Doxycycline Hyclate (Acticlate, Doryx), Doxycycline (Oracea) Form

Doxycycline (Acticlate®, Doryx®, Doryx® MPC, Oracea®) is a tetracycline-class drug.
FDA Approved Indication(s) Acticlate and Doryx/Doryx MPC are indicated for: • Rickettsial infections • Sexually transmitted infections
• Respiratory tract infections • Specific bacterial infections
• Ophthalmic infections
• Anthrax, including inhalational anthrax (post-exposure)
• Alternative treatment for selected infections when penicillin is contraindicated
• Adjunctive therapy in acute intestinal amebiasis and severe acne
• Prophylaxis of malaria Oracea is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. No meaningful effect was demonstrated for generalized erythema (redness) of rosacea. Limitation(s) of use:
• The Oracea formulation of doxycycline has not been evaluated in the treatment or prevention of infections. Oracea should not be used for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease. To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, Oracea should be used only as indicated. Oracea has not been evaluated for the treatment of the erythematous, telangiectatic, or ocular components of rosacea. • To reduce the development of drug-resistant bacteria and maintain the effectiveness of Acticlate, Doryx, and Doryx MPC, these agents should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. It is the policy of health plans affiliated with Centene Corporation® that Acticlate, Doryx, Doryx MPC, and Oracea are medically necessary when the following criteria are met:
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CLINICAL POLICY Doxycycline I. Initial Approval Criteria
A. Rosacea (must meet all):

1. Diagnosis of rosacea with inflammatory lesions (papules and pustules);
   2. Request is for Oracea;
   3. Age ≥ 18 years;
   4. Member must use immediate-release doxycycline, unless contraindicated or clinically significant adverse effects are experienced;
2. Failure of ≥ 4-week trial of one additional preferred oral tetracycline antibiotic (e.g., immediate-release minocycline), unless contraindicated or clinically significant adverse effects are experienced;
3. Dose does not exceed both of the following (a and b): a. 40 mg per day; b. 1 capsule per day. Approval duration: 16 weeks B. Acne Vulgaris (must meet all):
   1. Diagnosis of acne vulgaris;
   2. Request is for Acticlate, Doryx, or Doryx MPC;
   3. Member must use immediate-release doxycycline, unless contraindicated or clinically significant adverse effects are experienced;
4. Failure of a ≥ 4-week trial of one additional preferred oral tetracycline antibiotic (e.g., immediate-release minocycline), unless clinically significant adverse effects are experienced or all are contraindicated;
5. Dose does not exceed: a. Acticlate, Doryx: 200 mg per day; b. Doryx MPC: 240 mg per day.
   Approval duration: 3 months C. Prophylaxis of Malaria (must meet all):
   
   1. Prescribed for malaria prophylaxis;
   2. Request is for Acticlate, Doryx, or Doryx MPC;
   3. Member must use immediate-release doxycycline, unless contraindicated or clinically significant adverse effects are experienced;

6. Dose does not exceed:
   a. Acticlate, Doryx: 100 mg per day; b. Doryx MPC: 120 mg per day. Approval duration: 4 months or duration of travel and up to 4 weeks after member leaves the malarious area, whichever is less D. FDA-Approved Acute Infection Indications for Acticlate, Doryx/Doryx MPC (must meet all):

   1. Prescribed for the treatment of one of the following conditions or diseases (refer to Appendix D for conditions or diseases that are applicable): a. Rickettsial infections; b. Sexually transmitted infections; Page 2 of 12

   CLINICAL POLICY Doxycycline c. Respiratory tract infections; d. Specific bacterial infections; e. Ophthalmic infections; f. Anthrax, including inhalational anthrax (post-exposure); g. Selected infections when penicillin is contraindicated; h. Acute intestinal amebiasis;

7. Request is for Acticlate, Doryx, or Doryx MPC;
   3. Member must use immediate-release doxycycline, unless contraindicated or clinically significant adverse effects are experienced;
8. Failure of one additional preferred oral tetracycline antibiotic (e.g., immediate-release minocycline), unless clinically significant adverse effects are experienced or the other preferred tetracycline antibiotics are not indicated for the member’s diagnosis;
9. Dose does not exceed: a. Acticlate, Doryx: 200 mg per day; b. Doryx MPC: 240 mg per day. Approval duration: 60 days or duration of request, whichever is less
   E. Other diagnoses/indications (must meet 1 or 2):
10. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
11. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    II. Continued Therapy A. Rosacea (must meet all):
12. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);

