Regulatory Decision Summary for Doxycycline for Injection USP

This New Drug Submission (NDS) was filed to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Doxycycline for Injection United States Pharmacopeia (USP) (doxycycline hyclate). This submission was filed as a Submission Relying on Third-Party Data (SRTD) according to the Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience). In accordance with the SRTD guidance, the Sponsor conducted a comprehensive, systematic review of the scientific literature to identify publicly available clinical evidence to support the safety and efficacy of doxycycline, a broad-spectrum antibiotic derived from oxy-tetracycline. Upon review of the submitted data package, Health Canada recommends authorization of Doxycycline for Injection USP for the following indications: pneumonia, respiratory and urinary tract infections, skin and soft tissue infections, sexually transmitted infections, Rickettsial infections (Rocky Mountain spotted fever, typhus fever, the typhus group, Q fever, rickettsial pox, and tick fevers), anthrax, malaria and other bacterial infections (Psittacosis and ornithosis, brucellosis, cholera, the plague, relapsing fever, tularemia, and Oroya fever and verruga peruana infections).

Doxycycline is a broad-spectrum antibiotic that is employed worldwide in the treatment of numerous Gram-positive and Gram-negative bacterial infections. This is reflected in its long list of potential indications. Doxycycline hyclate is a recognized treatment option for respiratory and urinary infections, sexually transmitted infections, malaria, and outbreaks (e.g., cholera, tularemia, typhus, and Rickettsial infections). These infections can be treated using oral and/or IV doxycycline as first-line or second-line treatment, alone or in combination with other antibiotics.

The IV route of administration has several benefits such as in critical care settings where oral intake is not feasible, for instance in unconscious patients, or in severe infections where rapid action is needed. As stated in the proposed Product Monograph, parenteral therapy is indicated only when oral therapy is not indicated. Therapy with oral doxycycline should be instituted as soon as possible.

Doxycycline administered IV was originally approved over 50 years ago as an antibiotic by the United States Food and Drug Administration (FDA). Vibramycin (Pfizer) serves as the reference list drug (RLD) for intravenous (IV) doxycycline while DOXY 100/DOXY 200 (Fresenius Kabi) is the reference standard (RS) and is currently marketed in the United States (for more than 40 years). The Sponsor’s proposed formulation of Doxycycline for Injection USP is identical to the RS formulation. A doxycycline hyclate injection product was previously approved and marketed in Canada in 1997 (Vibramycin) but is not currently marketed for reasons not related to safety (cancelled in 2000).

This submission was filed as a Submissions Relying on Third-Party Data (SRTD). The Sponsor conducted a comprehensive, systematic review of the scientific literature to identify publicly available clinical evidence to support the safety and efficacy of doxycycline. In accordance with the Health Canada SRTD Guidance Document, the Sponsor’s proposed product, Doxycycline for Injection USP, was bridged to the United States (US) RS, DOXY 100/DOXY 200.

The efficacy and safety of doxycycline was demonstrated in 9 pivotal studies, 38 supportive studies from the original literature search (from 44 references), 16 supportive studies from an expanded literature search (including retrospective studies and other non-randomized controlled trials conducted with IV doxycycline), and 93 supportive studies from a targeted literature search (including studies for specific indications for which pivotal or supportive studied had not yet been identified in the previous searches, and oral doxycycline).

Across the pivotal and supportive studies, doxycycline demonstrated efficacy in both adult and pediatric patients across a broad range of Gram-positive and Gram-negative bacteria in respiratory, urinary, gynecological, and other infections. Doxycycline (alone or in combination with other antibiotics) was as effective or more effective in comparison to other antibacterial treatments in pelvic inflammatory disease, respiratory infections including pneumonia, and urinary infections. Combination treatment with doxycycline and other antibiotics often resulted in greater clinical success than monotherapy. Doxycycline demonstrated efficacy in Rickettsial diseases, which are often very severe and associated with high mortality rates, and for which prompt treatment is an important factor in survival probability. Doxycycline, alongside a second antimalarial drug, such as quinine, was also effective in the treatment of severe or complicated Plasmodium falciparum malaria.

