Flávio Mascarenhas Starlinga,e; Einstein Francisco Camargosa,b; Felipe Ferreiraa,c; Marco Polo Dias Freitasa,b; José Reinaldo Silva Costaa,d; Patrícia Medeiros-Souzaa
BACKGROUND: Tablet splitting appears common in older adults, but its safety, and the factors associated with this practice, remain unclear.
OBJECTIVE: To identify which psychotropic drugs are most often split, which doses are intended with this practice, and whether these doses are provided by the Brazilian Unified Health System (SUS) or commercially available.
METHODS: Cross-sectional descriptive study of 632 geriatric outpatients. The number of individuals who split tablets was identified, as well as the psychotropic drugs they used and split. The availability of these drugs on the SUS network and on the market was assessed by checking the 2017 National Formulary of Essential Medicines (RENAME 2017) and the Dictionary of Proprietary Medicinal Products (Dicionário de Especialidades Farmacêuticas) "respectively.
RESULTS: Tablet splitting was reported by 178 patients (28.2%). This practice was significantly more common among those aged 80 years or older. Tablet splitting was significantly associated with a greater number of medical visits and a higher pill burden. The most commonly affected therapeutic classes were antipsychotics (23.9%), other psychotropic drugs (18.7%) and antidepressants (12.3%). Of the 20 psychotropic drugs split, 45% were available on the SUS.
CONCLUSIONS: Tablet splitting poses a challenge, as there is no guarantee of uniformity of concentration of the active ingredient in the split halves. Although the psychotropic drugs that were split in this sample are commercially available, most were not available from SUS in the desired dose forms for older adults.
Keywords: psychotropic drugs; aged; drugs, essential; Unified Health System; fractionated drugs.
INTRODUÇÃO: O fracionamento de comprimidos é comum em pacientes geriátricos, mas a segurança e os fatores associados a essa prática permanecem incertos.
OBJETIVO: Identificar quais medicamentos psicotrópicos são mais frequentemente fracionados, quais doses se destinam a essa prática e se essas dosagens são fornecidas pelo Sistema Único de Saúde (SUS) ou comercialmente disponíveis.
MÉTODOS: Estudo descritivo transversal de 632 pacientes ambulatoriais geriátricos. O número de indivíduos que fracionou os comprimidos foi identificado, bem como os medicamentos psicotrópicos que foram usados e fracionados. A disponibilidade desses medicamentos na rede SUS e no mercado foi avaliada através da verificação do Formulário Nacional de Medicamentos Essenciais (RENAME) de 2017 e do Dicionário de Especialidades Farmacêuticas, respectivamente.
RESULTADOS: A partição de comprimidos foi relatada por 178 pacientes (28,2%). Essa prática foi significativamente mais comum entre aqueles com 80 anos ou mais. O fracionamento dos comprimidos foi significativamente associado a um maior número de consultas médicas e a uma maior carga de comprimidos. As classes terapêuticas mais comumente afetadas foram antipsicóticos (23,9%), outros medicamentos psicotrópicos (18,7%) e antidepressivos (12,3%). Dos 20 medicamentos psicotrópicos fracionados, 45% estavam disponíveis no SUS.
CONCLUSÕES: O fracionamento de comprimidos representa um desafio, pois não há garantia de uniformidade de concentração do ingrediente ativo nas metades fracionadas. Embora os medicamentos psicotrópicos fracionados nesta amostra estejam disponíveis comercialmente, a maioria não estava disponível no SUS nas formas de dosagem desejadas para a população geriátrica.
Palavras-chave: psicotrópicos; idoso; medicamentos essenciais; Sistema Único de Saúde; medicamentos fracionados.
