Question: Does medicine packaging affect adherence?

Grading: 1++High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias
Orton L;Barnish G;
Unit-dose packaged drugs for treating malaria. [Review] [40 refs]
Ref ID 12512005
Study TypeSystematic ReviewFundingCochrane review
Number of participant3 quasi RCTs and one cluster RCT
Inclusion/Exclusion Criteria
Patient Characteristics
Interventions/Test/Factor being investigated
Length of Study/Follow-up
Outcome measures studied
Safety and adverse effects
Does the study answer the question?A meta analysis of two trials (596 participants) showed that participant reported treatment adherence was higher with blister packed tablets compared with tablets in paper envelopes RR 1.18 (95% CI 1.12 to 1.25). Two trials using tablets in sectioned polythene bags as the intervention also noted an increase in participant reported treatment adherence. The cluster RCT (6 clusters) compared it with tablets in paper envelopes and the other trial compared it with syrup in bottles, RR 2.15 (95% CI 1.76 to 2.61), 299 participants.
The authors stated that there was insufficient evidence to determine the effect of unit dose packaged antimalarial drugs on treatment failure. Unit dose packaging supported by prescriber training and patient information appears to improve participant reported treatment adherence, but these data come from trials with methodological limitations.
Effect due to factor in study?
Consistency of results with other studies?
Directly applicable to guideline population?
Internal Validity
Grading: 1+Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
Connor J;Rafter N;Rodgers A;
Do fixed-dose combination pills or unit-of-use packaging improve adherence? A systematic review. [Review] [26 refs]
Ref ID 15012004
Study TypeSystematic ReviewFundingUnknown
Number of participantRandomized or quasi-randomized controlled trials
Inclusion/Exclusion Criteria
Patient Characteristics
Interventions/Test/Factor being investigated
Length of Study/Follow-up
Outcome measures studied
Safety and adverse effects
Does the study answer the question?15 trials met inclusion criteria: fixed dose combination pills were investigated in three of these while unit-of-use packaging was studied in 12 trials. The results of the trials suggested that there were trends towards improved adherence which reached statistical significance in seven out of thirteen trials reporting medication adherence. Measures of adherence were however heterogeneous and interpretation was further limited by methodological issues, particularly small sample size, short duration and loss to follow up. Uncertainty remains about the size of the benefits of drug formulation and packaging.
Effect due to factor in study?
Consistency of results with other studies?
Directly applicable to guideline population?
Internal Validity
Lee JK;Grace KA;Taylor AJ;
Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol: a randomized controlled trial.[see comment]
Ref ID 1902006
Study TypeRandomised Controlled TrialFundingThis study was partially funded by a competitive junior investigator grant award from the American Society of Health-System Pharmacists Research and Education Foundation, managed under the auspices of the TRUE Research Foundation.
Number of participantTotal 200. 159 after randomization for 2nd stage of study: 83 in follow up group, 76 in return to usual care group.
Inclusion/Exclusion CriteriaInclusion: aged 65 years or over, taking 4 or more chronic medications daily.
Exclusion: Patients were excluded if they did not live independently (assisted living or nursing home residents were excluded) or in the presence of any serious medical condition for which 1-year survival was expected to be unlikely.
Patient CharacteristicsAge, mean (s.d), y: Usual Care (UC) Group: 78 (s.d=6.2); Intervention group: 77 (s.d=10.5). Men: UC group: 56 (s.d=73.7), Intervention group: 62 (s.d=74.7). Race: White: Intervention group: 51 (s.d=61.4), UC group: 43 (s.d=56.6); Black: Intervention group: 29 (s.d=34.9), UC group: 29 (s.d=34.9). No. of chronic medications, mean: intervention group: 9.1 (s.d=3.2), UC group: 8.3 (s.d=2.8). Significant differences between groups prior to randomisation in antidepressant usage, using medication or chart listing and the number of participants taking ACE inhibitors and niacin. These differences are addressed by using multi-variable analysis.
SettingWalter Reed Army Medical Center.
Interventions/Test/Factor being investigatedMonths 3–8 received by all patients: The comprehensive pharmacy care program consisted of 3 elements, including individualised medication education (using standardised scripts), medications dispensed using an adherence aid (blister packs) and regular follow-up with clinical pharmacists every 2 months. Individualized educational interventions were performed to teach participants their drug names, indications, strengths, adverse effects, and usage instructions during each visit. Patients in intervention group continued to receive intervention for study months 9–14. Patients in control group returned to usual care for this period.
ComparisonsIntervention for months 3–8 vs intervention for months 3–14.
Length of Study/Follow-up14 months.
Outcome measures studiedAdherence was assessed at baseline via pill counts and expressed as amount of medication taken compared to what should have been taken. Measured again at 1, 2, 4, 6, 8, 10, 12 and 14 months. Also measured: changes in blood pressure and LDL-C.
ResultsAdherence: 1–8 months: Mean baseline medication adherence at completion of run-in phase was 61.2% (s.d=13.5%). After initiation of the 6-month pharmacy care program, there was improvement in medication adherence noted at the 4-month pharmacy visit. At 4, 6, and 8 months, medication adherence was 96% or higher. At the conclusion of phase 1 (8 months), the primary end point was met with a mean medication adherence of 96.9% (s.d=5.2%), representing an absolute change in adherence of 35.5% (95% CI 31.2% to 38.5%) p<0.001). Adherence 8–14 months: For the primary end point of the randomised clinical trial, the continued pharmacy care group showed sustained mean medication adherence 95.5% (s.d=7.7%), whereas medication adherence declined in the usual care group 69.1% (s.d=16.4%) p<.001. However, medication adherence at the conclusion of phase 2 for the usual care group was modestly higher than at study entry (run-in phase, 66.5% (s.d=14.0%) vs 61.1% (s.d=14.1%) p=0.02). At the end of the study, those elderly patients assigned to usual care had a similar frequency (compared with their baseline method of medication administration) of receiving help with their medications (11.6% vs 15.9%; p=0.58) and using a pillbox (62.3% vs 49.3%; p=.09), but were more likely to use a medication chart (65.2% vs 13.0%; p<0.001). Multiple linear regression analysis controlling for baseline differences (p<0.20) in the study groups showed that the assignment to usual care (B=0.81; p<0.001) and taking medications for psychiatric or memory problems (B=0.15; p=0.007) were independently related to the change in medication adherence during phase 2.
