PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption: Female patients with singleton pregnancy received intramuscular doses of 250 mg hydroxyprogesterone caproate for the reduction of preterm birth starting between 16 weeks days and 20 weeks days. All patients had blood drawn daily for days to evaluate pharmacokinetics. Table Summary of Mean (Standard Deviation) Pharmacokinetics Parameters for Hydroxyprogesterone Caproate Group (N)Cmax (ng/mL)Tmax (days)a AUC(1 to t)b (ngohr/mL)Group (N=6)5.0 (1.5)5.5 (2.0 to 7.0)571.4 (195.2)Group (N=8)12.5 (3.9)1.0 (0.9 to 1.9)1269.6 (285.0)Group (N=11)12.3 (4.9)2.0 (1.0 to 3.0)1268.0 (511.6)Blood was drawn daily for days (1) starting 24 hours after the first dose between Weeks 16 to 20 (Group 1), (2) after dose between Weeks 24 to 28 (Group 2), or (3) after dose between Weeks 32 to 36 (Group 3)aReported as median (range)bt 7 daysFor all three groups, peak concentration (Cmax) and area under the curve (AUC(1 to days)) of the mono-hydroxylated metabolites were approximately to 8-fold lower than the respective parameters for the parent drug, hydroxyprogesterone caproate. While di-hydroxylated and tri-hydroxylated metabolites were also detected in human plasma to lesser extent, no meaningful quantitative results could be derived due to the absence of reference standards for these multiple hydroxylated metabolites. The relative activity and significance of these metabolites are not known. The elimination half-life of hydroxyprogesterone caproate, as evaluated from patients in the study who reached full-term in their pregnancies, was 16.4 (+3.6) days. The elimination half-life of the mono-hydroxylated metabolites was 19.7 (+6.2) days. In single-dose, open-label, randomized, parallel design bioavailability study in 120 healthy post-menopausal women, comparable systemic exposure of hydroxyprogesterone caproate was seen when hydroxyprogesterone caproate injection was dosed intramuscularly (1 mL) in the upper outer quadrant of the gluteus maximus.Distribution: Hydroxyprogesterone caproate binds extensively to plasma proteins including albumin and corticosteroid binding globulins. Metabolism:In vitro studies have shown that hydroxyprogesterone caproate can be metabolized by human hepatocytes, both by phase 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. 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 to 12 weeks gestation, approximately 50% of dose was recovered in the feces and approximately 30% recovered in the urine. Drug InteractionsCytochrome P450 (CYP) enzymes: An in vitro inhibition 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. However, in another in vitro study using human hepatocytes under conditions where the prototypical inducers or inhibitors caused the anticipated increases or decreases in CYP enzyme activities, hydroxyprogesterone caproate did not induce or inhibit CYP1A2, CYP2A6, or CYP2B6 activity. Overall, the findings indicate that hydroxyprogesterone caproate has minimal potential for CYP1A2, CYP2A6, and CYP2B6 related drug-drug interactions at the clinically relevant concentrations.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.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. For the most serious adverse reactions to the use of progestins, see Warnings and Precautions 5 ). In study where the hydroxyprogesterone caproate intramuscular injection was compared with placebo, the most common adverse reactions reported with hydroxyprogesterone caproate intramuscular injection (reported incidence in >=2% of subjects and higher than in the control group) were: injection site reactions (pain [35%], swelling [17%], pruritus [6%], nodule [5%]), urticaria (12%), pruritus (8%), nausea (6%), and diarrhea (2%). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 caproate injection and 153 received vehicle formulation containing no drug by weekly intramuscular injection beginning at 16 to 20 weeks of gestation and continuing until 37 weeks of gestation or delivery, whichever occurred first. [See Clinical Studies 14.1 ).] Certain pregnancy-related fetal and maternal complications or events were numerically increased in the hydroxyprogesterone caproate injection-treated subjects as compared to control subjects, including miscarriage and stillbirth, admission for preterm labor, preeclampsia or gestational hypertension, gestational diabetes, and oligohydramnios (Tables and 2). Table Selected Fetal ComplicationsPregnancy ComplicationHydroxyprogesterone Caproate Injectionn/NControln/NMiscarriage (< 20 weeks)1 5/2090/107Stillbirth (>= 20 weeks)2 6/3052/1531 = Total number of subjects enrolled prior to 20 weeks days N Total number of subjects at risk >= 20 weeks Table Selected Maternal ComplicationsPregnancy ComplicationHydroxyprogesterone Caproate InjectionN=310%ControlN=153%Admission for preterm labor1 16.013.8Preeclampsia or gestational hypertension8.84.6Gestational diabetes5.64.6Oligohydramnios3.61.31 Other than delivery admission.Common Adverse Reactions:The most common adverse reaction with intramuscular injection was injection site pain, which was reported after at least one injection by 34.8% of the hydroxyprogesterone caproate injection group and 32.7% of the control group. Table lists adverse reactions that occurred in >= 2% of subjects and at higher rate in the hydroxyprogesterone caproate injection group than in the control group.Table Adverse Reactions Occurring in >= 2% of Hydroxyprogesterone Caproate Injection-Treated Subjects and at Higher Rate than Control SubjectsPreferred Term Hydroxyprogesterone Caproate InjectionN=310%ControlN=153%Injection site pain34.832.7Injection site swelling 17.17.8Urticaria12.311.1Pruritus7.75.9Injection site pruritus5.83.3Nausea5.84.6Injection site nodule4.52.0Diarrhea2.30.7In the clinical trial using intramuscular injection, 2.2% of subjects receiving hydroxyprogesterone caproate injection 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 caproate injection-treated subjects. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of hydroxyprogesterone caproate injection. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Body as whole: Local injection site reactions (including erythema, urticaria, rash, irritation, hypersensitivity, warmth); fatigue; fever; hot flashes/flushesDigestive disorders: VomitingInfections: Urinary tract infectionNervous system disorders: Headache, dizzinessPregnancy, puerperium and perinatal conditions: Cervical incompetence, premature rupture of membranesReproductive system and breast disorders: Cervical dilation, shortened cervixRespiratory disorders: Dyspnea, chest discomfortSkin: Rash. Body as 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Hydroxyprogesterone caproate is synthetic progestin. The mechanism by which hydroxyprogesterone caproate reduces the risk of recurrent preterm birth is not known.. 12.2 Pharmacodynamics. No specific pharmacodynamic studies were conducted with hydroxyprogesterone caproate injection.. 12.3 Pharmacokinetics. Absorption: Female patients with singleton pregnancy received intramuscular doses of 250 mg hydroxyprogesterone caproate for the reduction of preterm birth starting between 16 weeks days and 20 weeks days. All patients had blood drawn daily for days to evaluate pharmacokinetics. Table Summary of Mean (Standard Deviation) Pharmacokinetics Parameters for Hydroxyprogesterone Caproate Group (N)Cmax (ng/mL)Tmax (days)a AUC(1 to t)b (ngohr/mL)Group (N=6)5.0 (1.5)5.5 (2.0 to 7.0)571.4 (195.2)Group (N=8)12.5 (3.9)1.0 (0.9 to 1.9)1269.6 (285.0)Group (N=11)12.3 (4.9)2.0 (1.0 to 3.0)1268.0 (511.6)Blood was drawn daily for days (1) starting 24 hours after the first dose between Weeks 16 to 20 (Group 1), (2) after dose between Weeks 24 to 28 (Group 2), or (3) after dose between Weeks 32 to 36 (Group 3)aReported as median (range)bt 7 daysFor all three groups, peak concentration (Cmax) and area under the curve (AUC(1 to days)) of the mono-hydroxylated metabolites were approximately to 8-fold lower than the respective parameters for the parent drug, hydroxyprogesterone caproate. While di-hydroxylated and tri-hydroxylated metabolites were also detected in human plasma to lesser extent, no meaningful quantitative results could be derived due to the absence of reference standards for these multiple hydroxylated metabolites. The relative activity and significance of these metabolites are not known. The elimination half-life of hydroxyprogesterone caproate, as evaluated from patients in the study who reached full-term in their pregnancies, was 16.4 (+3.6) days. The elimination half-life of the mono-hydroxylated metabolites was 19.7 (+6.2) days. In single-dose, open-label, randomized, parallel design bioavailability study in 120 healthy post-menopausal women, comparable systemic exposure of hydroxyprogesterone caproate was seen when hydroxyprogesterone caproate injection was dosed intramuscularly (1 mL) in the upper outer quadrant of the gluteus maximus.Distribution: Hydroxyprogesterone caproate binds extensively to plasma proteins including albumin and corticosteroid binding globulins. Metabolism:In vitro studies have shown that hydroxyprogesterone caproate can be metabolized by human hepatocytes, both by phase 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. 