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Travel Medicine and Infectious Disease (2014) xx, 1e8
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid
Malaria chemoprophylaxis regimens: A descriptive drug utilization study* Q4
¨chliger a, Patricia Schlagenhauf b, Stephen Toovey c, Marlene Blo Gabriel Schnetzler d, Iain Tatt d, Danitza Tomianovic d, Susan S. Jick e, Christoph R. Meier a,e,f,* a Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy & Epidemiology, Department of Pharmaceutical Sciences, University Basel, Switzerland b University of Zurich Centre for Travel Medicine, Institute for Social and Preventive Medicine, Zurich, Switzerland c Division of Infection and Immunity, Royal Free and University College Medical School, Academic Centre for Travel Medicine and Vaccines, London, UK d F.Hoffmann-La Roche Ltd., Basel, Switzerland e Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, Lexington, MA, United States f Hospital Pharmacy, University Hospital Basel, Switzerland
Received 3 December 2013; accepted 8 May 2014
KEYWORDS Mefloquine; Atovaquone; Proguanil; Chloroquine; Doxycycline
Summary Background: Mefloquine belongs to the priority chemoprophylaxis drugs for travelers to malaria endemic regions. We aimed to assess the prescribing patterns for mefloquine and other antimalarials. Methods: We conducted a descriptive drug utilization study using the U.K. Clinical Practice Research Datalink (CPRD). We assessed characteristics of individuals with a first-time antimalarial prescription for mefloquine, atovaquone/proguanil, chloroquine and/or proguanil, or doxycycline between 2001 and 2012. Results: Of 165,218 individuals with a first-time antimalarial prescription, 108,344 (65.6%), 25,294 (15.3%), 23,195 (14.0%), and 8385 (5.1%) were prescribed atovaquone/proguanil, mefloquine, doxycycline, and chloroquine and/or proguanil, respectively. Among mefloquine users, 7.5% had a history of a neuropsychiatric disorder (versus 12.6%e13.7% among other antimalarial users) and 0.04% had a history of severe liver disease (versus 0.04%e0.1% among other
* The abstract of this paper was presented as a poster at the 8th European Conference on Tropical Medicine and International Health in Copenhagen, Denmark, September 10e13, 2013. * Corresponding author. Basel Pharmacoepidemiology Unit, Hospital Pharmacy, University Hospital Basel, Spitalstrasse 26, CH-4031 Basel, Switzerland. Tel.: þ41 61 556 53 69; fax: þ41 61 265 88 75. E-mail addresses: [email protected] (M. Blo ¨chliger), [email protected] (P. Schlagenhauf), [email protected] (S. Toovey), [email protected] (G. Schnetzler), [email protected] (I. Tatt), [email protected] (D. Tomianovic), sjick@bu. edu (S.S. Jick), [email protected] (C.R. Meier).
http://dx.doi.org/10.1016/j.tmaid.2014.05.006 1477-8939/ª 2014 Published by Elsevier Ltd.
Please cite this article in press as: Blo ¨chliger M, et al., Malaria chemoprophylaxis regimens: A descriptive drug utilization study, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.05.006
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122
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M. Blo ¨chliger et al. antimalarial users). A total of 19.4% mefloquine users were children younger than 12 years (versus 0.4%e15.8% among other antimalarials), and 1.3% pregnant or postpartum women (versus 0.4%e1.4% among users of other antimalarials). Conclusions: The most frequently prescribed antimalarial chemoprophylaxis was atovaquone/ proguanil. Mefloquine was occasionally prescribed for patients with comorbidities listed as contraindications, but most practitioners observed contraindications. Mefloquine was often prescribed for children and pregnant women. ª 2014 Published by Elsevier Ltd.