The current picture of population aging is leading to one of the major epidemiological trends of the 21st century: the emergence of chronic and degenerative diseases in countries around the world, regardless of income level.1,2 One particular issue in pharmacotherapy of geriatric patients with and without dementia is polypharmacy,3 which can lead to significant drug interactions. Another common limitation of treatment is the fact that some dosage strengths and forms prescribed by physicians are unavailable on the market, leading patients (or their caregivers) to split tablets to obtain the prescribed dosage.4,5 Several aspects must be taken into account when tablet-splitting, including the half-life of the drug, its pharmaceutical form, and whether the tablet is scored.6 Different pharmaceutical forms, such as tablets, enteric-coated tablets, capsules, and solutions, may have a significant impact on pharmacokinetics.7 When used alone, the term "tablet" refers to an uncoated tablet.8 The term "coated tablet", as the name implies, refers to a tablet with one or more thin layers of coating, whereas a "capsule" is a solid pharmaceutical form in which the active ingredient(s) and/or excipients are contained in a hard or soft soluble shell.8 A solution is defined as a clear, homogeneous liquid pharmaceutical form, while a suspension is a liquid pharmaceutical form which contains insoluble solid particles dispersed in a liquid carrier.8 Our group recently published a study of tablet splitting at a referral center for older adults with dementia.9 In this study, we found that the presence of dementia was significantly associated with tablet splitting, a practice reported by 88 older adults with dementia (34.9%) versus 90 older adults without dementia (23.7%) (p = 0.002). Of those who split tablets, 64 (72.7%) were on psychotropic drugs. The objectives of the present study were to identify the psychotropic drugs most often involved in tablet splitting, which dosage strengths are intended by tablet splitting, and which of these strengths are available on the Unified Health System and commercially, as well as discuss the context of tablet splitting in this sample of older adults. No such studies have been conducted in Brazil to date.
This cross-sectional, descriptive study was conducted in Brasília, Federal District, Brazil. The sample comprised older adults who were managed on an outpatient basis at a referral center for patients with dementia, the Multidisciplinary Center for the Elderly (Centro Multidisciplinar para o Idoso, CMI) at Hospital Universitário de Brasília—Universidade de Brasília (UnB). The study was approved by the Research Ethics Committee of the Faculdade de Ciências da Saúde — UnB (no. 056/2012 — protocol 02529612.4.0000.0030). As a retrospective chart review design was used, the informed consent requirement was waived by the Ethics Committee.
Data were extracted from standardized charts included in the medical records of patients seen from January 1, 2012, to December 31, 2012. The sociodemographic variables of interest were sex (male or female) and age (in full years). Information was also collected on history of presence or absence of a formal diagnosis of dementia and current medications (active ingredient, strength, dosage, and tablet splitting, when present).
All outpatients seen in 2012 for whom at least one appointment had been recorded in the medical record were included in the study. Individuals whose medical records were not located on more than one occasion; those who only had records of inpatient admissions, not outpatient care, during the year 2012; and records with inconsistent data were all excluded.
Tablet splitting was identified by the presence of fractional dose notation (1/2, 1/3, 2/3, 1/4) in the "current medications" field of the medical record. This standard notation is used by all physicians at the study facility.
Assessment of the use of controlled substances took into account individual patients themselves, the diagnosis of dementia, and the following therapeutic classes of psychotropic drugs: antidepressants, antipsychotics, antiepileptics, acetylcholinesterase inhibitors, NMDA antagonists, and other classes (such as benzodiazepines and imidazopyridines). All of these classes of drugs are included in schedule C1 of substances subject to special control, as set forth in Ordinance no. 344/98.10 by the Brazilian Ministry of Health Psychotropics that did not fit into these classes and which belonged to another schedule under Ordinance No. 344/98 were classified as "other classes" for comparison purposes.
Once this subdivision was complete, each drug was adopted as the unit of analysis, to quantify which drugs were used by the overall study population, considering all recorded prescriptions and eliminating duplicate instances (e.g., when the same drug was prescribed on more than one visit).
The overall analysis of tablet splitting took into consideration social and clinical aspects associated with the act of tablet splitting. For this assessment, the individual patient was adopted as the unit of analysis. We analyzed possible relationships between the number of patients who split tablets and the characteristics of the study population, namely sex, age, and current medications.
