Other: Bulging fontanels in infants and intracranial hypertension in adults. When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid function studies are known to occur. In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures.
Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage. The usual dosage and frequency of administration of doxycycline differs from that of the other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of side effects. In the management of more severe infections particularly chronic infections of the urinary tract , mg every 12 hours is recommended.
For all pediatric patients weighing less than 45 kg with severe or life-threatening infections e. Children weighing 45 kg or more should receive the adult dose. For pediatric patients with less severe disease greater than 8 years of age and weighing less than 45 kg , the recommended dosage schedule is 4. For pediatric patients weighing over 45 kg, the usual adult dose should be used.
The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage. Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration. If gastric irritation occurs, it is recommended that doxycycline be given with food or milk. The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk.
Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of doxycycline in patients with renal impairment. Uncomplicated gonococcal infections in adults except anorectal infections in men : mg, by mouth, twice a day for 7 days.
As an alternate single visit dose, administer mg stat followed in one hour by a second mg dose. The dose may be administered with food, including milk or carbonated beverage, as required. Uncomplicated urethral, endocervical, or rectal infection in adults caused by Chlamydia trachomatis : mg, by mouth twice a day for 7 days. Nongonococcal urethritis NGU caused by C. Syphilis — early: Patients who are allergic to penicillin should be treated with doxycycline mg, by mouth, twice a day for 2 weeks.
Syphilis of more than one year's duration: Patients who are allergic to penicillin should be treated with doxycycline mg, by mouth, twice a day for 4 weeks. Acute epididymo-orchitis caused by N. Acute epididymo-orchitis caused by C. For prophylaxis of malaria: For adults, the recommended dose is mg daily. Prophylaxis should begin 1 to 2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area.
Doxycycline hyclate capsules, USP contain doxycycline hyclate equivalent to doxycycline 50 mg or mg. Doxycycline hyclate capsules USP, 50 mg are yellowish powder filled in size '3' hard gelatin capsule with light blue opaque cap imprinted with 'CHL' in white ink and white opaque body imprinted with 'D75' in black ink. Doxycycline hyclate capsules USP, mg contains yellowish powder filled in size '1' hard gelatin capsule with light blue opaque cap imprinted with 'CHL' in white ink and light blue opaque body imprinted with 'D76' in black ink.
Dispense in tight, light-resistant containers USP. Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO 4 , and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO 4 , and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.
Minocycline, tetracycline PO 4 , methacycline, doxycycline, tetracycline base, oxytetracycline hydrochloride and tetracycline hydrochloride were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake.
Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet. Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs minocycline ; in chickens chlortetracycline ; and in rats and mice oxytetracycline. Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.
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View Package Photos. Drug Label Info. NDC National Drug Code - Each drug product is assigned this unique number which can be found on the drug's outer packaging. Drug Label Information Updated January 8, If you are a consumer or patient please visit this version. The structural formula of doxycycline hyclate is. Hemodialysis does not alter serum half-life. Microbiology Mechanism of Action Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit.
Resistance Cross resistance with other tetracyclines is common. Treatment Doxycycline is indicated for the treatment of the following infections: Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. Respiratory tract infections caused by Mycoplasma pneumoniae. Lymphogranuloma venereum caused by Chlamydia trachomatis. Psittacosis ornithosis caused by Chlamydophila psittaci. Trachoma caused by Chlamydia trachomatis , although the infectious agent is not always eliminated, as judged by immunofluorescence.
Inclusion conjunctivitis caused by Chlamydia trachomatis. Uncomplicated urethral, endocervical, or rectal infections in adults caused by Chlamydia trachomatis.
It also contains ascorbic acid mg and mannitol mg as inactive ingredients and does not contain preservatives. Tetracyclines are readily absorbed and are bound to plasma proteins in varying degree. They are concentrated by the liver in the bile, and excreted in the urine and feces at high concentrations and in a biologically active form. Following a single mg dose administered in a concentration of 0. Studies have shown no significant difference in serum half-life of doxycycline range 18 to 22 hours in individuals with normal and severely impaired renal function.
Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria.
