y-related fetal and maternal complications or events were numerically increased in the Makena-treated subjects as compared to control subjects, including miscarriage and stillbirth, admission for preterm labor, preeclampsia or gestational hypertension, gestational diabetes, and oligohydramnios (Tables 1 and 2).
Common Adverse Reactions:
The most common adverse reaction was injection site pain, which was reported after at least one injection by 34.8% of the Makena group and 32.7% of the control group. Table 3 lists adverse reactions that occurred in ≥2% of subjects and at a higher rate in the Makena group than in the control group.
In the clinical trial, 2.2% of subjects receiving Makena were reported as discontinuing therapy due to adverse reactions compared to 2.6% of control subjects. The most common adverse reactions that led to discontinuation in both groups were urticaria and injection site pain/swelling (1% each).
Pulmonary embolus in one subject and injection site cellulitis in another subject were reported as serious adverse reactions in Makena-treated subjects.
Table 1 Selected Fetal Complications
1 N = Total number of subjects enrolled prior to 20 weeks 0 days.
2 N = Total number of subjects at risk ≥20 weeks.
Pregnancy Complication Makena Control
n/N n/N
Miscarriage (<20 weeks)1 5/209 0/107
Stillbirth (≥20 weeks)2 6/305 2/153
Table 2 Selected Maternal Complications
1 Other than delivery admission.
Pregnancy Complication Makena
N=310
% Control
N=153
%
Admission for preterm labor1 16.0 13.8
Preeclampsia or gestational hypertension 8.8 4.6
Gestational diabetes 5.6 4.6
Oligohydramnios 3.6 1.3
Table 3 Adverse Reactions Occurring in ≥2% of Makena-Treated Subjects and at a Higher Rate than Control Subjects
Preferred Term Makena
N=310
% Control
N=153
%
Injection site pain 34.8 32.7
Injection site swelling 17.1 7.8
Urticaria 12.3 11.1
Pruritus 7.7 5.9
Injection site pruritus 5.8 3.3
Nausea 5.8 4.6
Injection site nodule 4.5 2.0
Diarrhea 2.3 0.7
No drug-drug interaction studies were conducted with Makena.
Drugs Metabolized by CYP1A2, CYP2A6 and CYP2B6
The metabolism of drugs metabolized by CYP1A2 (such as theophylline, tizadine, clozapine), CYP2A6 (such as acetaminophen, halothane, nicotine) and CYP2B6 (such as efavirenz, bupropion, methadone) may be increased during treatment with Makena [See Clinical Pharmacology (12.3)].
Pregnancy Category B: There are no adequate and well-controlled studies of Makena use in women during the first trimester of pregnancy. Data from a vehicle (placebo)-controlled clinical trial of 310 pregnant women who received Makena at weekly doses of 250 mg by intramuscular injection in their second and third trimesters, as well as long-term (2-5 years) follow-up safety data on 194 of their infants , did not demonstrate any teratogenic risks to infants from in utero exposure to Makena.
Reproduction studies have been performed in mice and rats at doses up to 95 and 5, respectively, times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Makena.
Makena administration produced embryolethality in rhesus monkeys but not in cynomolgus monkeys exposed to 1 and 10 times the human dose equivalent every 7 days between days 20 and 146 o |
