Hydroxyprogesterone

Pregnancy Category B.

There are no adequate and well-controlled studies of hydroxyprogesterone use in women during the first trimester of pregnancy. Data from a vehicle (placebo)-controlled clinical trial of 310 pregnant women who received hydroxyprogesterone 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 hydroxyprogesterone.

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 hydroxyprogesterone.

Hydroxyprogesterone 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 of gestation. There were no teratogenic effects in either species.

Labor and Delivery

Hydroxyprogesterone is not intended for use to stop active preterm labor. The effect of hydroxyprogesterone in active labor is unknown.

Discontinue hydroxyprogesterone at 37 weeks of gestation or upon delivery. Detectable amounts of progestins have been identified in the milk of mothers receiving progestin treatment. Many studies have found no adverse effects of progestins on breastfeeding performance, or on the health, growth, or development of the infant.

Hydroxyprogesterone caproate has not been adequately evaluated for carcinogenicity.

No reproductive or developmental toxicity or impaired fertility was observed in a multigenerational study in rats. Hydroxyprogesterone 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 Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a vehicle (placebo)-controlled clinical trial of 463 pregnant women at risk for spontaneous preterm delivery based on obstetrical history, 310 received 250 mg of hydroxyprogesterone and 153 received a vehicle formulation containing no drug by a weekly intramuscular injection beginning at 16 to 20 weeks of gestation and continuing until 37 weeks of gestation or delivery, whichever occurred first.

Certain pregnancy-related fetal and maternal complications or events were numerically increased in the hydroxyprogesterone-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).

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

Table 2. Selected Maternal Complications:

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 hydroxyprogesterone 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 hydroxyprogesterone group than in the control group.

Table 3. Adverse Reactions Occurring in ≥2% of Hydroxyprogesterone-Treated Subjects and at a Higher Rate than Control Subjects:

In the clinical trial, 2.2% of subjects receiving hydroxyprogesterone 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 hydroxyprogesterone-treated subjects.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of hydroxyprogesterone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a whole: Local injection site reactions (including erythema, urticaria, rash, irritation, hypersensitivity, warmth); fatigue; fever; hot flashes/flushes

Digestive disorders: Vomiting

Infections: Urinary tract infection

Nervous system disorders: Headache, dizziness

Pregnancy, puerperium and perinatal conditions: Cervical incompetence, premature rupture of membranes

Reproductive system and breast disorders: Cervical dilation, shortened cervix

Respiratory disorders: Dyspnea, chest discomfort

Skin: Rash