"In a drug safety communication issued today, the US Food and Drug Administration (FDA) says it is aware of recent reports "questioning" the safety of prescription and over-the-counter (OTC) pain medicines when used during pregnancy, but that it l"...
Mechanism of Action
Hydroxyprogesterone caproate is a synthetic progestin. The mechanism by which hydroxyprogesterone caproate reduces the risk of recurrent preterm birth is not known.
No specific pharmacodynamic studies were conducted with Makena (hydroxyprogesterone caproate injection) .
Peak serum levels of hydroxyprogesterone caproate appeared after 3-7 days in non-pregnant female subjects following a single intramuscular injection of 1000 mg hydroxyprogesterone caproate. Based on pharmacokinetic analysis of five non-pregnant female subjects who received a single intramuscular administration of 1000 mg hydroxyprogesterone caproate, the mean (±SD) Cmax is estimated to be 27.8 (±5.3) ng/mL, and the Tmax is estimated to be 4.6 (±1.7) days. The elimination half-life of hydroxyprogesterone caproate was 7.8 (±3.0) days. Once-weekly intramuscular administration of 1000 mg hydroxyprogesterone caproate to non-pregnant women resulted in trough concentration of 60.0 (±14) ng/mL after 13 weeks. The pharmacokinetics of the 250 mg dose of hydroxyprogesterone caproate has not been evaluated.
Hydroxyprogesterone caproate binds extensively to plasma proteins including albumin and corticosteroid binding globulins.
In vitro studies have shown that hydroxyprogesterone caproate can be metabolized by human hepatocytes, both by phase I and phase II reactions. Hydroxyprogesterone caproate undergoes extensive reduction, hydroxylation and conjugation. The conjugated metabolites include sulfated, glucuronidated and acetylated products. In vitro data indicate that the metabolism of hydroxyprogesterone caproate is predominantly mediated by CYP3A4 and CYP3A5. The in vitro data indicate that the caproate group is retained during metabolism of hydroxyprogesterone caproate.
Both conjugated metabolites and free steroids are excreted in the urine and feces, with the conjugated metabolites being prominent. Following intramuscular administration to pregnant women at 10-12 weeks gestation, approximately 50% of a dose was recovered in the feces and approximately 30% recovered in the urine.
Renal Impairment: The effect of renal impairment on the pharmacokinetics of Makena (hydroxyprogesterone caproate injection) has not been evaluated.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Makena (hydroxyprogesterone caproate injection) has not been evaluated.
Cytochrome P450 (CYP) enzymes: An in vitro study using human liver microsomes and CYP isoform-selective substrates indicated that hydroxyprogesterone caproate increased the metabolic rate of CYP1A2, CYP2A6, and CYP2B6 by approximately 80%, 150%, and 80%, respectively. The clinical implication of this in vitro metabolic acceleration is not well understood.
In vitro data indicated that therapeutic concentration of hydroxyprogesterone caproate is not likely to inhibit the activity of CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
The metabolic induction potential of hydroxyprogesterone caproate has not been evaluated.
Clinical Trial to Evaluate Reduction of Risk of Preterm Birth
In a multicenter, randomized, double-blind, vehicle (placebo)-controlled clinical trial, the safety and effectiveness of Makena (hydroxyprogesterone caproate injection) for the reduction of the risk of spontaneous preterm birth was studied in women with a singleton pregnancy (age 16 to 43 years) who had a documented history of singleton spontaneous preterm birth (defined as delivery at less than 37 weeks of gestation following spontaneous preterm labor or premature rupture of membranes).1 At the time of randomization (between 16 weeks, 0 days and 20 weeks, 6 days of gestation), an ultrasound examination had confirmed gestational age and no known fetal anomaly. Women were excluded for prior progesterone treatment or heparin therapy during the current pregnancy, a history of thromboembolic disease, or maternal/obstetrical complications (such as current or planned cerclage, hypertension requiring medication, or a seizure disorder).
A total of 463 pregnant women were randomized to receive either Makena (hydroxyprogesterone caproate injection) (N=310) or vehicle (N=153) at a dose of 250 mg administered weekly by intramuscular injection starting between 16 weeks, 0 days and 20 weeks, 6 days of gestation, and continuing until 37 weeks of gestation or delivery. Demographics of the Makena (hydroxyprogesterone caproate injection) -treated women were similar to those in the control group, and included: 59.0% Black, 25.5% Caucasian, 13.9% Hispanic and 0.6% Asian. The mean body mass index was 26.9 kg/m².