Other outcomes: 1–8 months: Improved adherence was associated with improvements in both secondary end points (BP and LDL-C). Among patients with drug-treated hypertension (n=184), mean systolic BP was reduced from 133.2 (s.d=14.9) mm Hg to 129.9 (s.d=16.0) mm Hg (p=0.02). Diastolic BP was not significantly reduced. There was no change in the number of antihypertensive agents taken from baseline to the end of phase 1. Among patients with drug-treated hyperlipidemia (n=162), mean (s.d) LDL-C decreased from 91.7 (s.d=26.1) mg/dL 2.38 (s.d=0.68) mmol/L) to 86.8 (s.d=23.4) mg/dL 2.25 (s.d=0.61) mmol/L) p=0.001. Other outcomes months 8–14: A pre-specified analysis of the associated changes in BP and lipid levels in the continued pharmacy care group showed significant reductions in systolic BP ?6.9mmHg (95% CI ?10.7 to ?3.1mmHg) p=.04 vs usual care) and diastolic BP ?2.5mmHg (95% CI ?4.9 to ?0.2 mm Hg) p=0.39 vs usual care. The mean number of antihypertensive agents used was similar between treatment groups. The LDL-C was not further reduced from 9 to 14 months in the continued pharmacy care group and was not different between study groups.
Safety and adverse effectsNone.
Does the study answer the question?Yes. Continued care in intervention group led to them keeping their improved adherence compared to control group.
Effect due to factor in study?Yes.
Consistency of results with other studies?
Directly applicable to guideline population?Direct.
Internal Validity
Grading: 1−Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias*
Schneider PJ;Murphy JE;Pedersen CA;
Impact of medication packaging on adherence and treatment outcomes in older ambulatory patients
Ref ID 179422008
Study TypeRandomised Controlled TrialFundingCenters for Medicare and Medicaid Services. Medications provided by Merck (Whitehouse Station, N.J)
Packaging by PCI services, Philadelphia.
Number of participant85 participants. 47 in the intervention group and 38 in the control group.
Inclusion/Exclusion CriteriaInclusion:
Patients taking or just starting lisinopril for hypertension.
65 years or over.
If assessed by physician as having cognitive impairment e.g psychoses or Alzeimers disease, visual impairment or severe asthma.
Patient CharacteristicsMean age 72 years
Mean no medications 5
26 men in the intervention group and 16 ment in the control group
RecruitmentNot reported.
Setting3 health centres/hospital clinics, USA.
Interventions/Test/Factor being investigatedRandomised to receive daily-dose blister packaged medication (pill calendar) as the intervention compared to traditional bottles of loose tablets as the control group. Patients returned for refills every 28 days during a 12 month period where the pharmacist would record the time between prescription refills for the medication and any study-related problems. At 6 and 12 months after enrolling the patients visited the physician to find out blood pressure management; the occurrence of morbidity in the past 6 months e.g. angina, myocardial infarction and stroke; and any medical services they had required in the past 6 months e.g. hospitalisations or emergency department visits. Medical charts were reviewed by two pharmacists to gather this information.
ComparisonsThe intervention group compared to usual care.
Length of Study/Follow-up12 months.
Outcome measures studied% of prescriptions refilled on time.
Medication possession ration (MPR -the sum of the day’s supply for all prescriptions received during the study divided by the number of days between the first and last prescription dispensed.
Blood pressure.
ResultsThe percentage of times prescriptions were refilled on time (within 5 days before or after due date) were significantly higher 80.4% (s.d=21.2) for the intervention group than the control group, 66.1% (s.d=28), p=0.012. The Medication possession rate was also significantly higher for the intervention group, 0.93 (s.d=11.4) and 0.87 (s.d=14.2) for the control group, p=0.039. No differences were found between the groups for systolic blood pressure and diastolic blood pressure measures at 6 and 12 months.
Safety and adverse effectsNone reported. Approval for study obtained from the human subjects committee at each centre and written informed consent obtained before enrollment from each participant.
Does the study answer the question?Two different ways of packaging medication, one which shows the day each dose is intended to be taken and provides information on how to take properly can improve the treatment regimen adherence and treatment outcomes in elderly patients.
Effect due to factor in study?Possibly.
Consistency of results with other studies?Yes as the intervention is simpler than most of the other interventions in the area which are multi-component.
Directly applicable to guideline population?The population is relevant as they are taking medications.
Internal ValidityPossible selection bias.

From: Appendix C, Clinical Evidence Extractions

Cover of Medicines Adherence
Medicines Adherence: Involving Patients in Decisions About Prescribed Medicines and Supporting Adherence [Internet].
NICE Clinical Guidelines, No. 76.
National Collaborating Centre for Primary Care (UK).
Copyright © 2009, Royal College of General Practitioners.

All rights reserved. No part of this publication may be reproduced in any form (including photocopying or storing it in any medium by electronic means and whether or not transiently or incidentally to some other use of this publication) without the written permission of the copyright owner. Applications for the copyright owner’s written permission to reproduce any part of this publication should be addressed to the publisher.

PubMed Health. A service of the National Library of Medicine, National Institutes of Health.