The selected pivotal studies were all randomized and controlled. One study was double-blinded and three studies were single-blinded. Most studies were open-label; in some cases, the blinding was not described, but based on the treatment regimens given (e.g., frequency of IV administration), it could be assumed that the studies were open-label. The studies were moderate in size, enrolling from 48 up to 157 patients. In total, there were 876 patients included in the 9 pivotal studies that provided efficacy and/or safety information. Of these, 415 were treated with doxycycline including 330 that received doxycycline monotherapy.

All nine pivotal studies were described in the proposed product monograph (PM). While the proposed route of administration and strengths for the proposed product are the same as for the RLD used in the pivotal studies and are also the same as the RS DOXY 100/DOXY 200, it is not clear if the patient populations in the pivotal studies are fully relevant. The proposed indications in the Canadian PM also do not completely line up with the pivotal studies; most pivotal studies (7 of 9) concern prophylaxis, which is not specifically included in the proposed indications. Also, most of the pivotal studies do not address treatment of infections caused by the specific microorganisms listed in the proposed indications. Because of these limitations with the pivotal studies, additional evidence was utilized from supportive studies , Canadian and international treatment guidelines and data from the Canadian Special Access Program (SAP) requests.

For some of the proposed indications (Borrelia recurrentis, Yersinia pestis, Francisella tularensis, Bartonella bacilliformis, Vibrio cholerae, Bacillus anthracis), oral doxycycline studies were relied upon rather than strictly IV doxycycline. These studies are included where no IV doxycycline data exist and were considered acceptable evidence, given the comparable pharmacokinetic profiles of the IV formulation and oral dosage forms of doxycycline hyclate. Furthermore, in many Canadian hospitals, antimicrobial stewardship programs treat oral and IV doxycycline as equivalent when providing guidance on indications and susceptibility and advise that it can be used when oral therapy is not feasible.

The known safety findings for Doxycycline for Injection USP are adequately captured in the PM. Doxycycline hyclate is well tolerated, with limited evidence of serious adverse effects. The adverse events listed in the proposed PM are consistent with the safety findings of the pivotal and supportive studies, safety findings described in the labelling for the RS, DOXY 100 and the PM of other oral doxycycline hyclate products, as well as the post-market reactions included in the FDA Adverse Events Reporting System (FAERS) database, with nausea, vomiting, diarrhea, rash, pruritus, pain at infusion site, headache and hypersensitivity-type reactions being the most commonly reported. Although tooth discolouration and enamel hypoplasia are known concerns for doxycycline, tooth or dental issues were not reported in the pivotal or supportive studies and were rarely reported in the FAERS database.

The non-clinical review of the literature covered the pharmacology, pharmacodynamics, toxicology and microbiology of doxycycline. Almost all in vivo studies submitted employed the oral route of administration. As described above with respect to clinical evidence, non-clinical studies evaluating doxycycline administered orally were considered acceptable evidence to support the proposed IV formulation since both IV and oral doxycycline exhibit comparable pharmacokinetic properties and are generally considered equivalent. Consistent observations of fertility issues, embryo-fetal developmental retardation and tooth development effects following doxycycline administration, as well as its distribution in breastmilk, have been reported in animals. Doxycycline has not been tested in pregnant women, and is not recommended in pregnancy and breastfeeding and in children under 8 years old.

The quality review examined the comparative physicochemical testing conducted to demonstrate equivalence with the RS (DOXY 100/DOXY 200). The comparative testing results between the RS and the proposed product, Doxycycline for Injection USP, adequately demonstrated that the proposed and reference products are pharmaceutically equivalent. Overall, the quality information reviewed as part of this submission was considered acceptable.

Due to the established safety profile of this product, a risk management plan (RMP) was not required.

Overall, the benefit-harm-uncertainty profile was favourable for Doxycycline for Injection USP for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) is recommended. While many oral doxycycline products are currently approved in Canada, the intravenous form is considered of significant clinical benefit by allowing treatment when no oral intake is feasible, or treatment of patients with more severe infections where rapid action is needed.

For further details about Doxycycline for Injection USP, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.