Doxycycline Hyclate (doxycycline hyclate)

Dosage of doxycycline hyclate and doxycycline monohydrate is expressed in terms of doxycycline.

Because of differing bioavailability, doxycycline hyclate delayed-release tablets (Doryx(R), Doryx(R) MPC) are not substitutable on a mg-per-mg basis with other oral doxycycline preparations; Doryx(R) and Doryx(R) MPC also are not substitutable for one another on a mg-per-mg basis. When switching from Doryx(R) to Doryx(R) MPC, Doryx(R) 50 mg can be replaced by Doryx(R) MPC 60 mg, and Doryx(R) 100 mg can be replaced by Doryx(R) MPC 120 mg.

Doxycycline hyclate and doxycycline monohydrate are administered orally.

When oral therapy is not feasible, doxycycline hyclate may be administered by slow IV infusion; however, patients should transition to oral therapy as soon as possible. Prolonged IV administration of doxycycline may result in thrombophlebitis.

Doxycycline also has been administered by intrapleural infusion+.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Oral Tetracyclines/Strontium Ranelate

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strontium may form a complex with oral tetracyclines, preventing their absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of strontium with oral tetracyclines may result in decreased levels and effectiveness of the tetracycline.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK(1) and US(2) manufacturers of strontium states that strontium therapy should be suspended during the treatment with an oral tetracycline.

DISCUSSION: Divalent cations such as strontium can form complexes with oral tetracyclines.(1,2)

Selected Antibiotics/Cholera Vaccine Live

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Antibiotics with activity against Vibrio cholerae may attenuate the immunization response to the live cholera vaccine.(1)

CLINICAL EFFECTS: Concurrent or recent antibiotic use may make the cholera vaccine ineffective.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of live cholera vaccine states that it should not be administered to patients who have received antibiotics within 14 days prior to vaccination.(1) If antimalarial prophylaxis with chloroquine is required, administer the live cholera vaccine at least 10 days before beginning chloroquine.(1) Antibiotics linked to this monograph are: macrolides, quinolones, tetracyclines, ampicillin, cefprozil, chloramphenicol, furazolidone, sulfamethoxazole-trimethoprim, and sulfametrole-trimethoprim.(2,3)

DISCUSSION: Antibiotics with activity against Vibrio cholerae may attenuate the immunization response to the live cholera vaccine, rendering the vaccine ineffective.

Tetracyclines/Selected Retinoids (SYSTEMIC)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both systemic tetracyclines(1-4,14) and systemic retinoids(5-14) have been independently associated with medication-induced intracranial hypertension.

CLINICAL EFFECTS: The concurrent use of oral retinoids(5-12) with tetracyclines has been associated with pseudotumor cerebri (benign intracranial hypertension). Early signs of pseudotumor cerebri include papilledema (inflammation of the optic nerve), headache, nausea, vomiting, and visual disturbances such as blurred vision, double vision, and loss of vision.(15)

PREDISPOSING FACTORS: Women of childbearing age who are overweight or have a previous history of intracranial hypertension are at a greater risk of developing intracranial hypertension.(15)

PATIENT MANAGEMENT: The UK(5) and US(6) manufacturers of acitretin state state that concurrent use with tetracyclines is contraindicated. The UK manufacturer of isotretinoin states that concurrent use with tetracyclines is contraindicated.(7) The US manufacturer of isotretinoin states that the concurrent use of tetracyclines should be avoided.(8) The US manufacturer of minocycline states that the administration of isotretinoin should be avoided shortly before, during and shortly after minocycline therapy.(2) The UK manufacturers of oral tretinoin and alitretinoin states that concurrent use with tetracyclines is contraindicated.(9,11) The Canadian manufacturer of palovarotene states that coadministration of tetracycline derivatives should be avoided.(12) Patients who present with symptoms of pseudotumor cerebri should be screened for papilledema. If papilledema is present, they should discontinue the drug and be referred to a neurologist for further treatment.(5-13)

DISCUSSION: The concurrent use of isotretinoin and tetracyclines has been associated with pseudotumor cerebri.(5-13) A review of ocular side effects from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, the Food and Drug Administration, and medical journals from 1979 to 2003 found 6 patients who developed intracranial hypertension while taking concurrent minocycline or tetracycline with tretinoin, acitretin, or etretinate.(13)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Tetracyclines/Methoxyflurane

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, combined renal toxicity appears to be a factor.

CLINICAL EFFECTS: Nephrotoxicity may occur.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible use alternative therapy.

DISCUSSION: Renal toxicity and death have been reported in patients receiving methoxyflurane and tetracycline. Since both drugs have been associated with nephrotoxicity, it is difficult to determine whether the effects are due to the drug combination or either drug alone. Additional studies are needed to clarify this potential interaction.