1. Introduction Malaria is a problem in the tropical and subtropical regions of more than 100 countries, which are visited by more than 125 million travelers each year [1]. Traveler groups include non-immune individuals along with people who originally lived in malaria-endemic areas, then moved abroad and returned to visit friends and relatives (so called VFR travelers) [2]. VFR travelers may retain some degree of immunity to malaria, although this protection tends to be variable and to wane with time away from their country of origin. [3] The standard choices of chemoprophylaxis for travelers to regions with chloroquine resistant P. falciparum comprise atovaquone-proguanil, doxycycline, or mefloquine. [2] Chloroquine is occasionally a chemoprophylaxis option in regions not affected by P. falciparum and in the few areas where P. falciparum is not yet resistant to the drug. [4] Mefloquine has been available for malaria chemoprophylaxis since 1985 and is a highly effective chemoprophylactic drug except in areas of multi-drug resistance [5]. It can be particularly useful in special populations such as pregnant women, infants and small children, and VFR travelers [5]. Like any other agents used for chemoprophylaxis, mefloquine carries the risk of adverse events, predominantly of neuropsychiatric character [6]. Serious adverse events occurring in mefloquine users for malaria prophylaxis are rare [5,7]. However, the U.S. Food and Drug Administration has recently mandated the addition of a boxed warning to the drug label to alert patients and health care professionals of potentially persistent neuropsychiatric side effects associated with the use of the drug [8]. Similarly, additional safety measures (prescriber’s guide and checklist, patient alert card) are currently being implemented with the national health authorities throughout Europe to better manage the risk of adverse drug reactions [9,10]. Mefloquine is contraindicated in patients with severe liver impairment, a history of depression, psychiatric disorders or convulsions, a history of blackwater fever (a complication of falciparum malaria with massive intravascular hemolysis causing hemoglobinuria or the passage of breakdown pigments in urine), and in patients who concomitantly use halofantrine (a drug used for malaria treatment) [6]. Additional special warnings are given for patients with cardiac conduction abnormalities, renal impairment, or blood or lymphatic system disorders (such as aplastic anemia) [6]. We have previously conducted drug safety studies on the risk of severe depression, psychosis or
panic attacks [11], on the risk of central nervous system disorders [7], and on the risk of ocular disorders [13] in association with prophylactic use of antimalarials. We conducted these studies using data from the U.K.-based General Practice Research Database (GPRD), now called Clinical Practice Research Datalink (CPRD). The aim of this study was to better understand the utilization of mefloquine and other antimalarials for chemoprophylaxis within a large real-world setting.
2. Methods 2.1. Study design and data source We conducted a retrospective descriptive drug utilization study using data from the U.K.-based CPRD. This large database encompasses some seven million people who are enrolled with selected general practitioners (GPs), as described in detail elsewhere [13e15]. GPs record patient characteristics (such as sex, year of birth, body mass index [BMI]), medical information (such as diagnoses, drug prescriptions, and laboratory parameters), and practice location in a standard manner and provide it anonymously. Read codes are used to record diagnoses and procedures, and Multilex codes to record drug prescriptions. The records on drug exposure and diagnoses have been validated and proven to be of high quality. [16e18] This study was approved by ISAC (Independent Scientific Advisory Committee for MHRA research).
2.2. Setting We identified in the CPRD all persons who had one or more prescriptions recorded for mefloquine, atovaquoneproguanil, chloroquine and/or proguanil, or doxycycline between January 1st, 2001 and June 30th, 2012. The index date was defined as the date of the initial prescription of one of these four drug groups (henceforth called exposure groups).
