s retained during metabolism of hydroxyprogesterone caproate.
Excretion: 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.
Specific Populations
Renal Impairment: The effect of renal impairment on the pharmacokinetics of Makena has not been eva luated.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Makena has not been eva luated.
Drug Interactions
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 eva luated.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Hydroxyprogesterone caproate has not been adequately eva luated for carcinogenicity.
No reproductive or developmental toxicity or impaired fertility was observed in a multigenerational study in rats. Makena administered intramuscularly, at gestational exposures up to 5 times the recommended human dose, had no adverse effects on the parental (F0) dams, their developing offspring (F1), or the latter offspring's ability to produce a viable, normal second (F2) generation.
Clinical Studies
Clinical Trial to eva luate Reduction of Risk of Preterm Birth
In a multicenter, randomized, double-blind, vehicle (placebo)-controlled clinical trial, the safety and effectiveness of Makena 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 (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-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 d |