Nocardiae and other aerobic Actinomyces species. The precise mechanism of action of the drug is not known. To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline for injection and other antibacterial drugs, doxycycline for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Because many strains of the following groups of microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended.
Doxycycline is indicated for treatment of infections caused by the following gram-negative microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug:. Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug:.
Up to 44 percent of strains of Streptococcus pyogenes and 74 percent of Streptococcus faecalis have been found to be resistant to tetracycline drugs.
Therefore, tetracyclines should not be used for streptococcal disease unless the organism has been demonstrated to be sensitive. For upper respiratory infections due to group A beta-hemolytic streptococci, penicillin is the usual drug of choice, including prophylaxis of rheumatic fever.
Streptococcus pneumoniae , Staphylococcus aureus , respiratory skin and soft tissue infections. Tetracyclines are not the drugs of choice in the treatment of any type of staphylococcal infections. Anthrax due to Bacillus anthracis , including inhalational anthrax post-exposure : to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.
When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of infections due to:. Doxycycline is indicated in the treatment of trachoma, although the infectious agent is not always eliminated, as judged by immunofluorescence. This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. The use of drugs of the tetracycline class during tooth development last half of pregnancy, infancy and childhood to the age of 8 years may cause permanent discoloration of the teeth yellow-gray-brown.
This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions e.
Clostridium difficile associated diarrhea CDAD has been reported with use of nearly all antibacterial agents, including doxycycline, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. Hypertoxin producing strains of C. CDAD must be considered in all patients who present with diarrhea following the use of antibacterial drugs. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms DRESS have been reported in patients receiving doxycycline.
If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted. Intracranial hypertension IH, pseudotumor cerebri has been associated with the use of tetracyclines including doxycycline. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy.
Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and doxycycline should be avoided because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists.
If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. The usual dosage and frequency of administration of doxycycline differs from that of the other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of side effects.
In the management of more severe infections particularly chronic infections of the urinary tract , mg every 12 hours is recommended. For all pediatric patients weighing less than 45 kg with severe or life-threatening infections e. Children weighing 45 kg or more should receive the adult dose. For pediatric patients with less severe disease greater than 8 years of age and weighing less than 45 kg , the recommended dosage schedule is 4.
For pediatric patients weighing over 45 kg, the usual adult dose should be used. The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage. Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration.
If gastric irritation occurs, it is recommended that doxycycline be given with food or milk. The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of doxycycline in patients with renal impairment. Uncomplicated gonococcal infections in adults except anorectal infections in men : mg, by mouth, twice a day for 7 days.
As an alternate single visit dose, administer mg stat followed in one hour by a second mg dose. The dose may be administered with food, including milk or carbonated beverage, as required. Uncomplicated urethral, endocervical, or rectal infection in adults caused by Chlamydia trachomatis: mg, by mouth twice a day for 7 days.
Nongonococcal urethritis NGU caused by C. Syphilis — early: Patients who are allergic to penicillin should be treated with doxycycline mg, by mouth, twice a day for 2 weeks. Syphilis of more than one year's duration: Patients who are allergic to penicillin should be treated with doxycycline mg, by mouth, twice a day for 4 weeks.
Acute epididymo-orchitis caused by N. Acute epididymo-orchitis caused by C. For prophylaxis of malaria: For adults, the recommended dose is mg daily. Prophylaxis should begin 1—2 days before travel to the malarious area.
Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area. Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO 4 , and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO 4 , and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.
Minocycline, tetracycline PO 4 , methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet.
Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs minocycline ; in chickens chlortetracycline ; and in rats and mice oxytetracycline. Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.
This product's labeling may have been updated. For the most recent prescribing information, please visit www. The structural formula of doxycycline monohydrate is. Hemodialysis does not alter serum half-life. Microbiology Mechanism of Action Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Resistance Cross resistance with other tetracyclines is common. Gram-Negative Bacteria Acinetobacter species Bartonella bacilliformis Brucella species Klebsiella species Klebsiella granulomatis Campylobacter fetus Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Neisseria gonorrhoeae Shigella species Vibrio cholerae Yersinia pestis.