Tetracyclines/Topical Tretinoin (PHOTODAMAGE)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of topical tretinoin with tetracyclines may increase the risk of phototoxicity(1) in some patients.(2)

PREDISPOSING FACTORS: Patients using topical tretinoin for the treatment of photodamage may be predisposed to photosensitivity.(2)

PATIENT MANAGEMENT: Concurrent use of topical tretinoin and tetracycline is standard practice in the treatment of acne.(3) However, patients taking tetracyclines should not use topical tretinoin (e.g Renova) for the treatment of photodamage.(1,2)

DISCUSSION: The concurrent use of topical tretinoin and tetracyclines may result in an increased risk of phototoxicity.(1,2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Doxycycline/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of doxycyline.

CLINICAL EFFECTS: Concurrent or recent use of an inducer of CYP3A4 may result in decreased antimicrobial activity of doxycycline.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: If both drugs are administered, monitor the response to doxycycline. Adjust the dose of the drug or consider administration of a non-interacting tetracycline analogue (e.g. tetracycline) if necessary.

DISCUSSION: The effects of the interaction develop over approximately one to two weeks after starting the inducer and reverse over a period of several weeks after stopping the inducer. The elimination of demeclocycline, methacycline, oxytetracycline and tetracycline are not expected to be altered by CYP3A4 inducers as these tetracyclines are primarily excreted by the kidneys. Serum doxycycline concentrations may increase when the inducer is stopped. In a study, the half-life of doxycycline in 7 patients on long-term phenytoin therapy, 5 patients on long-term carbamazepine therapy, 4 patients on long-term combination phenytoin and carbamazepine therapy, and 9 control subjects was 7.2 hours, 8.4 hours, 7.4 hours, and 15.1 hours, respectively.(1) In a study, the half-life of doxycycline was significantly reduced in patients receiving barbiturate therapy.(2) In a study that compared healthy-controls with patients on long-term antiepileptic therapy, the half-life of doxycyline was significantly decreased in patients receiving barbiturates, phenytoin, or carbamazepine. The half-lives of chlortetracycline, demethylchlortetracycline, methacycline, oxytetracycline, and tetracycline were unaffected.(3) In a study in 7 patients, the half-life of doxycycline (200 mg/day) decreased from 17.9 hours to 9.2 hours following the addition of rifampin (10 mg/kg/day) to therapy.(4) CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, primidone, rifamycins, and St. John's Wort.

Tetracyclines/Coumarin Anticoagulants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Tetracyclines may interfere with vitamin-K producing gut flora.

CLINICAL EFFECTS: The addition of a tetracycline to a patient maintained on a coumarin anticoagulant may result in increased anticoagulant effects, including bleeding.

PREDISPOSING FACTORS: he risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients maintained on coumarin anticoagulants should be closely monitored when tetracyclines are initiated and discontinued. The dosage of the anticoagulant may need to be adjusted. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: In a retrospective review of patients receiving either acenocoumarol or phenprocoumon, use of doxycycline and tetracycline was associated with relative risk of major bleeding of 3 and 9, respectively.(1) There are several case reports of bleeding following the addition of doxycycline(2-4) and tetracycline(5,6) to warfarin therapy.

Tetracyclines/Divalent & Trivalent Cations

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Di- and trivalent cations may form chelation complexes with tetracyclines, preventing their absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of di- or trivalent cations may result in decreased levels of and therapeutics effects from tetracyclines.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Administer tetracyclines at least two hours before or after the di- or trivalent cations. When used for the treatment of H. pylori infection, tetracyclines and bismuth should be given simultaneously. The US manufacturer of omadacycline states to fast for at least four hours, administer omadacycline, and then wait four hours before taking di- or trivalent cations.(21) The US manufacturer of ferric maltose recommends separation of ferric maltose by at least 4 hours.(22)

DISCUSSION: Concurrent administration of aluminum hydroxide or divalent cations (such as calcium, magnesium, or zinc) has been shown to significantly decrease the gastrointestinal absorption of tetracycline.(3-5) Concurrent administration of tetracycline and magnesium-aluminum hydroxide gel has been shown to decrease the tetracycline area-under-curve (AUC) by 90%.(6) Magnesium-aluminum silicate has been shown to decrease the AUC of tetracycline by 27%.(7) Demeclocycline(8,9) methacycline,(10) chlortetracycline,(11) and oxytetracycline(10,12) have been shown to interact with aluminum hydroxide and/or dairy products. Doxycycline has been reported to interact with aluminum hydroxide gel.(13) Aluminum magnesium hydroxide has been shown to decrease doxycycline absorption by 84%.(14) Minocycline absorption has been shown to be impaired by aluminum, calcium, and magnesium.(15) Bismuth subsalicylate has been shown to decrease absorption of doxycycline and tetracycline by 37%(16) and 34%,(17) respectively. Since sucralfate is an aluminum salt of a sulfated disaccharide, it may also prevent absorption of tetracyclines. This complex has been used to provide site-specific delivery of tetracycline to gastric ulcers in the treatment of Helicobacter pylori gastric ulcer disease and may be useful in some indications.(18) Quinapril tablets contain a high percentage of magnesium and have been shown to decrease the absorption of tetracycline by 28-37%.(19) Lanthanum is expected to interact with tetracyclines as well.(20)

Tetracyclines; Tigecycline/Contraceptives

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not established.