The proportions of women in each treatment arm who delivered at < 37 (the primary study endpoint), < 35, and < 32 weeks of gestation are displayed in Table 4.
Table 4 : Proportion of Subjects Delivering at < 37, <
35 and < 32 Weeks Gestational Age (ITT Population)
|Delivery Outcome||Makena (hydroxyprogesterone caproate injection) 1
|Treatment difference and 95% Confidence Interval2|
|< 37 weeks||37.1||54.9||-17.8% [-28.0%, -7.4%]|
|< 35 weeks||21.3||30.7||-9.4% [-19.0%, -0.4%]|
|< 32 weeks||11.9||19.6||-7.7% [-16.1%, -0.3%]|
|1 Four Makena (hydroxyprogesterone caproate injection) -treated subjects
were lost to follow-up. They were counted as deliveries at their gestational
ages at time of last contact (184, 220, 343 and 364 weeks).
2 Adjusted for interim analysis.
Compared to controls, treatment with Makena (hydroxyprogesterone caproate injection) reduced the proportion of women who delivered preterm at < 37 weeks. The proportions of women delivering at < 35 and < 32 weeks also were lower among women treated with Makena (hydroxyprogesterone caproate injection) . The upper bounds of the confidence intervals for the treatment difference at < 35 and < 32 weeks were close to zero. Inclusion of zero in a confidence interval would indicate the treatment difference is not statistically significant. Compared to the other gestational ages evaluated, the number of preterm births at < 32 weeks was limited.
After adjusting for time in the study, 7.5% of Makena (hydroxyprogesterone caproate injection) -treated subjects delivered prior to 25 weeks compared to 4.7% of control subjects; see Figure 1.
Figure 1 : Proportion of Women Remaining Pregnant as a Function
of Gestational Age
The rates of fetal losses and neonatal deaths in each treatment arm are displayed in Table 5. Due to the higher rate of miscarriages and stillbirths in the Makena (hydroxyprogesterone caproate injection) arm, there was no overall survival difference demonstrated in this clinical trial.
Table 5 : Fetal Losses and Neonatal Deaths
|Complication||Makena (hydroxyprogesterone caproate injection)
n (%) B
n (%) B
|Miscarriages < 20 weeks gestation C||5 (2.4)||0|
|Stillbirth||6 (2.0)||2 (1.3)|
|Antepartum stillbirth||5 (1.6)||1 (0.6)|
|Intrapartum stillbirth||1 (0.3)||1 (0.6)|
|Neonatal deaths||8 (2.6)||9 (5.9)|
|Total Deaths||19 (6.2)||11 (7.2)|
|A Four of the 310 Makena (hydroxyprogesterone caproate injection) -treated
subjects were lost to follow-up and stillbirth or neonatal status could
not be determined
B Percentages are based on the number of enrolled subjects and not adjusted for time on drug
C Percentage adjusted for the number of at risk subjects (n=209 for Makena (hydroxyprogesterone caproate injection) , n=107 for control) enrolled at < 20 weeks gestation.
A composite neonatal morbidity/mortality index evaluated adverse outcomes in livebirths. It was based on the number of neonates who died or experienced respiratory distress syndrome, bronchopulmonary dysplasia, grade 3 or 4 intraventricular hemorrhage, proven sepsis, or necrotizing enterocolitis. Although the proportion of neonates who experienced 1 or more events was numerically lower in the Makena (hydroxyprogesterone caproate injection) arm (11.9% vs. 17.2%), the number of adverse outcomes was limited and the difference between arms was not statistically significant.
Infant Follow-Up Safety Study
Infants born to women enrolled in this study, and who survived to be discharged from the nursery, were eligible for participation in a follow-up safety study. Of 348 eligible offspring, 79.9% enrolled: 194 children of Makena (hydroxyprogesterone caproate injection) -treated women and 84 children of control subjects. The primary endpoint was the score on the Ages & Stages Questionnaire (ASQ), which evaluates communication, gross motor, fine motor, problem solving, and personal/social parameters. The proportion of children whose scores met the screening threshold for developmental delay in each developmental domain was similar for each treatment group.2
1 Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379-85.
2 Northen A, Norman G, Anderson K, et al. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate. Obstet & Gynecol. 2007;110:865-872.
Last reviewed on RxList: 9/25/2013
This monograph has been modified to include the generic and brand name in many instances.
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