Anaerobic Bacteria Clostridium species Fusobacterium fusiforme Propionibacterium acnes. Other Bacteria Nocardiae and other aerobic Actinomyces species Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pallidum subspecies pertenue Ureaplasma urealyticum.
Parasites Balantidium coli Entamoeba species Plasmodium falciparum 1 1 Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum , but not against the gametocytes of P.
The precise mechanism of action of the drug is not known. Treatment Doxycycline is indicated for the treatment of the following infections: Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. Respiratory tract infections caused by Mycoplasma pneumoniae. Lymphogranuloma venereum caused by Chlamydia trachomatis. Psittacosis ornithosis caused by Chlamydophila psittaci. Trachoma caused by Chlamydia trachomatis , although the infectious agent is not always eliminated, as judged by immunofluorescence.
Inclusion conjunctivitis caused by Chlamydia trachomatis. Uncomplicated urethral, endocervical, or rectal infections in adults caused by Chlamydia trachomatis. Nongonococcal urethritis caused by Ureaplasma urealyticum.
Relapsing fever due to Borrelia recurrentis. Doxycycline is also indicated for the treatment of infections caused by the following gram-negative microorganisms: Chancroid caused by Haemophilus ducreyi.
Plague due to Yersinia pestis. Tularemia due to Francisella tularensis. Cholera caused by Vibrio cholerae. Campylobacter fetus infections caused by Campylobacter fetus. However, there is little scientific evidence of adverse pregnancy outcomes associated with doxycycline use during pregnancy. An expert review of published data on experiences with doxycycline use during pregnancy by the Teratogen Information System concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk the quantity and quality of data were judged to be limited to fair , but the data are insufficient to state that there is no risk Friedman and Polifka, Czeizel and Rockenbauer conducted a case—control study in mothers of infants with and without congenital anomalies 18, and 32,, respectively and found a weak, marginally significant association with total malformations and doxycycline use anytime during pregnancy; however, the association was not seen when the analysis was restricted to maternal treatment during the period of organogenesis i.
Other studies have reported mixed results on the impact of doxycycline use during pregnancy on congenital malformations; Cooper et al. While the tetracycline class of antibiotics is associated with increased blood urea levels, doxycycline specifically was shown to be safe for use in patients with renal failure or insufficiency George and Evans, The dosage of doxycycline should be doubled in individuals taking antiepileptic drugs, such as carbamazepine, phenytoin, and phenobarbitone.
These drugs cause doxycycline to be metabolized more quickly than usual and can reduce the effectiveness of this antimalarial medication; therefore, some research has suggested that twice the normal prophylactic doxycycline dose should be taken to ensure sufficient protection from malaria Minshall, Overall, there is a lack of systematic studies of the long-term actions of doxycycline at prophylactic doses mg per day in adult humans on brain or nervous system function.
There is little evidence to support or refute a role for doxycycline in promoting somatic and brain dysfunction. 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. Doxycycline inhibits matrix metalloproteases MMPs , which are enzymes that break down extracellular matrix and are associated with enhanced tissue damage and inflammation Bench et al. Studies performed in multiple organisms mice, rats, cattle, chickens indicate beneficial effects in the prevention or treatment of connective tissue—related conditions joint inflammation, cardiac fibrotic changes, etc.
Bench et al. Given their mechanism of action, interference with MMPs would not be predicted to have adverse neurologic consequences. Indeed, increased MMP activity is associated with central nervous system damage and neurodegenerative processes Rempe et al. For example, one study showed doxycycline treatment can reduce blood—brain barrier leakage following malarial infection in mice Schmidt et al.
Long-term doxycycline is used to turn gene expression on or off in mouse models using tetracycline-responsive transgene promoters. In these types of studies, doxycycline may be either injected or administered continuously over protracted time periods weeks via the drinking water; the latter method is more common.
The drug binds to a tetracycline-sensitive promoter in a transgene, and once bound it will promote either activation or inhibition of the expression of downstream gene products.
These studies often involve a doxycycline-only control group, and doxycycline alone does not affect the reported endpoints being measured in these studies many null effects Belteki et al. However, doxycycline alone has not been examined as an independent variable, and thus the neurologic and behavioral impact of doxycycline has not been tested against non-doxycycline controls.
