Preventing Preterm Birth: An Unmet Need in the US
Despite having one of the most advanced healthcare systems in the world, the rate of preterm birth (PTB) in the US is among the highest in the world. Approximately 1 in 10 babies (380,000 each year) are born between 20 and 37 weeks of pregnancy. More concerning is the fact that the PTB rate increased between 2015 and 2017 after decreasing the previous 7 years, earning the US a “C” grade on the latest March of Dimes Premature Birth Report Card.1 PTB and its complications are the leading cause of death of babies, accounting for approximately 70% of newborn deaths and 36% of infant deaths.2 Long-term complications include cerebral palsy, chronic lung disease, blindness, hearing loss, and intellectual disabilities.1
Clinical Guidelines on Preterm Birth Prevention
The Society for Maternal Fetal Medicine (SMFM), the American College of Obstetricians and Gynecologists (ACOG), and the American College of Nurse-Midwives (ACNM) have published guidelines providing specific recommendations regarding the diagnosis and management of women at risk for PTB.3-5 They all emphasize the use of progestogen, which has consistently demonstrated beneficial effects in reducing early PTB risk in appropriate patients.6 The SMFM also provides a toolkit of algorithms for managing women with and without a history of PTB.
In women with singleton gestations and prior history of PTB between 20-36 6/7 weeks, 17-alpha-hydroxy-progesterone caproate (17-OHCP) 250 mg administered once weekly intramuscularly (IM), from 16-20 weeks and continued until 36 weeks, is recommended.3 Several randomized trials of women with singleton gestations, short cervical length (≤20 mm at ≤24 weeks), and no prior history of PTB demonstrated that vaginal progesterone, 90-mg gel or 200-mg suppository, was associated with a reduction in PTB, perinatal morbidity, and mortality. In women with prior PTB and cervical length <25 mm at <24 weeks, cervical cerclage may be considered.3 Progesterone has not been associated with the prevention of premature birth in women who have multiple gestations in the current pregnancy, preterm labor, or preterm premature rupture of membranes and should not be administered to these women.3-5
In February 2018, the US Food and Drug Administration (FDA) approved a bioequivalent subcutaneous (SC) formulation of 17-OHPC. This formulation provides an alternative to the intramuscular injectable formulation for women who should receive 17-OHPC to reduce their risk of PTB.7
Recently, Dr. Bahaeddine M. Sibai, Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of Texas Health Science Center at Houston and a primary investigator on the initial studies for 17-OHCP, provided his perspective on the new SC formulation’s place in treatment during an interview.
Overview of Subcutaneous 17-OHPC Formulation
The subcutaneous formulation of 17-OHPC was approved by the FDA on February 14, 2018 to reduce the risk of PTB in pregnant women with a singleton pregnancy with history of spontaneous PTB. The approval was based on data demonstrating the bioequivalence and bioavailability of 17-OHPC administered SC to that of 17-OHPC administered IM. Subcutaneous 17-OHPC, 1.1-mL (275-mg), is available in a ready-to-administer autoinjector that utilizes a short, thin 27-gauge needle. The subcutaneous formulation is given in the back of the upper arm and takes less than 15 seconds to administer.7 In comparison, since its approval in 2011, the intramuscular 17-OHPC formulation has been administered as a 1-mL (250-mg) solution in the upper-outer quadrant of the gluteus maximus muscle using a syringe with a large 21-gauge needle. The administration of the intramuscular regimen also requires that health care professionals draw the drug from a vial using a large-gauge needle and then switch needles to administer the dose with the 21-gauge needle.
For a manufacturer to demonstrate bioequivalence, the study must show that there is no significant difference between the time (Tmax) to reach the maximum serum concentration (Cmax) and the extent or area under the curve between the new formulation or new route of administration of a drug. The FDA guidance allows the drug to demonstrate 80% to 125% variability from the original product or route to claim bioequivalence. There also must be a 90% confidence interval (CI) where all the values within the CI range are within that 80% to 125% variability of the original product.8
The bioequivalence of subcutaneous 17-OHPC was studied in a randomized, multicenter, open-label study in 90 postmenopausal women. This trial compared the bioavailability of a single dose of 17-OHPC administered as a subcutaneous injection in the back of the upper arm (n = 45 women) compared with intramuscular injection of 17-OHPC in the gluteus maximus (n = 45 women).9
The pharmacokinetic parameters for the single-dose SC and IM injections are summarized in Table 1. SC administration resulted in a slightly higher mean Cmax than IM administration; however, median Tmax values were comparable. All of the 90% confidence intervals for least square geometric mean ratios for AUC were within the 80% to 125% window that defines bioequivalence.
