Doxycycline Use and Adverse Events

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Doxycycline use and adverse events search strategy:

MEDLINE/PubMed was searched for clinical studies that reported on adverse events with doxycycline use, specifically focusing on side-effects and metabolic effects of long-term use. Search terms included “doxycycline” AND (“adverse reaction” OR “adverse event” OR “side effect). Some studies prior to 2003 were included but the systematic review was focused on studies published subsequent to a prior systematic review published by Smith and Leyden (Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther. 2005 Sep;27(9):1329-42.).

Inclusion criteria for initial screening included any retrospective or prospective clinical study with an average duration of 2 months (8 weeks) or more on doxycycline. No restrictions set regarding country, publication language, date or patient age, race, gender or sexuality. Exclusion criteria included: non-human subjects or in-vitro studies, unrelated papers, duplicates, unavailable full texts, abstract only papers, case reports and any papers that reported on doxycycline use in combination with other drugs since it would not be possible to identify side effects from doxycycline alone. After the initial screening, review articles from the initial search were reviewed to identify additional studies to include.

Characteristics of studies identified by the systematic literature review that assess longer-term1 doxycycline use and adverse events
First Author Publication Year Study Population Study Site Drug Duration (Days) Doxycycline (N) Mild*
(n)		 Moderate*
(n)		 Severe*
(n)		 Stopped (adverse events)
Akhyani (27) 2008 Rosacea Treatment 27-72 years old Iran Doxycycline 100mg once daily 91 30 NR NR NR 0
Alexis (28) 2012 Rosacea Treatment 18+ years old United States Doxycycline 40mg once daily (30 mg immediate release and 10 mg delayed release beads) once daily 84 1196 NR NR NR NR
Andersen (29)** 1998 Malaria Prophylaxis 18-55 years old Kenya Doxycycline 100mg once daily 70 55 NR NR NR 1
Angelakis (30) 2014 Q Fever Endocarditis Treatment 18+ years old France Doxycycline 100mg twice a day (and hydroxychloroquine) 540+ 48 NR NR NR NR
Arman (31) 2015 Rosacea Treatment Adults Turkey Doxycycline 100mg BID for one month then once daily for two months 90 19 NR NR NR NR
Babaeinejad (32) 2011 Acne Treatment 13+ years old Iran Doxycycline 100mg once daily 90 50 4 0 0 0
Baudon (33) 1999 Malaria Prophylaxis Adult soldiers Gabon and the Central African Republic Doxycycline 100mg once daily 120+ 171 NR NR NR 11
Baxter (34) 2002 Abdominal Aortic Aneurysm Treatment 54-84 years old United States (Multiple States) Doxycycline 100mg twice per day 90+ 36 NR NR NR 3
Berende (35) 2016 Lyme Disease Treatment Adults Netherlands Doxycycline 100mg twice a day 84 86 39 (Mild or Moderate) 39 (Mild or Moderate) 3 3
Brandt (36)** 2005 Osteoarthritis Treatment 45-64 years old United States (Indiana) Doxycycline 100mg twice a day 900 218 NR NR 31 25
Brill (37) 2015 COPD Treatment 45+ years old United Kingdom Doxycycline 100mg once daily 91 25 2 (Mild or Moderate) 2 (Mild or Moderate) 0 0
Caton (38)** 2000 Chronic Periodontitis 30-75 years old United States (Multiple) Doxycycline 20mg twice a day 274 93 NR NR 1 1
Del Rosso (39)** 2007 Rosacea Treatment 18+ years old United States and Puerto Rico Doxycycline monohydrate 40mg once daily (formulation: 30-mg immediate-release and 10-mg delayed-release beads) 112 269 133 (Mild or Moderate) 133 (Mild or Moderate) 16 19
Del Rosso (40)** 2022 Acne Treatment 12+ years old United States (Multiple Sites) Doxycycline 120mg once daily (with trifarotene cream) 84 133 3 (Mild or Moderate) 3 (Mild or Moderate) 0 0
