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, 2014
Objectives
 Discuss the importance of drug adherence, specifically compliance
in home regimens
 Define 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 regimens
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.
Definition: Drug Adherence
 Early 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.
Impacts: Non-adherence
Misjudgment of medication as ineffective
Ordering 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.
Non-adherence and Relapse
 Majority of children with ALL enter remission after induction
 20% 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.
Assessing Adherence
 Self-reporting
 Drug Assays
 Microelectronic Monitoring (MEMS)
Tebbi, Cameron et al. Compliance of Pediatric and Adolescent Cancer Patients. Cancer. 1986;58:1179-1184.
Self-Reporting
Noncompliance by Chemotherapy Agents Over the Course of Therapy
2 Weeks
Noncompliance
20 Weeks
50 Weeks
Pred (n)
6MP (n)
Other (n)
Pred (n)
6MP (n)
Other (n)
Pred (n)
6MP (n)
Other (n)
None
9
3
1
9
9
4
3
5
5
Occasional
2
0
0
3
4
2
0
3
2
Frequent
1
0
0
2
2
1
0
1
1
Prednisone (pred), 6mercaptopurine (6MP)
•
Noncompliance in Various Age Groups
2 weeks
Noncompliance
20 weeks
50 weeks
<10 (n)
> 10 (n)
<10 (n)
> 10 (n)
<10 (n)
> 10 (n)
None (mean age 9.5)
9
4
13
8
9
4
Occasional (mean age 10.5)
0
2
6
3
4
1
Frequent (mean age 17.4)
1
0
1
4
0
2
Tebbi, Cameron et al. Compliance of Pediatric and Adolescent Cancer Patients. Cancer. 1986;58:1179-1184.
•
•
2 week point: 81.2%
reported complete
compliance
20 week point: 60.5%
reported complete
compliance
50 week point: 65.0%
reported complete
compliance
Drug Assays
• 327 children in UK all on the same
6MP dose (75 mg/m2)
• Intracellular metabolites assay of 6MP
• Thioguanine nucleotides vs
methylmercaptopurine metabolites
(inverse relationship)
• It appears that 10% or more of
children in the study were noncompliant
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.
Drug Assays
•Black line: patients
with higher than
median RBC-TGN
concentrations
•Grey/dotted line:
patients with lower
than median RBCTGN concentrations
•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.
Microelectronic Monitoring (MEMS)
Entire cohort
older age (> 12 years) (blue) vs
younger age (< 12 years) (dotted)
Hispanics (blue) vs nonhispanic whites (dotted)
single mother (blue) vs
multiple caregiver (dotted)
Median adherence rate over 6 months: Relapse 88.2%; Continuous Remission 96.2% p=0.001
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.
Microelectronic Monitoring (MEMS)
Cumulative incidence of relapse: 11.0% + 2.1%
<95% adherence
>95% adherence
Hispanics
Non-Hispanics Whites
Adherence rate < 95% associated with increase risk of relapse
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.
Microelectronic Monitoring (MEMS)
Whites
Asian-Americans
African-American
Entire cohort
Singe parent/single child
Nuclear family
Single parent/multiple children
Annual income >$50G
Annual income <$50G
mother full time caregiver
other caregiver configuration
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.
Difficulties with Drug Adherence
 Mercaptopurine (6MP)
 Methotrexate
 Thioguanine
 Steroids
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 tablet
 Total 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
6MP Compounded Liquid
 Compounding pharmacy
 Difficult 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 bottle
Orphan Drug Act
Orphan 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.
6MP and the Orphan Drug Act
I, 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
2012
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.
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
Mercaptopurine (6MP) - Purixan
 New formulation (Purixan)
 20 mg/ml raspberry flavored suspension
 vs 5 mg/ml compounded suspension
 Less volume
 Expiration: 6 weeks once opened
 vs 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 copay
 Can provide accurate daily dosing
 Less confusion for families and providers
 Better outcomes for patients (???)
Mercaptopurine – 6MP
 Counseling 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 well
 Poor (<50%) absorption
 Give 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, NSAIDS
Mercaptopurine – 6MP
 Toxicities






Hepatotoxicity
Myelosuppression
Immunosuppression
Embro-Fetal Toxicity
Treatment Related Malignancies
Nausea/vomiting
Other Home Chemotherapy Meds - MTX
 Methotrexate (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 dose
 Liquid: IV for PO use
 Coverage by insurance
 Taste
Other Home Chemotherapy Meds - MTX
 Counseling Points





Can 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, probenecid
 Side Effects






Hepatotoxicity
Myelosuppression
Immunosuppression
Embro-Fetal Toxicity
Treatment Related Malignancies
Nausea/Vomiting
Other Home Chemotherapy Meds - 6TG
 Thioguanine (6TG)
 One tablet size 40 mg
 Difficult for children to take
 Safety in weekly dose vs appropriate daily dose
 Compounded liquid
 Compounding pharmacy
 Insurance coverage
 Inconsistent absorption
 Refrigeration
 Expiration: 63 days
Other Home Chemotherapy Meds - 6TG
 Counseling Points:
 Take on an empty stomach
 1 hour before or 2 hours after food
 Should 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 NSAIDS
 Side Effects






Hepatotoxicity
Myelosuppression
Immunosuppression
Embro-Fetal Toxicity
Treatment Related Malignancies
Nausea/Vomiting
Chemotherapy at Home
Precautions 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 formulation
Other Home Chemotherapy Meds - Steroids
 Steroids
 Dexamethasone 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/ml
Other Home Chemotherapy Meds - Steroids
 Counseling Points:






Take with food to avoid stomach irritation
Ensure GI prophylaxis (zantac, tums)
May take after Zofran to avoid nausea from GI irritation
Contact provider if notice blood in stool
May 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
 Acne
Back to our Patient
 What are some of the things you want to make sure RF’s family
knows?
Conclusion
 Drug adherence is pertinent to the overall cure of childhood
cancer
 Drug 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
Questions
References











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.
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.pdf
http://www.goodrx.com/purixan
www.pharmacyonesource.com