13. Request is for Oracea;

    3. Member is responding positively to therapy;
    4. Member has not received Oracea daily for > 16 weeks; Page 3 of 12

    CLINICAL POLICY Doxycycline

14. If request is for a dose increase, new dose does not exceed both of the following (a and b): a. 40 mg per day; b. 1 capsule per day. Approval duration: up to 16 weeks of treatment (total) B. Acne Vulgaris (must meet all):
15. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
16. Request is for Acticlate, Doryx, or Doryx MPC;
    3. Member is responding positively to therapy;
    4. If request is for a dose increase, new dose does not exceed: a. Acticlate, Doryx: 200 mg per day; b. Doryx MPC: 240 mg per day.
       Approval duration: 3 months C. Prophylaxis of Malaria and FDA-Approved Acute Infection Indications for Acute Infections
    5. Re-authorization is not permitted. Members must meet the initial approval criteria. Approval duration: Not applicable
       D. Other diagnoses/indications (must meet 1 or 2):
17. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

18. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – Page 4 of 12

    CLINICAL POLICY Doxycycline CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration Appendix B: Therapeutic Alternatives
    This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
    Dosing Regimen Drug Name Dose Limit/ Maximum Dose Varies doxycycline (Vibramycin®) Acne vulgaris, adults: 100 mg PO every 12 hrs on day 1, followed by a maintenance dose of 100 PO QD Acne vulgaris, children 8 years and older and adolescents weighing less than 45 kg: 2.2 mg/kg/dose PO every 12 hours on day 1, then 2.2 mg/kg/dose PO QD Rosacea: 40 mg or 50 mg PO QAM Malaria (off label): 100 mg PO BID for 7 days See Full Prescribing Information for additional indication specific dosage information. Acne vulgaris, adults: 200 mg PO initially, then 100 mg PO every 12 hours. Alternatively, if more frequent oral doses are preferred, 100 to 200 mg PO initially, then 50 mg PO every 6 hours.
    Acne vulgaris, children ≥ 8 years and adolescents: 4 mg/kg PO (max: 200 mg) initially, then 2 mg/kg/dose PO every 12 hours (max: 100 mg/dose) as adjunctive therapy 200 mg/day
    minocycline (Minocin) tetracycline See Full Prescribing Information for additional indication specific dosage information Acne vulgaris, adult: 1 gram PO in divided doses, then decrease slowly to 125 to 500 mg PO daily or every other day.
    Varies Page 5 of 12

    CLINICAL POLICY Doxycycline Drug Name Dosing Regimen Dose Limit/ Maximum Dose Acne vulgaris, children≥ 9 years and adolescents: 1 g/day PO in divided doses, then decrease slowly to 125 to 500 mg PO QD or QOD Rosacea: 250 to 1,500 mg PO QD Malaria (off label): 250 mg PO four times daily for 7 days.
    See Full Prescribing Information for additional indication specific dosage information. Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings • Contraindication(s): hypersensitivity to any of the tetracyclines. • Boxed warning(s): none reported
    Appendix D: Other FDA-Approved Acute Infection Indications for Doryx/Doryx MPC and Acticlate
    FDA-approved indications Rickettsial infections Applicable conditions or diseases Sexually transmitted infections Respiratory tract infections Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae Uncomplicated urethral, endocervical or rectal infections caused by Chlamydia trachomatis Nongonococcal urethritis caused by Ureaplasma urealyticum Lymphogranuloma venereum caused by Chlamydia trachomatis Granuloma inguinale caused by Klebsiella granulomatis Uncomplicated gonorrhea caused by Neisseria gonorrhoeae Chancroid caused by Haemophilus ducreyi. Respiratory tract infections caused by Mycoplasma pneumoniae Psittacosis (ornithosis) caused by Chlamydophila psittaci Doxycycline is indicated for treatment of infections caused by the following micro- organisms, when bacteriological testing indicates appropriate susceptibility to the drug: Respiratory tract infections caused by Haemophilus influenzae Respiratory tract infections caused by Klebsiella species Upper respiratory infections caused by Streptococcus pneumoniae Page 6 of 12