The fact that doxycycline has antibiotic and antimicroglial activity makes it possible that the drug can alter brain inflammatory processes. Microglia are receiving a lot of attention as possible mediators of brain disorders, including depression. There is some evidence to suggest that doxycycline may be beneficial in limiting microglial-related neuroinflammatory processes, showing efficacy in reducing microglial proliferation following the intracerebral injection of toxic amyloid beta peptide and attenuating cytokine expression in a murine model of Alzheimer disease Balducci et al.
Similarly, the gut microbiome appears to modulate affective behaviors in mice and rats Bastiaanssen et al. There are not a lot of data analyzing the impact of doxycycline on microbiota Saarela et al. 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.
Doxycycline is an antibiotic that affects inflammatory processes as well as decreases gut microbiota including beneficial probiotic bacteria Saarela et al. One study found that doxycycline can exacerbate colon cancer in a murine model and that it can actually enhance gut inflammation in this paradigm Nanda et al. However, there is also evidence for gastroprotection in an ulcer model Singh et al. The weight of the data suggest that adverse doxycycline effects on gastrointestinal function may be related to inflammatory changes in the gut, which is likely to vary substantially between individuals.
These occur in a minority of users and dissipate once treatment is discontinued. Doxycycline can cause gastrointestinal symptoms in other species, including rats, mice, horses, cattle, and cats Davis et al.
The studies often involve suprapharmacologic dosing over short time periods. Some of the consequences can be severe and usually involve the foregut esophagus, stomach. The intensity of symptoms appears to be related to the formulation acidity Malmborg, The exact mechanism by which doxycycline produces esophagitis and esophageal ulcers is not completely understood. Its acidity has been considered a major factor with respect to its ability to damage the esophageal mucosa.
Doxycycline accumulates within the basal layer of squamous epithelium in rats Giger et al. Human case reports of doxycycline-induced esophageal ulcers have supported the experimental evidence, in which diffuse degeneration of the basal layer was observed while the upper layer of esophageal mucosa was unaffected Banisaeed et al. Other factors such as the drug dissociation rate Bailey et al. Doxycycline is known to produce photosensitivity in response to ultraviolet UV -A radiation, mediated by oxidative stress and mitochondrial toxicity.
Accordingly, individuals undergoing doxycycline treatment including for malarial prophylaxis are warned to avoid sun exposure, and encouraged to wear protective clothing and apply broad-spectrum sunscreen protecting against both UV-A and UV-B radiation Tan et al. 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.
The studies are heterogeneous in the populations that were included active military, veterans, U. Peace Corps volunteers, travelers, and endemic populations , in the modes of data collection on drug exposure, adverse events, and covariates administrative records, researcher collected, self-report , and particularly in the nature of the health outcomes that were considered.
In most cases the focus of the studies was on neurologic or psychiatric conditions or a general assessment of adverse events of all types. Within a particular adverse event category, such as psychiatric conditions, the information elicited ranged from more minor symptoms such as anxiety to severe clinical disorders e. Furthermore, the relevant studies were notably inconsistent in the reporting of results, and they covered different time periods in relation to the cessation of drug exposure.
Given the inherently imperfect information generated by any one study, it would be desirable to have similar studies to assess the consistency of findings, but the diversity of methods used makes it very difficult to combine information across studies with confidence. Each of the included epidemiologic studies possessed strengths and limitations related to the specific methodology used, and the findings from those studies with the highest methodologic quality were given more weight when drawing conclusions.
To avoid repetition for each outcome category, a short summary of the attributes of each study that was considered to be most contributory to the evidence base or that presented evidence germane to multiple outcome categories is presented first.
The evidence summaries for each outcome category refer back to these short assessment summaries. In addition to the post-cessation epidemiologic studies, the committee also considered supplemental evidence when making its conclusions, including recognized concurrent adverse events, case reports of persistent or latent adverse events, studies of adverse events in pregnant women and people with comorbid conditions, and information from experimental animal models or cell cultures.
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.