To ascertain which drugs were available through the public Unified Health System, we cross-referenced the National Formulary of Essential Medicines (RENAME), 2017 edition,11 and the Standardized Formulary of the State Department of Health of the Brazilian Federal District (SES-DF).12
To ascertain which drugs were commercially available, we consulted the Dictionary of Proprietary Medicinal Products (Dicionário de Especialidades Farmacêuticas—DEF), which identifies all pharmaceutical forms and presentations available in Brazil.13
The obtained data were processed, tabulated, and cross-referenced in the Microsoft Access® software environment to obtain the quantitative data necessary for our analyses.
Comparative analysis of tablet splitting across several parameters was analyzed using the chi-square (%2) statistical test for categorical variables (sex, age, pathological conditions, psychotropic drugs involved in tablet splitting, all drugs used) and the Mann-Whitney U test for number of pathological conditions, medical visits, and current medications. Between-group differences of less than 5% (p < 0.05) were deemed statistically significant. Statistical analyses were performed in SAS.
Overall, 178 patients split tablets, which represents approximately 28.2% of the total sample (n = 632). There was no difference in the rate of tablet splitting between men (n = 59, 29.9%) and women (n = 119, 27.4%) (p = 0.502) (Table 1).
Tablet splitting was significantly more frequent among patients over the age of 80 (n=74, 33.5%) than in other age groups, with p = 0.0207 (Table 1). Patients under the age of 60 were excluded from analysis because of their small number (n = 6) (Table 1). Dementia was diagnosed in 252 (39.8%) patients, who accounted for 49.4% (n = 88) of those that split tablets.
Tablet splitting was also significantly associated with a greater number of medical visits (p = 0.003) and a higher pill burden (p = 0.008). The number of pathological conditions was not associated with tablet splitting (p = 0.1062).
Splitting of psychotropic drugs was observed in 22.5% of cases (n = 112); some patients used and split more than one psychotropic drug. Tablet splitting was significantly more frequent among patients using psychotropic drugs than among patients using other therapeutic classes (n = 15, 11.1%), with p = 0.003.
The following results take into account the use of psychotropic drugs, not the overall number of patients. A total of 1,052 prescriptions for psychotropic drugs were issued for the included patients in the year 2012, considering all recorded visits and eliminating repeat prescriptions for the same patient. Of these, 12.3% (n = 129) called for tablet splitting. Nine subjects split more than one type of psychotropic drug, which is why the number of split psychotropic drugs is higher than the total number of individuals who split their tablets.
Antipsychotics were the most commonly affected therapeutic class (n = 33, 23.9%; p = 0.001), followed by other psychotropic drugs (n = 23, 18.7%) and antidepressants (n = 64, 12.3%). The difference between antidepressants and antipsychotics was statistically significant (p < 0.001). Proportionately, the most common antidepressant split was mirtazapine (n = 17, 28.8%), followed by trazodone (n = 20, 21.5%). Risperidone was the most common antipsychotic division (n = 19, 44.2%), followed by olanzapine (n = 5, 38.5%), haloperidol (n = 3, 18.8%), quetiapine (n = 4, 8.3%) and clozapine (n = 2, 8.3%).
Table 2 shows the original dosage strengths of the psychotropic drugs that were split and the doses intended to be achieved by tablet splitting. Trazodone at the dosage strength 150 mg was the only drug for which 1/3 or 2/3 doses were recorded, i.e., the only tablet split into 3 parts. All others were split into halves (1/2 dose).
Of the 20 psychotropic drugs affected by tablet-splitting in this sample, only 45% are available in the Brazilian Unified Health System, according to the 2017 RENAME (Table 3). Considering the target doses intended to be obtained through tablet-splitting, only 16.7% of the psychotropic drugs would be available in the public network, considering both tablets (olanzapine 5 mg and donepezil 5 mg) and liquid dosage forms (haloperidol and carbamazepine), which can also have their dosage adapted to achieve the target dose.
The same drugs listed in RENAME are listed in the Standardized Formulary of the State Department of Health of the Brazilian Federal District (SES/DF), last updated in January 2014, with the addition of imipramine 25 mg (tablet, capsule, or lozenge). Oxcarbazepine is listed in the SES/DF Standardized Formulary, but only in liquid dosage form (oral suspension).