Del Rosso (41)** 2022 Rosacea Treatment 18-80 years old United States (Multiple Sites) Doxycycline 40mg modified-release capsules once daily 84+ 300 12 (Mild or Moderate) 12 (Mild or Moderate) 0 0
Del Rosso (42) 2012 Rosacea Treatment Adults United States Doxycycline modified-release 40mg once daily (30mg immediate-release and 10 mg delayed-release) 84 1196 NR NR NR NR
Del Rosso (43) 2018 Acne Treatment 12+ years old United States Doxycycline hyclate delayed-release 100mg twice daily 84 175 26 (Mild or moderate) 26 (Mild or moderate) 1 4
Del Rosso (44) 2008 Rosacea Treatment 18+ years old United States Doxycycline 100mg daily or 40mg delayed-release daily (with topical metronidazole 1% gel) 112 91 16 18 6 9
Donta (45)** 2004 Gulf War Illness Treatment Adult veterans United States (Multiple sites) Doxycycline 200mg once daily 365 245 NR NR 12 7
Frenzel (46) 2008 Treatment of Brain Vascular Malformations 15-78 years old United States (California) Doxycycline 100mg twice a day 730 13 NR NR 1 2
Gollnick (47) 2010 Rosacea Treatment 19-91 years old Germany Doxycycline 100mg once daily for 14 days then 50mg once daily 84 143 NR NR NR NR
Golub (48) 2001 Chronic periodontitis treatment 18-75 years old United States Doxycycline 20mg once or twice daily 84 75 NR NR NR 3
Kaneshiro (49)** 2012 Prevention of Menstrual Bleeding 18-45 years old females United States Doxycycline 40mg once daily 84 32 NR NR NR 0
Kitchener (50) 2005 Malaria Prophylaxis Adult soldiers Australian soldiers settled in East Timor at risk for malaria Doxycycline (Dose not reported) 180+ 388 245* 78* 7* 1
Kus (51) 2005 Acne Treatment 18-30 years old Turkey Doxycycline 100mg BID for one month and then once daily for the next two months 90 26 NR NR NR NR
Layton (18) 1993 Acne Treatment 13-49 years old United Kingdom Doxycycline 150 or 200 mg/day 183 106 NR NR NR 37
Lee (52)** 2004 Chronic periodontitis treatment Adults South Korea Doxycycline hyclate 20mg twice daily 274 24 NR NR NR NR
Leijtens (53) 2019 Suppression of Prosthetic Joint Infection 40-88 years old Netherlands Doxycycline 100-200mg once daily 1157 14 NR NR NR 1
Leyden (54)** 2013 Acne Treatment 12-45 years old United States Doxycycline calcium 40-160mg (weight based) 84 190 NR NR NR 1
Lin (55) 2015 Graves Disease Treatment 18-60 years old China Doxycycline 50mg once daily 84 16 2 0 0 0
Makunde (56) 2006 Wuchereria Bancrofti Treatment 14-68 years old Tanzania Doxycycline 200mg once daily 60 19 7 0 0 0
Maleszka (57) 2011 Acne Treatment 14+ years old Poland and Croatia Doxycycline 100mg once daily 84 120 NR NR NR 0
Molina (3) 2017 STI Prophylaxis Adult Males France Single dose doxycycline 200mg within 24 hrs after sex and no later then 72 hrs 261+ 116 102 (Mild or Moderate) 102 (Mild or Moderate) 4 8
Moore (58)** 2015 Acne Treatment 12-59 years old United States Doxycycline 40-100mg once daily 112 440 NR NR 2 2
Naini (59) 2007 Diabetic Proteinuria Treatment 49-77 years old Iran Doxycycline 100mg once daily 61 35 NR NR 0 3
Novak (60) 2002 Chronic periodontitis treatment 29-45 years old United States Doxycycline hyclate 20mg twice daily 183 10 NR NR NR NR
Ohrt (61)** 1997 Malaria Prophylaxis Adult soldiers Indonesia Doxycycline 100mg once daily 91 67 NR NR NR 0
Pagès (62) 2002 Malaria Prophylaxis Adult soldiers French soldiers deployed in Gabon and Chad Doxycycline monohydrate 100mg once daily 120 275 NR NR NR 15
Pan (63)** 2022 Thyroid Disease Adults China Doxycycline 50mg once daily 84 50 1 0 0 0
Pang (64)** 1998 Malaria Prophylaxis 10-16 years old Thailand Doxycycline 25-100mg daily depending on weight 105 144 NR NR NR 0
Pang (65) 1987 Malaria Prophylaxis 10-15 years old Thailand Doxycycline 100mg once daily for those over 40kg;