CLINICAL EFFECTS: Reduced pharmacologic effects of oral contraceptives with resultant breakthrough bleeding and pregnancy may occur.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Current guidelines suggest that additional precautions are not necessary when non-enzyme inducing antibiotics are used concurrently with hormonal contraceptives; however, some patients may still prefer to use an additional method of contraception.

DISCUSSION: Evidence for this interaction is limited and conflicting; however, the CDC and the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit no longer recommend use of a backup contraceptive method during use of a non-enzyme inducing antibiotic. Pregnancy has been reported following the addition of tetracycline to oral contraceptive therapy.(1) In contrast, a study in 7 healthy women found no effect of tetracycline on ethinyl estradiol or norethindrone levels.(2) A study in 24 healthy women found no significant effects of doxycycline on ethinyl estradiol, norethindrone, or progesterone levels. However, the authors noted that there large inter-patient and inter-patient variability in these levels and that the interaction may just manifest itself in a small proportion of women.(3)

*Known hypersensitivity to doxycycline or any tetracycline.

There are no contraindication contraindications for this drug.

• Clostridioides difficile infection
• Esophageal dysmotility
• Intracranial hypertension
• Myasthenia gravis
• Pregnancy

There are no moderate contraindications for this drug.

Common adverse effects reported in patients receiving tetracyclines include anorexia, nausea, vomiting, diarrhea, rash, photosensitivity, urticaria, and hemolytic anemia.

More Frequent

• Dental discoloration

Less Frequent

• Hypertension
• Serum sickness
• Skin photosensitivity

Rare or Very Rare

• Acute eruptions of skin
• Acute lupus erythematosus
• Anaphylaxis
• Angioedema
• Clostridioides difficile infection
• Depression
• DRESS syndrome
• Erythema multiforme
• Esophageal ulcer
• Exfoliative dermatitis
• Fungal infection
• Hallucinations
• Hemolytic anemia
• Hepatitis
• Hypersensitivity drug reaction
• Idiopathic intracranial hypertension
• Insomnia
• Intracranial hypertension
• Maculopapular rash
• Neutropenic disorder
• Pancreatitis
• Pericarditis
• Purpura
• Stevens-johnson syndrome
• Suicidal ideation
• Symptoms of anxiety
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Urticaria

More Frequent

• Nausea
• Vomiting

Less Frequent

• Anorexia
• Diarrhea
• Headache disorder
• Pharyngitis
• Upper abdominal pain
• Vaginitis
• Vulvovaginal candidiasis

Rare or Very Rare

• Anogenital candidiasis
• Dream disorder
• Dysphagia
• Enterocolitis
• Eosinophilia
• Erythema
• Esophagitis
• Glossitis
• Jarisch-herxheimer reaction
• Skin pigmentation enhancement
• Skin rash

No enhanced messaging available.

Like other tetracyclines, because of the potential effects on tooth development and growth, doxycycline should not be used in children <8 years of age unless other appropriate drugs would be ineffective or are contraindicated. However, the manufacturers, AAP, CDC, and Infectious Diseases Society of America (IDSA) state that use of doxycycline in children <8 years of age can be considered in certain circumstances when the potential benefits outweigh the risks. These circumstances include the treatment or prophylaxis of anthrax (including inhalational anthrax (postexposure)), treatment of moderate to severe cholera, treatment of leptospirosis, and treatment of presumed or confirmed rickettsial infections, including RMSF, Q fever, ehrlichiosis+, and anaplasmosis+.

Doxycycline is recommended by AAP and CDC as the drug of choice for presumed or confirmed Rickettsial infections (including RMSF) or ehrlichiosis+ (including human granulocytotropic anaplasmosis+ and human monocytotropic ehrlichiosis+) in children of any age.

The CDC states that children <8 years of age with uncomplicated malaria may receive a regimen that includes doxycycline (or tetracycline) if other treatment options are not available or not tolerated and the potential benefits outweigh risks.

