Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis (2020) / Chapter Skim
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7 Doxycycline
7 Doxycycline
Pages 247-290
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From page 247... ...
. The approved dosing regimen for malaria prophylaxis for adults is 100 mg per day 1–2 days before entering an endemic area, 100 mg per day while in the endemic area, and 100 mg daily for 28 days after leaving an endemic area.
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From page 248... ...
. Overall, studies suggest that adherence rates for doxycycline range from 70% to 84% when it is used for malaria prophylaxis, and adhering to the dosing regimen may be more challenging than adhering to dosing regimens for weekly prophylaxis medications (e.g., mefloquine, tafenoquine)
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From page 249... ...
This is followed by an overview of the pharmacokinetic properties of doxycycline. Known concurrent adverse events associated with use of doxycycline when used at the dose and interval as directed for malaria prophylaxis are summarized, followed by a presentation of detailed summaries and assessments of the seven identified epidemiologic studies that met the committee's inclusion criteria and were able to contribute some information on persistent or latent health outcomes following the cessation of doxycycline.
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. Because package inserts dated prior to 2005 were not available, it could not always be determined whether a formulation had ever been indicated for malaria prophylaxis or, if it was, when the indication was added.
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(2008) , the investigators examined the anticoagulant–doxycycline interaction by analyzing the PHARMO Record Linkage System where patients were followed through the end of coumarin treatment, and they found a 2.5-fold increased risk for increased bleeding episodes in participants who were concurrently using doxycycline and acenocoumarol or phenprocoumon; these findings have been confirmed in other studies (Hasan, 2007)
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From page 252... ...
, and doxycycline hyclate are or had been indicated for malaria prophylaxis. The 2005 package inserts for the three Doryx® formulations (FDA, 2005a,b)
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According to FDA, the absorption of doxycycline "is not markedly influenced by simultaneous ingestion of food and milk," despite the reduced absorption observed with other tetracyclines, and taking doxycycline with food is recommended to prevent concurrent adverse gastrointestinal events. Unlike the case with other tetracyclines, the excretion of doxycycline occurs primarily by the gastrointestinal tract and to a much lesser extent by the kidneys.
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From page 254... ...
Epidemiologic studies of persistent adverse events in which information was presented regarding the adverse events occurring at least 28 days post-doxycycline-cessation are then summarized, with the emphasis on reported results of persistent adverse events associated with the use of doxycycline, including results of studies in which other antimalarial drugs were used as a comparison group. Concurrent Adverse Events The FDA package insert for doxycycline uses information from trials that used doxycycline at dosages or for purposes other than for malaria prophylaxis (e.g., urogenital Chlamydia trachomatis infection)
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From page 255... ...
. The purpose of the assessment was to summarize the efficacy and safety of mefloquine for malaria prophylaxis in adult, children, and pregnant women travelers compared with other antimalarials (including doxycycline)
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However, for psychiatric adverse events reported in the cohort studies, doxycycline users were statistically significantly less likely than mefloquine users to report abnormal dreams, insomnia, anxiety, and depressed mood, although the pooled effect estimates were very imprecise. Whereas there were 15 episodes of abnormal thoughts and perceptions with mefloquine, no episodes were reported for doxycycline users in the cohort studies.
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From page 257... ...
The primary study objective was to assess and compare the risk of incident and recurrent International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) -coded neurologic and psychiatric outcomes (adjustment disorder, anxiety disorder, depressive disorder, posttraumatic stress disorder (PTSD)
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From page 258... ...
Effect estimates of the neurologic and psychiatric outcomes for mefloquine and A/P are reported in the relevant chapters. For doxycycline users, the highest incident rates in both the deployed and nondeployed were for adjustment disorder (56.92 versus 44.35 per 1,000 person-years, respectively)
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From page 259... ...
Although the authors report higher risks for several outcomes among doxycycline users compared with mefloquine users, particularly among the nondeployed, the IRRs are not adjusted for history of neurologic or psychiatric outcomes. Given the evidence that such a history is a very strong predictor of subsequent events (as shown in table 7 of the article)
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The deployed doxycycline users reported increased frequencies of mental health diagnoses compared with nondeployed doxycycline users: PTSD (17.9% versus 11.1%) , other anxiety disorders (11.2% versus 7.1%)
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, important covariates of deployment and combat exposure were considered in addition to demographics and other military characteristics, and the data were appropriately analyzed. It is noteworthy that adjusting for combat exposure consistently reduced the measures of association for adverse psychiatric events related to doxycycline use.
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. All doxycycline prescriptions taken by deployed individuals were assumed to be for malaria prophylaxis; in nondeployed individuals, the timing, duration, and indication for doxycycline were not collected.
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returned Peace Corps volunteers (who had served during 1995–2014) to compare the prevalence of selected health conditions after Peace Corps service between those who reported taking malaria prophylaxis (n = 5,055, 56.6%)
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and all of those who had not. Thus, the comparison group for each antimalarial was a mixture of those who did not report taking any antimalarials and those who reported taking antimalarial drugs other than the one being examined.
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. Using the GPRD, investigators identified individuals who had at least one prescription for mefloquine, A/P, doxycycline, or chloroquine and/or proguanil in the time period of interest and who had a pretravel consultation within 1 week of the date of the prescription that included specific codes indicating that the prescription was for malaria prophylaxis.
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From page 266... ...
Schwartz and Regev-Yochay (1999) performed a prospective observational study, and followed 158 Israeli male and female travelers aged 22–65 years who took part in rafting trips on the Omo River, Ethiopia, and who had visited a travel clinic to obtain malaria prophylaxis.