Eick-Cost et al. The primary study objective was to assess and compare the risk of incident and recurrent ICDCM-coded neurologic and psychiatric outcomes that were reported at medical care visits during concurrent antimalarial use plus days after the end of a prescription.
This was a well-designed study and included several important features that increased its methodologic quality: a large sample size, the use of an administrative data source for both exposure and outcomes, and careful consideration of potential confounders including demographics, psychiatric history, and the military characteristics of deployment and combat exposure. The use of medical diagnoses is likely to be more reliable for the outcomes than self-report, but there was no validation of the diagnoses recorded in the administrative databases, and symptoms or events that did not result in a medical visit or diagnosis would have been missed.
For PTSD diagnoses there was no information on when the index trauma occurred. Exposure and outcomes were systematically obtained, and psychiatric outcomes were measured by standardized assessment instruments. Antimalarial medication use was grouped by mefloquine, chloroquine, doxycycline, primaquine, mefloquine in combination with other drugs, other antimalarials, and not specified or no antimalarial drug exposures. The overall sample was large, and the researchers used a reasonably thorough set of covariates in models estimating drug—outcome associations, including deployment and combat exposure.
Although the time period of drug use and the timing of health outcomes were not directly addressed, given that the population was all veterans who had served between and and that the survey was not administered until —, it is reasonable to assume that antimalarial drug use had ceased some time before. The use of data from GPRD a well-established platform designed for both clinical practice and research allowed for adequate power to detect differences in outcomes and for the uniform collection of exposures although recorded drug prescriptions do not equate to use or adherence and outcomes based on clinical diagnoses coded from medical care visits that were not subject to recall bias.
Events that did not result in a medical care visit or that occurred outside of the national health care system would have been missed, and there may also be some differences between the travelers who traveled to malaria-endemic areas versus areas that are not endemic for malaria, which could lead to some apparent differences in outcomes between the groups.
However, it is unlikely that this would result in differential selection bias. Diagnoses were defined a priori, which excluded other outcomes, including the potential to identify rare outcomes. The antimalarial-exposed populations were large, an appropriate comparison group of travelers not using any form of malaria prophylaxis was included, and health outcomes were reported in defined time periods, including current use through 90 days after a prescription ended termed recent use in analyses and 91— days following the cessation of use termed past use in analyses.
Adjustments were made for several confounders, including age, sex, calendar time, practice, smoking status, and BMI using appropriate study design or analytic methods. Each study included a nested case—control component that allowed for the control of important covariates. The primary aim of Tan et al. A number of important covariates, such as psychiatric history and alcohol use, were collected, but the study had several methodologic limitations.
The evidence generated by this study was thus considered to only weakly contribute to the inferences of doxycycline use and persistent or latent adverse events or disorders. 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.
The risk of intracranial hypertension is increased in women of childbearing age who are overweight or have a history of intracranial hypertension and in those using isotretinoin concomitantly. Based on a systematic review of short-term travelers, there were no statistically significant differences for headache or dizziness associated with concurrent drug use when doxycycline users were compared with mefloquine users. Other concurrent neurologic adverse events were reported by individual cohort studies, including balance disorder, fatigue, hypoaesthesia numbness , and palpitations and tinnitus, but for all of these outcomes there was either no difference in risk or a higher risk for mefloquine users than for doxycycline users Tickell-Painter et al.
Individuals with epilepsy who are taking antiepileptic drugs may need to double the dosage of doxycycline because these drugs cause doxycycline to be metabolized more quickly than usual and may reduce its effectiveness against malaria Minshall, Experimental animal and human cell culture studies that used doxycycline were also examined for evidence of mechanisms that could plausibly support adverse events.
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. Doxycycline may inhibit matrix metalloproteases, but this is not predicted to have adverse neurologic consequences indeed, MMP activation is associated with central nervous system damage and neurodegenerative processes, suggesting doxycycline may be of benefit in this context.
Two epidemiologic studies included neurologic outcomes that occurred at least 28 days following the cessation of doxycycline Eick-Cost et al. Both studies examined different neurologic outcomes with little overlap and used different methods to identify neurologic events. While both studies have limitations, Eick-Cost et al. In their analysis of data from DoD administrative databases, Eick-Cost et al.