2.3. Definition of the study population We included all subjects in the study who had at least 12 months of history in the database prior to the index date. Doxycycline users without a code indicating malaria chemoprophylaxis or malaria infection (within a week before or after the index date) were excluded, as doxycycline can be used for various therapeutic indications other
Please cite this article in press as: Blo ¨chliger M, et al., Malaria chemoprophylaxis regimens: A descriptive drug utilization study, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.05.006
63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124
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MODEL
Malaria chemoprophylaxis regimens than malaria chemoprophylaxis or treatment. Chloroquine and/or proguanil users were categorized into one exposure group as these two drugs are mostly used in combination. We categorized the antimalarial drug users into two therapeutic indication groups: those using antimalarials for chemoprophylaxis and those using the drugs for malaria treatment. Chemoprophylaxis users were defined as subjects with Read code records (within a week before or after the index date) indicating an upcoming travel (such as ‘Travel advice’, ‘Antimalarial drug prophylaxis’, ‘Travel vaccinations’, ‘Yellow fever vaccination’), and with no records indicating an incident malaria infection. Users for treatment were defined as subjects with Read code records (within a week before or after the index date) for an incident malaria infection. However, there were antimalarial drug users who did not have Read code records indicating an upcoming travel or an incident malaria infection. These users were added to the chemoprophylaxis group, as chemoprophylaxis is far more common and likely in this study population.
2.4. Variables We assessed all information available on demographic variables and baseline characteristics of our study population, such as age, sex, weight (kg), body mass index (BMI [kg/ m2]), and ethnic background (based on available Read codes). We also determined the exposure time on chemoprophylaxis (days), where this could be evaluated. Moreover, based on Read codes (where not otherwise specified), we assessed all information available on the history of specific comorbidities (eye disorders; neuropathy; psychiatric disorders such as anxiety, phobia, panic attacks, psychosis, or schizophrenia; depression; seizure disorders; hypertension; diabetes and/or obesity [BMI 30 kg/m2]; atherosclerosis; arrhythmia; anemia [aplastic or dysplastic, hemolytic, or other anemia]; rheumatoid arthritis; lupus erythematosus; migraine; Lyme disease; HIV or AIDS; vitamin B12 deficiency; severe liver disease [defined as liver cirrhosis and/or liver failure]; hepatitis [A, B, C, or unspecified]; renal impairment, defined as an estimated glomerular filtration rate [eGFR]
TMAID747_proof ■ 2 June 2014 ■ 1/8
+
MODEL
Travel Medicine and Infectious Disease (2014) xx, 1e8
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid
Malaria chemoprophylaxis regimens: A descriptive drug utilization study* Q4
¨chliger a, Patricia Schlagenhauf b, Stephen Toovey c, Marlene Blo Gabriel Schnetzler d, Iain Tatt d, Danitza Tomianovic d, Susan S. Jick e, Christoph R. Meier a,e,f,* a Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy & Epidemiology, Department of Pharmaceutical Sciences, University Basel, Switzerland b University of Zurich Centre for Travel Medicine, Institute for Social and Preventive Medicine, Zurich, Switzerland c Division of Infection and Immunity, Royal Free and University College Medical School, Academic Centre for Travel Medicine and Vaccines, London, UK d F.Hoffmann-La Roche Ltd., Basel, Switzerland e Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, Lexington, MA, United States f Hospital Pharmacy, University Hospital Basel, Switzerland
Received 3 December 2013; accepted 8 May 2014
KEYWORDS Mefloquine; Atovaquone; Proguanil; Chloroquine; Doxycycline
Summary Background: Mefloquine belongs to the priority chemoprophylaxis drugs for travelers to malaria endemic regions. We aimed to assess the prescribing patterns for mefloquine and other antimalarials. Methods: We conducted a descriptive drug utilization study using the U.K. Clinical Practice Research Datalink (CPRD). We assessed characteristics of individuals with a first-time antimalarial prescription for mefloquine, atovaquone/proguanil, chloroquine and/or proguanil, or doxycycline between 2001 and 2012. Results: Of 165,218 individuals with a first-time antimalarial prescription, 108,344 (65.6%), 25,294 (15.3%), 23,195 (14.0%), and 8385 (5.1%) were prescribed atovaquone/proguanil, mefloquine, doxycycline, and chloroquine and/or proguanil, respectively. Among mefloquine users, 7.5% had a history of a neuropsychiatric disorder (versus 12.6%e13.7% among other antimalarial users) and 0.04% had a history of severe liver disease (versus 0.04%e0.1% among other
* The abstract of this paper was presented as a poster at the 8th European Conference on Tropical Medicine and International Health in Copenhagen, Denmark, September 10e13, 2013. * Corresponding author. Basel Pharmacoepidemiology Unit, Hospital Pharmacy, University Hospital Basel, Spitalstrasse 26, CH-4031 Basel, Switzerland. Tel.: þ41 61 556 53 69; fax: þ41 61 265 88 75. E-mail addresses: [email protected] (M. Blo ¨chliger), [email protected] (P. Schlagenhauf), [email protected] (S. Toovey), [email protected] (G. Schnetzler), [email protected] (I. Tatt), [email protected] (D. Tomianovic), sjick@bu. edu (S.S. Jick), [email protected] (C.R. Meier).