Despite the paucity of pediatric data, IDSA/American Academy of Neurology (AAN)/American College of Rheumatology (ACR) state that it is prudent to extrapolate the use of single-dose doxycycline prophylaxis of Lyme disease to children. Caregivers should be informed that there is no study of the efficacy of doxycycline prophylaxis for Lyme disease in pediatric patients <12 years of age and that it is still important to monitor pediatric patients who receive doxycycline prophylaxis for symptoms and signs of Lyme disease. IDSA/AAN/ACR and AAP also state that doxycycline is a drug of choice for the treatment of Lyme disease associated with erythema migrans, Lyme meningitis, Lyme carditis, and Lyme arthritis. Although doxycycline generally is not recommended for pediatric patients <8 years of age, AAP states that the drug is considered safe when used for <=21 days in pediatric patients of any age. IDSA/AAN/ACR state that a growing consensus accepts the safety of doxycycline in young children for at least up to 14 days' duration. AAP states that doxycycline is the preferred oral antibiotic treatment for pediatric patients of any age with Lyme disease-associated facial palsy.

There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. There are no available data on the risk of miscarriage following exposure to doxycycline in pregnancy; the effect of tetracyclines on labor and delivery also is not known. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, apprise the patient of the potential hazard to the fetus. The manufacturer states that doxycycline injection has not been studied in pregnant patients and should be used in pregnant patients only if it is essential for the welfare of the patient.

The vast majority of reported experience with doxycycline during human pregnancy is short-term, first-trimester exposure. An expert review of published data on experiences with doxycycline use during pregnancy by the Teratogen Information System (TERIS) concluded based on data assessed as limited to fair that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk; however, the data are insufficient rule out such risk.

Like other tetracycline-class antibacterial drugs, doxycycline may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy. Discoloration of the teeth, which may be permanent, is more common during long-term use of the drug but has been observed following repeated short-term courses.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy.

Current CDC guidelines on the treatment of anthrax state that while tetracycline and minocycline are not recommended in pregnant subjects, doxycycline has not been associated with fetal growth delays, infant tooth staining, or maternal fatty liver. The CDC guidelines state that doxycycline is considered a first-line agent for empiric postexposure anthrax prophylaxis, treatment of cutaneous anthrax without signs or symptoms of meningitis, and in combination regimens for the treatment of systemic anthrax with or without meningitis in pregnant adults.

Malaria infection in pregnant women is associated with high risks of maternal and perinatal morbidity and mortality (e.g., miscarriage, premature delivery, low birth weight, congenital infection and/or perinatal death). For the treatment of uncomplicated malaria acquired in areas with chloroquine-resistant P. falciparum in pregnant women, the CDC recommends treatment with artemether-lumefantrine, mefloquine, or a combination of quinine sulfate and clindamycin. For pregnant women diagnosed with uncomplicated malaria caused by P. malariae, P. ovale, chloroquine-sensitive P. vivax, or chloroquine-sensitive P. falciparum infection, prompt treatment with chloroquine or hydroxychloroquine is recommended. For chloroquine-resistant P. vivax infections, artemether-lumefantrine, quinine plus clindamycin, or mefloquine is recommended. However, CDC states that a regimen of quinine in conjunction with doxycycline (or tetracycline) may be used for the treatment of uncomplicated malaria in pregnant women in rare circumstances (e.g., if other treatment options are not available or not tolerated) if benefits outweigh risks. For the treatment of severe malaria in pregnant patients, the CDC recommends treatment with IV artesunate.

The CDC states that doxycycline has been used successfully to treat tickborne rickettsial diseases in pregnant women without adverse effects to the mother; however, follow-up to address potential adverse effects to the fetus has been limited. Data suggest that treatment with doxycycline at the recommended dose and duration for tickborne rickettsial diseases is unlikely to pose a substantial teratogenic risk; however, data are insufficient to rule out such risk. For potentially life-threatening illnesses, such as RMSF and Ehrlichia chaffeensis ehrlichiosis, consideration of disease-related risks for the mother and fetus is of paramount importance.

Tetracyclines are distributed into human milk; however, the extent of absorption of tetracyclines, including doxycycline, by the breast-fed infant is not known.

Short-term use in lactating women is not necessarily contraindicated. The effects of prolonged exposure to doxycycline on breast milk production and on breast-fed neonates, infants, and children are unknown. The American Academy of Pediatrics (AAP) and US Centers for Disease Control and Prevention (CDC) state that maternal use of tetracyclines usually is compatible with breast-feeding since absorption of the drugs by nursing infants is negligible.

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for doxycycline and any potential adverse effects on the breast-fed child from the drug or the underlying maternal condition. Some manufacturers state that because of the potential for serious adverse reactions in breast-feeding infants from doxycycline, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. At least one manufacturer states that breast-feeding is not recommended during treatment with doxycycline and for 5 days following the last dose.

Clinical studies of doxycycline did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently from younger adults. Other reported clinical experience has not identified differences in responses between geriatric patients and younger adults.