Table 2 compares the reported adverse events from both the patient and investigator perspective. Injection site pain was the most common adverse event reported by 37.3% of those receiving the SC injection vs. 8.2% of those receiving the IM injection. However, of those patients who reported pain with the SC injection, 85% reported it as “mild.”9
Table 2: Comparison of Most Common Treatment Emergent Adverse Events Between SC and IM Injection of 17-OHPC9
Dr. Sibai noted that the higher incidence of pain in the bioequivalence study may be explained by the fact that it was conducted in postmenopausal women who generally have less muscle mass in the upper arm. He also noted that none of the patients in his practice have complained of pain from the SC injection.
Compared to IM administration, the SC autoinjector improves the convenience and safety of administration and reduces the potential for dosing errors. Dr. Sibai also noted that the new formulation also reduces injection-related anxiety and pain for the patient. He emphasized that this is an important advantage that has improved adherence in his practice: “In the past year, before I started prescribing the subcutaneous injection, my experience has been about 10% to 15% of all women who are eligible to receive 17-OHPC were refusing to take it because they didn’t like the IM injections and they didn’t want to come to the office every week for the injection …about 15% of the women were not compliant and did not take their dose every week. This really was a major concern.” Dr Sibai noted that since he started to administer the SC formulation, no patient has refused the 17-OHPC injection.
Dr. Sibai also reported positive impacts on his staff and the work flow. In fact, his staff members now prefer the SC formulation because they find it faster and easier to administer than the IM formulation. They also recognize that the use of the autoinjector enhances safety by eliminating risks of needle sticks, controlling the administered dose, and reducing necessary manipulations associated with having to withdraw the IM formulation drug from a vial. Dr. Sibai suggested that some patients may even be taught to administer the medication at home, such as those patients who already self-administer SC low molecular weight heparin, or insulin. In fact, Dr. Sibai mentioned that he is leading an ongoing study evaluating patient outcomes after self-administration of SC 17-OHCP. He explained that patient education materials regarding the usage of subcutaneous 17-OHPC, like videos, can be often be obtained at local pharmacies.
Table 3: Comparison of Features of SC and IM 17-OHPC9
The subcutaneous formulation of 17-OHPC has been shown to have comparable bioequivalence and bioavailability compared to the IM formulation, resulting in its FDA approval for the prevention of PTB in women with a history of spontaneous preterm delivery. Compared to the IM formulation, the new SC formulation of 17-OHPC has several features that are designed to enhance ease of use for both health care professionals and patients (Table 3). Available in an autoinjector, it uses a smaller, thinner needle and is administered subcutaneously in the back of the arm vs. intramuscularly in the buttocks. Furthermore, the injection can be performed in a much shorter time (15 seconds) than with the IM formulation (over 1 minute).
- March of Dimes. U.S. preterm birth rate increases for second year in a row. Availablet at: https://www.multivu.com/players/English/8189251-march-of-dimes-premature-birth-report-card-2017/. Accessed Oct. 24, 2018.
- American College of Nurse-Midwives (ACNM). Position Statement: Prevention of Preterm Labor and Preterm Birth. Available at: http://midwife.org/ACNM/files/ACNMLibraryData/UPLOADFILENAME/000000000274/Prevention%20of%20Preterm%20Labor%20and%20Preterm%20Birth%20June%202012.pdf.
- Society for Maternal-Fetal Medicine Publications Committee; Berghella V. Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol. 2012;206:376-386.
- American College of Obstetricians and Gynecologists. Practice bulletin no. 159: Management of preterm labor. Obstet Gynecol. 2016 Jan. 127 (1):e29-38.
- American College of Nurse Midwives (ACNM). Position Statement: Prevention of preterm labor and preterm birth. Available at: http://midwife.org/ACNM/files/ACNMLibraryData/UPLOADFILENAME/000000000274/Prevention%20of%20Preterm%20Labor%20and%20Preterm%20Birth%20June%202012.pdf. Accessed Nov. 1, 2018.
- O’Brien JM, Lewis DF. Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety. Am J Obstet Gynecol. 2016 Jan;214(1):45-56.
- AMAG Pharmaceuticals. AMAG Pharmaceuticals Announces FDA Approval of Makena® (hydroxyprogesterone caproate injection) Subcutaneous Auto-Injector to Reduce the Risk of Preterm Birth in Certain At-Risk Women. Available at: https://globenewswire.com/news-release/2018/02/14/1348440/0/en/AMAG-Pharmaceuticals-Announces-FDA-Approval-of-Makena-hydroxyprogesterone-caproate-injection-Subcutaneous-Auto-Injector-to-Reduce-the-Risk-of-Preterm-Birth-in-Certain-At-Risk-Women.html. Accessed Oct. 24, 2018.
- US Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs — General Considerations. Available at: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm389370.pdf. Accessed Oct. 24, 2018.
- Krop J, Kramer WG. Comparative Bioavailability of Hydroxyprogesterone Caproate Administered via Intramuscular Injection or Subcutaneous Autoinjector in Healthy Postmenopausal Women: A Randomized, Parallel Group, Open-label Study. Clin Ther. 2017 Dec;39(12):2345-2354.