All formulations of the split psychotropic drugs are commercially available in Brazil. Considering the target doses intended to be obtained by tablet splitting, 45.8% (n = 11) are commercially available; an additional five are available in liquid dosage forms, which would raise the availability rate to 62.5% (Table 4).
The most common commercially available formulation is the coated tablet, which in fact was the only available dosage form available for 45% (n = 9) of the medicinal products in question. The psychotropic drugs that were most commonly split in the study (risperidone and mirtazapine) are commercially available in the desired doses (Table 4).
The frequency of psychotropic drug use in this study was 78.6%, probably due to the higher frequency of behavioral disorders observed in this population of individuals with dementia.14,15 The high frequency of tablet splitting of psychotropic drugs observed in this study (n = 112, 22.5%) may be related to the narrow therapeutic range of these drugs, which can often only be achieved with intermediate doses. Clinical management of drug dosage, especially of psychotropic drugs, is essential, both to minimize adverse drug reactions and to ensure the intended therapeutic effect.16 It is also worth noting that tablets are especially divided in the case of children and aging adults, populations that are more vulnerable to the negative clinical consequences of this procedure.17 A Canadian study of older adults in an inpatient geriatric facility found that psychotropic drugs were the therapeutic class most often split (36.3% of all split tablets).5 In addition, pharmacoeconomics studies have shown that tablet splitting is a practice that reduces the acquisition cost of drugs.18,19 A pharmacoeconomic study conducted in the United States, which included the antidepressants sertraline, paroxetine, nefazodone, venlafaxine, fluvoxamine, mirtazapine, and citalopram, found that tablet splitting could lead to annual savings of 30% in expenses related to these drugs, especially for sertraline, paroxetine, and citalopram.18
This may be another factor that makes tablet splitting a viable option for users of the Unified Health System.
Tablet splitting was not associated with patient gender. On the other hand, some studies have found a higher frequency of tablet splitting by women. A Canadian retrospective study of statin tablet splitting identified that women were 23% more likely to split tablets than men.20
Regarding age range, patients over the age of 80 had a significantly higher rate of tablet splitting (33.5%, p = 0.0207). Some studies have reported tablet splitting to be more common in the 61-to-67 age range.18,20-22 However, such studies were not restricted to patients of geriatric facilities, as was the present investigation, which precludes comparison of findings. However, it can be observed that, among populations, in general, the oldest individuals are those most likely to split tablets.
The unavailability of alternative dosage forms in the public health service or commercially may be related to the frequency of tablet splitting. For this analysis, we conducted a survey of the products available in the SUS and for general sale. Some target doses intended to be achieved by tablet splitting are not marketed in Brazil (or simply do not exist) and, thus, cannot be adapted to other dosage forms.
The RENAME contains few available dosage forms of the psychotropic drugs that were split in this study (16.7%), especially for antidepressants, of which the only included agent was bupropion, which is generally used as a smoking cessation aid.23 Regarding antipsychotics (the most commonly split therapeutic class), although all were listed in RENAME, not all had dosage forms available with the intended doses; only olanzapine 5 mg and quetiapine 25 mg were supplied by the public system.
