid
vs
1
x
50 mg tablet
Bioequivalent in regards to AUC (114%;CI 108-125%)
Plasma concentration for liquid is more consistent and predictable than tablet
Mulla
,
Hussain
et al.
A step toward more accurate dosing for
mercaptopurine
in childhood acute lymphoblastic leukemia.
Journal of Clinical Pharmacology. 2012;52:1610-1613.Slide20
COG’s take on the new 6MP formulation Memo
To: Principal Investigators and Clinical Research Associates
From: Mary Beth Sullivan, Protocol Coordinator
Re: FDA approval of an oral suspension of
mercaptopurine
for the treatment of acute lymphoblastic leukemia (ALL)
Date: May 2, 2014
On April 28, 2014 the FDA approved an oral suspension (20 mg/ml) of
mercaptopurine
(
Purixan
, NOVA Laboratories Limited).
Purixan
is indicated for the treatment of patients with acute lymphoblastic leukemia (ALL) as part of a combination regimen.
More Information is available at : http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm395156.htm
Purixan
will be available in mid-June. To order call 1 (888) 470-0904 Slide21
Mercaptopurine (6MP) - Purixan
New formulation (
Purixan
)
20 mg/ml raspberry flavored suspension
vs
5 mg/ml compounded suspension
Less volumeExpiration: 6 weeks once openedvs longer expiration of 90 days for compounded suspension
Can be stored at room temp
vs
compounded suspension stored in fridge
Expensive!!!!
Cost $1072.43 - $1155.94 “with free coupon”
Insurance company coverage
California Children’s Services (CCS)
State funded insurance
COVERS IT!!!
Private insurance
Prior authorization
$75-150 copayCan provide accurate daily dosingLess confusion for families and providersBetter outcomes for patients (???)Slide22
Mercaptopurine – 6MPCounseling Points
Shake for 30 seconds (
Purixan
)
Ensure equal distribution of the drug in the suspension
Take on an empty stomach
1 hour before or 2 hours after food
Should not be taken with other meds as wellPoor (<50%) absorptionGive Zantac, Zofran
, and
Septra
1 hour prior to 6MP
Give at bedtime – less chance of eating, sleep with nausea/less chance of vomiting
Avoid taking with
allopurinol
, NSAIDSSlide23
Mercaptopurine – 6MPToxicities
Hepatotoxicity
Myelosuppression
Immunosuppression
Embro
-Fetal Toxicity
Treatment Related Malignancies
Nausea/vomitingSlide24
Other Home Chemotherapy Meds - MTXMethotrexate (MTX)
2.5 mg tablet size
Lots of tablets for older kids
Compliance: lots to take, count tablets correctly
Other tablet sizes
10 mg, 15 mg
Possible errors in dispensing/prescribing
Difficult to change doseLiquid: IV for PO useCoverage by insurance
TasteSlide25
Other Home Chemotherapy Meds - MTXCounseling PointsCan be taken without regard to meals
Usually taken in the evening to decrease awareness of nausea
Usually taken once weekly
Take 30 minutes to 1 hour after antiemetic to help avoid nausea/vomiting
Should avoid
penicillins
, proton pump inhibitors, NSAIDS,
probenecidSide Effects
Hepatotoxicity
Myelosuppression
Immunosuppression
Embro
-Fetal Toxicity
Treatment Related Malignancies
Nausea/VomitingSlide26
Other Home Chemotherapy Meds - 6TGThioguanine (6TG)One tablet size 40 mg
Difficult for children to take
Safety in weekly dose
vs
appropriate daily dose
Compounded liquid
Compounding pharmacy
Insurance coverageInconsistent absorptionRefrigerationExpiration: 63 days Slide27
Counseling Points:Take on an empty stomach1 hour before or 2 hours after foodShould not be taken with other meds as well
Give Zantac,
Zofran
, and
Septra
1 hour prior to 6TG
Give at bedtime – less chance of eating, sleep with nausea/less chance of vomiting
Avoid taking NSAIDSSide EffectsHepatotoxicityMyelosuppression
Immunosuppression
Embro
-Fetal Toxicity
Treatment Related Malignancies
Nausea/Vomiting
Other Home Chemotherapy Meds - 6TGSlide28
Chemotherapy at HomePrecautions for Families
Keep in a safe location away from children
Wear appropriate protective wear prior to handling (NIOSH rules)
Proper cleaning and disposal of medications and dispensing equipment and patient waste
Safety profile between tablets (cutting, placing in gel caps) vs. liquid formulationSlide29
Other Home Chemotherapy Meds - SteroidsSteroidsDexamethasone or prednisone
Tablets
bitter taste
Multiple tablets and tablet sizes
Liquids
Dexamethasone
1 mg/ml (bitter taste)
Prednisone concentrate 5 mg/ml (bitter taste)Prednisolone grape flavor 3 mg/mlSlide30
Other Home Chemotherapy Meds - SteroidsCounseling Points:Take with food to avoid stomach irritation
Ensure GI prophylaxis (
zantac
,
tums
)
May take after
Zofran to avoid nausea from GI irritationContact provider if notice blood in stoolMay notice increased energy (“revved up” feeling)May notice mood swings, emotional instability, personality changes, insomnia (may take a bit earlier in the day to avoid)
Side Effects
Hepatotoxicity
Mood changes
AcneSlide31
Back to our PatientWhat are some of the things you want to make sure RF’s family knows?Slide32
ConclusionDrug adherence is pertinent to the overall cure of childhood cancerDrug formulations are not always perfect options for pediatric patients
It’s important to help ease the anxiety and frustration of family drug manipulation to ensure proper drug adherence Slide33
QuestionsSlide34
ReferencesTebbi, Cameron. Treatment compliance in childhood and adolescence
. Cancer. 1993;71:3441-3449.
Pritchard, Michelle T. et al.
Understanding medication adherence in pediatric acute lymphoblastic leukemia: a review
. Journal of pediatric hematology oncology. 2006;28:816-823.
Tebbi
, Cameron et al. Compliance of Pediatric and Adolescent Cancer Patients. Cancer. 1986;58:1179-1184.
Lennard
, L. et al.
Intracellular metabolites of
mercaptopurine
in children with lymphoblastic
leukaemia
: a possible indicator of non-compliance
. British journal of cancer. 1995;72:1004-1006.
Lennard
, Lynne et al.
Variable
mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. Journal of clinical oncology. 1989;7:1816-1823.Bhatia, Smita et al. Nonadherence to oral mercaptopurine and risk of relapse in hispanic and non-hispanic white children with acute lymphoblastic leukemia: a report from the children’s oncology group. Journal of clinical oncology. 2012;30:2094-2101.Bhatia, Smita et al. 6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a children’s oncology group study. Blood. 2014;124(15):2345-2353.Mulla, Hussain et al. A step toward more accurate dosing for mercaptopurine in childhood acute lymphoblastic leukemia. Journal of Clinical Pharmacology. 2012;52:1610-1613.http://www.purixan-us.com/resources/Expanded%20Brochure.pdfhttp://www.goodrx.com/purixanwww.pharmacyonesource.com