http://dx.doi.org/10.1016/j.tmaid.2014.05.006 1477-8939/ª 2014 Published by Elsevier Ltd.
Please cite this article in press as: Blo ¨chliger M, et al., Malaria chemoprophylaxis regimens: A descriptive drug utilization study, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.05.006
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122
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M. Blo ¨chliger et al. antimalarial users). A total of 19.4% mefloquine users were children younger than 12 years (versus 0.4%e15.8% among other antimalarials), and 1.3% pregnant or postpartum women (versus 0.4%e1.4% among users of other antimalarials). Conclusions: The most frequently prescribed antimalarial chemoprophylaxis was atovaquone/ proguanil. Mefloquine was occasionally prescribed for patients with comorbidities listed as contraindications, but most practitioners observed contraindications. Mefloquine was often prescribed for children and pregnant women. ª 2014 Published by Elsevier Ltd.
1. Introduction Malaria is a problem in the tropical and subtropical regions of more than 100 countries, which are visited by more than 125 million travelers each year [1]. Traveler groups include non-immune individuals along with people who originally lived in malaria-endemic areas, then moved abroad and returned to visit friends and relatives (so called VFR travelers) [2]. VFR travelers may retain some degree of immunity to malaria, although this protection tends to be variable and to wane with time away from their country of origin. [3] The standard choices of chemoprophylaxis for travelers to regions with chloroquine resistant P. falciparum comprise atovaquone-proguanil, doxycycline, or mefloquine. [2] Chloroquine is occasionally a chemoprophylaxis option in regions not affected by P. falciparum and in the few areas where P. falciparum is not yet resistant to the drug. [4] Mefloquine has been available for malaria chemoprophylaxis since 1985 and is a highly effective chemoprophylactic drug except in areas of multi-drug resistance [5]. It can be particularly useful in special populations such as pregnant women, infants and small children, and VFR travelers [5]. Like any other agents used for chemoprophylaxis, mefloquine carries the risk of adverse events, predominantly of neuropsychiatric character [6]. Serious adverse events occurring in mefloquine users for malaria prophylaxis are rare [5,7]. However, the U.S. Food and Drug Administration has recently mandated the addition of a boxed warning to the drug label to alert patients and health care professionals of potentially persistent neuropsychiatric side effects associated with the use of the drug [8]. Similarly, additional safety measures (prescriber’s guide and checklist, patient alert card) are currently being implemented with the national health authorities throughout Europe to better manage the risk of adverse drug reactions [9,10]. Mefloquine is contraindicated in patients with severe liver impairment, a history of depression, psychiatric disorders or convulsions, a history of blackwater fever (a complication of falciparum malaria with massive intravascular hemolysis causing hemoglobinuria or the passage of breakdown pigments in urine), and in patients who concomitantly use halofantrine (a drug used for malaria treatment) [6]. Additional special warnings are given for patients with cardiac conduction abnormalities, renal impairment, or blood or lymphatic system disorders (such as aplastic anemia) [6]. We have previously conducted drug safety studies on the risk of severe depression, psychosis or
panic attacks [11], on the risk of central nervous system disorders [7], and on the risk of ocular disorders [13] in association with prophylactic use of antimalarials. We conducted these studies using data from the U.K.-based General Practice Research Database (GPRD), now called Clinical Practice Research Datalink (CPRD). The aim of this study was to better understand the utilization of mefloquine and other antimalarials for chemoprophylaxis within a large real-world setting.