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. It is limited by its small sample size, the nonrandomized design, and the lack of details on adverse events beyond reporting that no severe events occurred and only one withdrawal was reported among doxycycline users.
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. Case Reports The committee reviewed 14 published studies, totaling 23 cases, of adverse events related to the use of doxycycline in malaria prophylaxis.
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Selected Subpopulations In the course of its review of the literature on doxycycline, the committee identified and reviewed available studies that reported results stratified by demographic, medical, or behavioral factors to assess whether the risk for adverse events when using doxycycline for prophylaxis is associated with being part of or affiliated with a specific group. This was not done exhaustively, and the evidence included in this section is generally limited to concurrent adverse events observed with use of doxycycline.
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From page 270... ...
The committee found no evidence of persistent or latent adverse neurologic or psychiatric consequences in human or in preclinical models at doses relevant to malarial prophylaxis. In one study comparing doxycycline with other tetracyclines, evidence for vertigo was reported following minocycline, but not doxycycline, treatment (Cunha et al., 1982)
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From page 271... ...
. Thus, while it is possible that doxycycline could affect the brain via a rearrangement of the microbiome, there is no definitive evidence to support adverse events of long-term doxycycline exposure on brain function via this mechanism.
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. SYNTHESIS AND CONCLUSIONS Although some people who take doxycycline do develop concurrent adverse events, such as photosensitivity, and there have been a few case reports of severe concurrent adverse events, the available post-cessation epidemiologic evidence does not find an association between the use of doxycycline for malaria prophylaxis and persistent or latent adverse events.
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From page 273... ...
Consistent with the chapter syntheses of other antimalarial drugs, this synthesis is organized by body system category: neurologic disorders, psychiatric disorders, gastrointestinal disorders, eye disorders, cardiovascular disorders, and other outcomes and disorders, including dermatologic and biochemical parameters. Each conclusion consists of two parts: the first sentence assigns the level of association, and the second sentence offers additional detail regarding whether further research in a particular area is merited based on consideration of all the available evidence.
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From page 274... ...
(2004) conducted a study using data from the UK-based GPRD to assess the incidence and to compare the odds of first-time neurologic or psychiatric diagnoses in individuals aged 17–79 years using mefloquine compared with individuals using other antimalarial drugs, including doxycycline, for malaria prophylaxis.
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From page 275... ...
Neurologic Disorders Although some studies grouped adverse events under a more general category of "neuropsychiatric effects" for discussion, the committee separated neurologic and psychiatric symptoms and conditions to the extent possible. The FDA label and package insert state that intracranial hypertension may be associated with use of doxycycline at the dose and frequency recommended for malaria prophylaxis, with clinical manifestations that include headache, blurred vision, diplopia, vision loss, and papilledema via fundoscopy.
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The committee found no evidence of persistent or latent adverse neurologic events in preclinical models at doses relevant to malaria prophylaxis. The committee found little evidence to support or refute a role for doxycycline in promoting somatic and brain dysfunction.
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Based on the available evidence, the committee concludes that there is insufficient or inadequate evidence of an association between the use of doxycycline for malaria prophylaxis and persistent or latent neurologic events. Current evidence does not suggest further study of such an association is warranted, given the lack of evidence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies.
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From page 278... ...
When comparisons between mefloquine and doxycycline use were stratified by deployment, the only statistically significant difference for any of the psychiatric outcomes for the deployed was a slightly decreased risk for anxiety disorders among doxycycline users. Among the nondeployed, doxycycline users had statistically significantly increased risks of adjustment disorder, insomnia, anxiety disorder, depressive disorder, and PTSD compared with mefloquine users, but no difference was found for the other five psychiatric outcomes.
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(2017) found its risk to be statistically significantly increased among nondeployed doxycycline users compared with mefloquine users.
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Based on the available evidence, the committee concludes that there is insufficient or inadequate evidence of an association between the use of doxycycline for malaria prophylaxis and persistent or latent psychiatric events. Current evidence does not suggest further study of such an association is warranted, given the lack of evidence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies.
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From page 281... ...
Eye Disorders The FDA package insert does not contain any information on eye disorders associated with the use of doxycycline, although secondary effects of blurred vision, diplopia, and vision loss may occur as a result of intracranial hypertension. A systematic review conducted in short-term travelers examining concurrent adverse events of malaria prophylaxis found that, based on two cohort studies, visual impairment was statistically significantly less commonly reported among doxycycline users than mefloquine users (Tickell-Painter et al., 2017)
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From page 282... ...
Based on the available evidence, the committee concludes that there is insufficient or inadequate evidence of an association between the use of doxycycline for malaria prophylaxis and persistent or latent eye disorders. Current evidence does not suggest further study of such an association is warranted, given the lack of evidence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies.
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From page 283... ...
Schwartz and Regev-Yochay (1999) followed 158 Israeli travelers who took part in rafting trips on the Omo River, Ethiopia, and who had visited a travel clinic to obtain malaria prophylaxis.
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1990. A comparative study of gastrointestinal infections in United States soldiers receiving doxycy cline or mefloquine for malaria prophylaxis.
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2012. Compliance with antimalaria prophylaxis in a combat zone.
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2005. Mefloquine and doxycycline malaria prophylaxis in Australian soldiers in East Timor.
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doxycycline–placebo for malaria prophylaxis in nonimmune soldiers: A double-blind random ized field trial in sub-Saharan Africa. Trans R Soc Trop Med Hyg 104(4)
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1993. Recent military experience with malaria prophylaxis.
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2017. Long-term health outcomes among returned Peace Corps volunteers after malaria prophylaxis, 1995-2014.
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1989. Malaria prophylaxis with doxycycline in soldiers deployed to the Thai–Kampuchean border.
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