    CLINICAL POLICY Doxycycline FDA-approved indications Specific bacterial infections Ophthalmic infections Anthrax including inhalational anthrax (post-exposure) Alternative treatment for selected infections when penicillin is contraindicated Adjunctive therapy for acute intestinal amebiasis Applicable conditions or diseases Relapsing fever due to Borrelia recurrentis Plague due to Yersinia pestis Tularemia due to Francisella tularensis
    Cholera caused by Vibrio cholerae Campylobacter fetus infections caused by Campylobacter fetus Brucellosis due to Brucella species (in conjunction with streptomycin) Bartonellosis due to Bartonella bacilliformis Doxycycline is indicated for treatment of infections caused by the following gram- negative microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Escherichia coli, Enterobacter aerogenes, Shigella species, Acinetobacter species, urinary tract infections caused by Klebsiella species Trachoma caused by Chlamydia trachomatis
    Inclusion conjunctivitis caused by Chlamydia trachomatis Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure) Syphilis caused by Treponema pallidum Yaws caused by Treponema pallidum subspecies pertenue Vincent’s infection caused by Fusobacterium fusiforme Actinomycosis caused by Actinomyces israelii Infections caused by Clostridium species Not applicable V. Dosage and Administration
    Drug Name Indication Dosing Regimen All indications listed in the FDA- approved indications section Doxycycline hyclate (Acticlate), doxycycline hyclate delayed- release (Doryx, Doryx MPC) Acticlate Adults: 200 mg PO on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg PO daily. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg PO every 12 hours is recommended.
    For all pediatric patients weighing less than 45 kg with severe or life-threatening infections (e.g., anthrax, Rocky Maximum Dose 200 mg/day
    Doryx MPC: 240 mg/day
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    CLINICAL POLICY Doxycycline Drug Name Indication Dosing Regimen Maximum Dose Mountain spotted fever): 2.2 mg per kg of body weight administered every 12 hours PO. For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg):
    4.4 mg per kg of body weight PO divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg per kg of body weight (given as a single daily dose or divided into two doses) PO.
    For pediatric patients weighing over 45 kg: the usual adult dose should be used.
    Doryx Adults: 200 mg PO on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg PO daily. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours PO is recommended.
    For children above eight years of age: The recommended dosage schedule for children weighing 45 kg or less is 4.4 mg/kg of body weight PO divided into two doses on the first day of treatment, followed by 2.2 mg/kg of body weight given as a single daily dose or divided into two doses PO on subsequent days. For more severe infections up to 2.2 mg/kg of body weight administered every 12 hours may be used. For children over 45 kg, the usual adult dose should be used. Doryx MPC Adults: 240 mg PO on the first day of treatment (administered 120 mg every 12 hours) followed by a maintenance dose of 120 mg daily. In the management of more severe infections (particularly chronic infections of the urinary tract), 120 mg every 12 hours PO is recommended.
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    CLINICAL POLICY Doxycycline Drug Name Indication Dosing Regimen Maximum Dose For all pediatric patients weighing less than 45 kg with severe or life threatening infections (e.g., anthrax, Rocky Mountain spotted fever): 2.6 mg per kg of body weight administered PO every 12 hours.
    For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg):
    5.3 mg per kg of body weight divided into two doses on the first day of treatment PO, followed by a maintenance dose of 2.6 mg per kg of body weight (given as a single daily dose or divided into twice daily doses) PO.
    For pediatric patients weighing over 45 kg: the usual adult dose should be used. 40 mg PO QD 40 mg/day Availability Tablets: 75 mg, 150 mg Generic: 20 mg, 50 mg, 75 mg, 100 mg, 150 mg Delayed-release tablets: 50 mg, 80 mg, 200 mg Delayed-release tablets (MPC): 60 mg, 120 mg
    Generic: 50 mg, 75 mg, 80 mg, 100 mg, 150 mg, 200 mg Delayed-release capsule: 40 mg Doxycycline capsule (Oracea) Inflammatory lesions (papules and pustules) of rosacea VI. Product Availability
    Drug Name Doxycycline hyclate (Acticlate)
    Doxycycline hyclate delayed-release tablets (Doryx, Doryx MPC) Doxycycline (Oracea) VII.