Source: FDA, National Drug Code (US) Revision Year: 2020
Dinoprostone is found in low concentrations in most tissues of the body and functions as a local hormone. In pregnancy, dinoprostone is secreted continuously by the fetal membranes and placenta and plays an important role in the final events leading to the initiation of labor including cervical ripening. Dinoprostone stimulates the production of prostaglandin F2α (PGF2α), which sensitizes the myometrium to endogenous or exogenously administered oxytocin. Available evidence indicates that dinoprostone, in the concentrations found during the early part of labor, plays an important role in cervical ripening without affecting uterine contractions.
In most patients, local effects of CERVIDIL on the cervix include changes in the tissue consistency, dilatation and effacement. Some women experience systemic effects, including uterine tachysystole, and uterine hypersystole/hypertonicity, as a result dinoprostone or PGF2α mediated sensitization of the myometrium to oxytocin [see Warnings and Precautions (5.4)].
No specific pharmacodynamic studies were conducted with CERVIDIL.
The delivery rate of dinoprostone from CERVIDIL in vivo is approximately 0.3 mg/per hour over a period of 12 hours. Dinoprostone is metabolized in the tissues of synthesis with the half-life estimated to be 2.5 to 5 minutes. The rate limiting step for inactivation is regulated by the enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH). Any dinoprostone that escapes local inactivation is cleared to the extent of 95% on the first pass through the pulmonary circulation.
No correlation could be established between the release of dinoprostone from CERVIDIL and plasma concentrations of metabolite of dinoprostone (PGEm). The relative contributions of endogenously and exogenously released dinoprostone to the plasma levels of the metabolite PGEm is not known.
Long-term carcinogenicity and fertility studies have not been conducted with dinoprostone. No evidence of mutagenicity has been observed with dinoprostone in the Unscheduled DNA Synthesis Assay, the Micronucleus Test, or the bacteria reverse mutation (Ames) test.
The effectiveness and safety of CERVIDIL for the induction of cervical ripening was evaluated in 658 pregnant women (320 CERVIDIL-treated women and 338 placebo-treated women) at or near term in three randomized, double-blind, placebo-controlled trials (Trials 1, 2, and 3). Efficacy outcomes included percentage with treatment success (defined as vaginal delivery within 12 hours, Bishop Score ≥6 in the 12-hour observation period, or ≥3 increase in the Bishop score in the 12-hour observation period), time to delivery, and time to onset of labor. Table 2 presents efficacy outcomes from Trials 1, 2, and 3.
Table 2. Efficacy Outcomes in Pregnant Women in Trials 1, 2, and 3† for CERVIDIL Ripening, Intent-to-Treat Population:
| Primipara/Nullipara | Multipara | ||||
|---|---|---|---|---|---|
| Study # | CERVIDIL | Placebo | CERVIDIL | Placebo | P-Value |
| Treatment Success‡ | |||||
| Trial 1 (N=81) | 65% (n=26) | 28% (n=32) | 87% (n=16) | 29% (n=7) | <0.001 |
| Trial 2 (N=371) | 68% (n=111) | 24% (n=123) | 77% (n=65) | 24% (n=72) | <0.001 |
| Trial 3 (N=206) | 72% (n=60) | 48% (n=63) | 55% (n=42) | 41% (n=41) | 0.003 |
| Median Time to Delivery (hours) | |||||
| Trial 1 (N=81) | 25.7 (n=26) | 34.5 (n=32) | 12.3 (n=16) | 24.6 (n=7) | 0.001 |
| Trial 3 (N=206) | 25.5 (n=60) | 37.2 (n=63) | 20.8 (n=42) | 27.4 (n=41) | <0.001 |
| Median Time to Onset of Labor (hours) | |||||
| Trial 1 (N=81) | 12 (n=26) | 19.2 (n=32) | 6.9 (n=16) | 18.3 (n=7) | <0.001 |
* Trial 1 and Trial 2 evaluated the dinoprostone insert only, without the use of a retrieval system.
† Trial 3 evaluated the dinoprostone insert with the retrieval system
‡ Treatment success was defined as vaginal delivery within 12 hours, Bishop score ≥6 in the 12-hour observation period, or ≥3 increase in the Bishop score in the 12-hour observation period.
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