Doxycycline 50mg once daily for those less than 40kg

 63 95 NR 0 0 0
Parish (66) 2005 Acne Treatment 14-36 years old United States Doxycycline hyclate 100mg twice a day 56 12 NR NR NR NR
Park (67) 2015 Rosacea Treatment 18+ years old South Korea Doxycycline 100mg twice a day 770 15 NR NR NR 0
Pfeffer (68) 2011 Rosacea Treatment Adults Germany Doxycycline 40mg once daily (slow-release form) 60+ 7 0 0 0 0
Pimenta (69) 2011 Lymphangioleiomyomatosis Treatment Adult Females Brazil Doxycycline 100mg once daily 180 41 NR NR NR 0
Pimenta (70) 2013 Lymphangioleiomyomatosis Treatment Adults Brazil Doxycycline 100mg once daily 365 41 NR NR NR 3
Popa (71) 2022 Colorectal Cancer Treatment Adults Romania Doxycycline (Dose not reported) 56 10 NR NR NR NR
Pradier (72) 2017 Suppression of Prosthetic Joint Infection Adults France Doxycycline 200mg once daily 508+ 39 NR NR NR 3
Pradier (73) 2018 Suppression of Prosthetic Joint Infection 18-91 years old France Doxycycline 200mg once daily 668 72 NR NR NR 6
Preshaw (74)** 2008 Chronic periodontitis treatment 24-81 years old United States Doxycycline monohydrate 40mg once daily (modified release) 274 133 79 (Mild or Moderate) 79 (Mild or Moderate) 9 7
Putschky (75) 2006 Reactive Arthritis Treatment 18-65 years old Germany Doxycycline 100mg twice a day 122 15 NR NR NR 0
Quarterman (76) 1997 Rosacea Treatment 31-66 years old Georgia Doxycycline 100mg once daily 84 39 NR NR NR NR
Sanchez (77)** 2005 Rosacea Treatment 18+ year old females United States and Puerto Rico Doxycycline hyclate 20mg twice daily for 12 weeks (with metronidazole 0.75% topical lotion) followed by 4 weeks of monotherapy with doxycycline hyclate 20mg 112 20 NR NR 0 0
Schlagenhauf (78) 2003 Malaria Prophylaxis 18-70 years old Travel clinics in Switzerland, Germany, and Israel Doxycycline monohydrate 100mg once daily 66 153 128 51 9 5
Sehgal (79) 2000 Leptospirosis prophylaxis 10+ years old India Doxycycline 200mg/week 84 386 NR NR NR 3
Smith (80) 2011 Rheumatoid Arthritis Treatment Adults United States Doxycycline 200mg once daily 90 484 31 53 26 35
Snijders (81)** 2011 Knee Osteoarthritis Treatment Adults Netherlands Doxycycline monohydrate 100mg twice a day 168 116 NR NR NR 19
Sonmez (82) 2005 Malaria Prophylaxis Adult soldiers Turkish soldiers in Kabul, Afghanistan Doxycycline 100mg once daily 84 506 395 32 0 NR
Tan (83) 2014 Acne Treatment 12-35 years old Canada Doxycycline hyclate 200mg once daily (with adapalene 0.1%/benzoyl peroxide 2.5% gel) 140 133 NR NR 0 6
Taylor (84)** 1999 Malaria Prophylaxis 18-55 years old Indonesia Doxycycline 100mg once daily 140 75 NR NR NR 1
Taylor (85) 2005 Wuchereria Bancrofti Treatment 15-68 year old males Tanzania Doxycycline 200mg once daily 56 34 8 NR NR 0
Thiboutot (86) 2005 Acne Treatment 12-36 years old United States (Multiple sites) Doxycycline 100mg once daily 84 467 NR NR 0 5
Thiboutot (87) 2009 Rosacea Treatment 19-83 years old United States Doxycycline monohydrate 100mg twice daily (with topical azelaic acid 15% gel) 28-84 172 19 8 4 12
Ullah (88) 2014 Acne Treatment 14-30 years old Pakistan Doxycycline 100mg once daily 90 193 NR NR NR 0
Ullah (89) 2022 Acne Treatment 12-24 years old Pakistan Doxycycline 100mg once daily 84 37 NR NR NR NR
van der Linden (90) 2016 Rosacea Treatment 18+ years old Netherlands Doxycycline 40mg once daily 112 40 23 (Mild or Moderate) 23 (Mild or Moderate) 0 3
Weiss (91) 1995 Malaria Prophylaxis 9-14 years old Kenya Doxycycline 50mg once daily 77 32 NR NR NR 2
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NR=Not reported
1Longer term was defined as 8+ weeks
*Events (not individuals)
**Included in the meta-analysis (N=18)

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