A study of 50 patients with moderate and severe Alzheimer’s disease and their caregivers, conducted at the Geriatrics Division of the Universidade de São Paulo, revealed that difficulty in swallowing and the need for caregiver assistance when eating were significant issues.24 Considering high rates of comorbidities and polypharmacy in older adults,3 the ideal scenario would be the availability of psychotropic drugs in the form of solutions. This need may also extend to patients with schizophrenia, whose treatment requires antipsychotics such as clozapine, haloperidol, and chlorpromazine.25 Of these, only clozapine is not listed in the 2017 RENAME as a solution. The psychotropic drug most commonly split in this study was risperidone (n = 19, 44.2%). Considering that risperidone was among the most widely used atypical antipsychotics in the sample, it is worth noting that it has increased potential for pharmacodynamic interactions in older adults, such as prolongation of the QT interval.26 In the second half of 2017, the solution of risperidone was included in RENAME, but with no provision for its use in patients with Alzheimer’s disease.11
Donepezil is available in the 5 mg dosage strength, thus preventing the splitting of 10-mg tablets. Memantine is not listed in the 2017 RENAME, and is only available commercially in the 10 mg and 20 mg dosage strength; however, the package insert expressly states that tablets can be split. In fact, use of the 5 mg dosage is specifically indicated in the first 3 weeks of treatment.27,28 One factor to consider when splitting tablets is the drug delivery matrix or mechanism. Of the 20 psychotropic drugs split by patients in our sample, 9 (45%) were enteric-coated tablets or extended-release capsules. Some tablet coatings serve to protect the active pharmaceutical ingredient from the effects of gastric acid and promote delivery of the drug into the bowel, thus ensuring absorption in a more alkaline milieu.7 Splitting these tablets causes some of the coating to be lost; the drug is then exposed to gastric acids, leading to a decrease in intestinal absorption and, consequently, lower bioavailability.7 Another type of coating prolongs the disintegration time of the tablet within the gastrointestinal tract, enabling sustained release of the active ingredient and, thus, a different peak absorption time.7 Splitting could lead to faster release of the drug, causing the peak absorption time to be reached sooner and thus altering the dynamic equilibrium of the drug in the body.7 As we were unable to assess the type of coating of the tablets split in this study, we could not analyze potential changes in their pharmacokinetics.
Given the scarcity of studies on this topic, whether due to methodological limitations or to lack of interest from the pharmaceutical industry, the pharmacokinetic consequences of tablet splitting are still largely unknown. A review of the literature found no experimental studies on the absorption profile of the psychotropic drugs included in this study after tablet splitting. Thus, we cannot recommend tablet splitting in clinical practice, and cannot ascertain its safety. In the case of coated tablets, the pharmaceutical purpose of the coating (purely aesthetic, change in the drug release or delivery profile, or protection of the active ingredient) should always be taken into account. Only tablets coated for aesthetic purposes may be split. There has been little research on the uniformity of active ingredient content after tablet splitting, and the current data are insufficient to support any conclusion regarding the efficacy of specific medicinal products after splitting.
One limitation of this study was the fact that analysis was based on secondary data from medical records. The use of secondary data is subject to lack of standardized record keeping, missing data, and difficulty in interpreting data due to illegible writing, all of which may lead to loss of important information.
Furthermore, the medical records used in this study did not contain information on the timing of drug administration or whether drugs were taken with food, both of which are essential factors when analyzing the potential for pharmacokinetic interactions and the effect of tablet splitting on drug absorption. Important details about the act of tablet splitting itself, such as the instrument used to perform it, were also missing from medical records. Such information could only have been obtained by questioning patients or their caregivers.
This study has limited external validity, considering that it was conducted in a sample of predominantly geriatric patients with dementia. Among the split psychotropic drug tablets, few were listed in the 2017 RENAME and, consequently, made available by the Unified Health System. Inclusion of risperidone oral solution 1 mg/mL for the treatment of Alzheimers disease could increase safety, as target doses may be achieved more effectively. In addition, approximately 50% of the doses intended to be achieved via tablet splitting are commercially available as finished medicinal products. Obtaining the input of prescribers and other members of the multidisciplinary team regarding dosage of psychotropics drugs would be important to guide further research and support the inclusion of such drugs in subsequent RENAME updates. In addition, experimental research is needed to evaluate the pharmacotechnical properties and bioavailability of antipsychotics and antidepressants, which were the most commonly split psychotropic drugs in this sample.
Tablet splitting poses a significant challenge, as there is no guarantee of uniformity of concentration of the active ingredient in the split portions. Although the psychotropic drugs that were split in this sample are commercially available, most were not available from the Brazilian Unified Health System in the desired dosage strengths for geriatric patients.
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May 30 2019.
Accepted em August 24 2019.
Conflict of interests: The authors declare no conflict of interests.