The results of a sensitivity analysis in which the risk period was restricted to 30 days post-prescription were not reported, although the authors stated that the results were similar to those of the primary analyses. Adjusted incident rates for confusion, vertigo, and convulsions—but not for tinnitus—were higher among the nondeployed than among the deployed groups who used doxycycline. When stratified by deployment, no statistically significant difference for any of the neurologic outcomes was found between deployed doxycycline users and mefloquine users.
Among the nondeployed, doxycycline users had a statistically significantly increased risk of vertigo compared with mefloquine users, but no difference was found for the other three neurologic outcomes. When the population was restricted to the first mefloquine or doxycycline prescription per individual and included individuals with a prior history of a neurologic or psychiatric diagnosis, individuals with a neurologic diagnosis in the year preceding the prescription had statistically significantly elevated risks for a subsequent diagnosis of the same condition for all neurologic conditions reported tinnitus, vertigo, and convulsions compared with individuals without a diagnosis in the prior year.
There were no statistically significant differences between mefloquine and doxycycline users for tinnitus, vertigo, or convulsions for people who had a prior neurologic diagnosis or for when users of these drugs were compared in people without a prior neurologic diagnosis.
Overall, the largely null results that were reported suggest that null results would also be found if the analysis were restricted to outcomes occurring 28 days post-cessation. 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. No psychiatric adverse events are listed in the FDA label or package insert for doxycycline. In a systematic review of concurrent symptoms among short-term travelers, doxycycline users were statistically significantly less likely than mefloquine users to report psychiatric events, including abnormal dreams, insomnia, anxiety, and depressed mood, but the pooled effect estimates were very imprecise.
Whereas there were 15 episodes of abnormal thoughts and perceptions among mefloquine users, no episodes were reported for doxycycline users in the cohort studies examined Tickell-Painter et al. The committee identified 14 published case reports and case series, totaling 23 individuals, of adverse events related to the use of doxycycline for malaria prophylaxis. One case of irritable mood and suicidality was reported that resolved once doxycycline was discontinued, and no other concurrent or persistent psychiatric symptoms associated with the use of doxycycline were reported.
Considering experimental animal and other biologic plausibility studies overall, systematic studies of the long-term actions of doxycycline at prophylactic doses on brain or central nervous system function are generally lacking.
There is little evidence to support or refute a role for doxycycline in promoting somatic and brain dysfunction, and the committee found no evidence of persistent or latent adverse psychiatric or behavioral events in human or in preclinical models at doses relevant to malaria prophylaxis. The gut microbiome appears to modulate affective behaviors in mice and rats, but there is no definitive evidence to support an effect of doxycycline exposure on brain function via this mechanism.
Four of the epidemiologic studies with post-cessation follow-up included information on at least one adverse psychiatric outcome Eick-Cost et al. While all of these studies have methodologic limitations, Eick-Cost et al. All four studies used different methods for measuring outcomes, and the psychiatric outcomes of interest varied across studies.
In their analysis of active-duty service members, Eick-Cost et al. 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. When the population was restricted to the first mefloquine or doxycycline prescription per individual and included individuals with a prior history of a neurologic or psychiatric diagnosis, individuals with a psychiatric diagnosis in the year preceding the prescription had statistically significantly elevated risks for a subsequent diagnosis of the same condition for all of the psychiatric conditions that were reported adjustment disorder, anxiety, insomnia, depressive disorder, and PTSD compared with individuals without a diagnosis in the prior year.
There were no statistically significant differences between mefloquine and doxycycline users for any of the psychiatric outcomes when comparisons were limited to people who had a prior psychiatric diagnosis or for when users of these drugs were compared in people without a prior psychiatric diagnosis.
However, in the adjusted logistic regression models with all covariates considered including demographics, deployment, and combat exposure , the use of doxycycline was not associated with any of the adverse psychiatric events in comparison with nonusers of antimalarial drugs: lower composite mental health score, PTSD, thoughts of death or self-harm, other anxiety, and major depression.