2. Methods 2.1. Study design and data source We conducted a retrospective descriptive drug utilization study using data from the U.K.-based CPRD. This large database encompasses some seven million people who are enrolled with selected general practitioners (GPs), as described in detail elsewhere [13e15]. GPs record patient characteristics (such as sex, year of birth, body mass index [BMI]), medical information (such as diagnoses, drug prescriptions, and laboratory parameters), and practice location in a standard manner and provide it anonymously. Read codes are used to record diagnoses and procedures, and Multilex codes to record drug prescriptions. The records on drug exposure and diagnoses have been validated and proven to be of high quality. [16e18] This study was approved by ISAC (Independent Scientific Advisory Committee for MHRA research).
2.2. Setting We identified in the CPRD all persons who had one or more prescriptions recorded for mefloquine, atovaquoneproguanil, chloroquine and/or proguanil, or doxycycline between January 1st, 2001 and June 30th, 2012. The index date was defined as the date of the initial prescription of one of these four drug groups (henceforth called exposure groups).
2.3. Definition of the study population We included all subjects in the study who had at least 12 months of history in the database prior to the index date. Doxycycline users without a code indicating malaria chemoprophylaxis or malaria infection (within a week before or after the index date) were excluded, as doxycycline can be used for various therapeutic indications other
Please cite this article in press as: Blo ¨chliger M, et al., Malaria chemoprophylaxis regimens: A descriptive drug utilization study, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.05.006
63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124
TMAID747_proof ■ 2 June 2014 ■ 3/8
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MODEL
Malaria chemoprophylaxis regimens than malaria chemoprophylaxis or treatment. Chloroquine and/or proguanil users were categorized into one exposure group as these two drugs are mostly used in combination. We categorized the antimalarial drug users into two therapeutic indication groups: those using antimalarials for chemoprophylaxis and those using the drugs for malaria treatment. Chemoprophylaxis users were defined as subjects with Read code records (within a week before or after the index date) indicating an upcoming travel (such as ‘Travel advice’, ‘Antimalarial drug prophylaxis’, ‘Travel vaccinations’, ‘Yellow fever vaccination’), and with no records indicating an incident malaria infection. Users for treatment were defined as subjects with Read code records (within a week before or after the index date) for an incident malaria infection. However, there were antimalarial drug users who did not have Read code records indicating an upcoming travel or an incident malaria infection. These users were added to the chemoprophylaxis group, as chemoprophylaxis is far more common and likely in this study population.
2.4. Variables We assessed all information available on demographic variables and baseline characteristics of our study population, such as age, sex, weight (kg), body mass index (BMI [kg/ m2]), and ethnic background (based on available Read codes). We also determined the exposure time on chemoprophylaxis (days), where this could be evaluated. Moreover, based on Read codes (where not otherwise specified), we assessed all information available on the history of specific comorbidities (eye disorders; neuropathy; psychiatric disorders such as anxiety, phobia, panic attacks, psychosis, or schizophrenia; depression; seizure disorders; hypertension; diabetes and/or obesity [BMI 30 kg/m2]; atherosclerosis; arrhythmia; anemia [aplastic or dysplastic, hemolytic, or other anemia]; rheumatoid arthritis; lupus erythematosus; migraine; Lyme disease; HIV or AIDS; vitamin B12 deficiency; severe liver disease [defined as liver cirrhosis and/or liver failure]; hepatitis [A, B, C, or unspecified]; renal impairment, defined as an estimated glomerular filtration rate [eGFR]