When combat exposure intensity was specifically considered, the weighted prevalence estimates indicated that the prevalence of disorders increased with increasing combat exposure intensity. The results of Meier et al. Both Eick-Cost et al. Regarding insomnia, Eick-Cost et al. However, Tan et al. Both studies found that deployed doxycycline users reported increased frequencies of PTSD compared with nondeployed doxycycline users.
In fully adjusted models, Schneiderman et al. Similarly, Eick-Cost et al. However, among the nondeployed, Eick-Cost et al. When the population was restricted to the first mefloquine or doxycycline prescription per individual and included individuals with a prior history of a neurologic or psychiatric diagnosis, individuals with a PTSD diagnosis in the year preceding the prescription had statistically significantly elevated risks for a subsequent diagnosis of PTSD compared with individuals without a diagnosis in the prior year.
When comparing doxycycline and mefloquine users to those with and without prior psychiatric diagnoses, there were no statistically significant differences between mefloquine and doxycycline users for PTSD.
In sum, although there are a few findings of increased risk among specific outcomes relative to certain groups and in comparison with mefloquine, in general the results of the post-cessation epidemiologic studies provide modest evidence of no increase in risk of persistent adverse psychiatric events among individuals using doxycycline for malaria prophylaxis. 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.
The well-established concurrent adverse events of doxycycline on gastrointestinal symptoms, including nausea, vomiting, and diarrhea, justify a closer look at potentially persistent or latent gastrointestinal disorders following the cessation of use. The FDA label and package insert warn users of Clostridium difficile —associated diarrhea that can occur more than 2 months after drug cessation and further warn that this can cause increased morbidity and mortality because these infections can be refractory to antimicrobial therapy and may require colectomy.
Although Clostridium difficile infection is listed as an adverse event of doxycycline, the current evidence suggests that doxycycline may provide protection against such infections Tariq et al.
The package insert also includes language warning that patients can develop watery and bloody stools with or without stomach cramps and fever as late as 2 or more months after antibiotic cessation, as well as pancreatitis. A systematic review in short-term travelers found that doxycycline users were statistically significantly more likely than mefloquine users to report nausea, vomiting, and diarrhea Tickell-Painter et al. Post-diarrheal syndromes can be associated with persistent adverse gastrointestinal events, but neither the post-cessation epidemiologic studies nor the evidence presented in the systematic reviews examining concurrent adverse gastrointestinal adverse events support such an association.
There is some evidence from the biologic plausibility literature indicating that doxycycline may exert effects on the gastrointestinal tract, especially the esophagus and stomach, but the findings are inconsistent, and the studies often involve suprapharmacologic dosing over short time periods. The intensity of symptoms appears to be related to the acidity of the formulation. Other factors such as the drug dissociation rate, pH, osmolarity, and intrinsic chemical toxicity are also implicated in the pathogenesis of drug-induced esophageal injury Bailey et al.
Doxycycline is an antibiotic and consequently affects inflammatory processes and also decreases gut microbiota including beneficial probiotic bacteria , suggesting that adverse doxycycline outcomes on gastrointestinal function may be related to inflammatory changes in the gut, which are likely to vary substantially among individuals. Although there is the potential for a concurrent irritant to become a chronic problem, there is no biologic-plausibility support for acute diarrhea that could be indicative of more chronic symptoms.
Two of the post-cessation epidemiologic studies provided information on gastrointestinal disorders Lee et al. Given the peculiar approach to the analysis, the inability to directly examine the impact of doxycycline, the small number of cases, exposures to doxycycline being based on self-report, and the other design limitations and likely biases, these results are quite limited in value. In a similarly methodologically limited study, Tan et al. 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 gastrointestinal events.
Current evidence suggests further study of such an association is warranted, given the evidence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies. 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.
One case report of intracranial hypertension that resulted in a loss of vision was identified, but no other case reports that presented information on eye disorders persisting beyond 28 days post-doxycycline cessation were found.
No studies of experimental animal studies were identified that examined the biologic plausibility of eye disorders. One methodologically limited post-cessation epidemiologic study Tan et al.
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.
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