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 to 12 weeks gestation, approximately 50% of dose was recovered in the feces and approximately 30% recovered in the urine. Drug InteractionsCytochrome P450 (CYP) enzymes: An in vitro inhibition 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. However, in another in vitro study using human hepatocytes under conditions where the prototypical inducers or inhibitors caused the anticipated increases or decreases in CYP enzyme activities, hydroxyprogesterone caproate did not induce or inhibit CYP1A2, CYP2A6, or CYP2B6 activity. Overall, the findings indicate that hydroxyprogesterone caproate has minimal potential for CYP1A2, CYP2A6, and CYP2B6 related drug-drug interactions at the clinically relevant concentrations.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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Clinical Trial to Evaluate Reduction of Risk of Preterm Birth. In multicenter, randomized, double-blind, vehicle (placebo)-controlled clinical trial, the safety and effectiveness of hydroxyprogesterone caproate injection for the reduction of the risk of spontaneous preterm birth was studied in women with singleton pregnancy (age 16 to 43 years) who had 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). At the time of randomization (between 16 weeks, days and 20 weeks, 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, history of thromboembolic disease, or maternal/obstetrical complications (such as current or planned cerclage, hypertension requiring medication, or seizure disorder). total of 463 pregnant women were randomized to receive either hydroxyprogesterone caproate injection (N=310) or vehicle (N=153) at dose of 250 mg administered weekly by intramuscular injection starting between 16 weeks, days and 20 weeks, days of gestation, and continuing until 37 weeks of gestation or delivery. Demographics of the 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 5. Table Proportion of Subjects Delivering at 37, 35 and 32 Weeks Gestational Age (ITT Population)DeliveryOutcomeHydroxyprogesterone Caproate Injection1 (N=310)%Control(N=153)%Treatment difference and 95% Confidence Interval2 <37 weeks37.154.9-17.8% [-28.0%, -7.4%]<35 weeks21.330.7-9.4% [-19.0%, -0.4%]<32 weeks11.919.6-7.7% [-16.1%, -0.3%]1 Four 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 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 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 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 hydroxyprogesterone caproate injection-treated subjects delivered prior to 25 weeks compared to 4.7% of control subjects; see Figure 1. Figure Proportion of Women Remaining Pregnant as Function of Gestational AgeThe rates of fetal losses and neonatal deaths in each treatment arm are displayed in Table 6. Due to the higher rate of miscarriages and stillbirths in the hydroxyprogesterone caproate injection arm, there was no overall survival difference demonstrated in this clinical trial.Table Fetal Losses and Neonatal DeathsComplicationHydroxyprogesterone Caproate InjectionN=306 n (%) ControlN=153n (%) Miscarriages <20 weeks gestation 5 (2.4)0Stillbirth6 (2.0)2 (1.3)Antepartum stillbirth5 (1.6)1 (0.6)Intrapartum stillbirth1 (0.3)1 (0.6)Neonatal deaths8 (2.6)9 (5.9)Total Deaths19 (6.2)11 (7.2)A Four of the 310 hydroxyprogesterone caproate injection-treated subjects were lost to follow-up and stillbirth or neonatal status could not be determined Percentages are based on the number of enrolled subjects and not adjusted for time on drug Percentage adjusted for the number of at risk subjects (n=209 for 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 or intraventricular hemorrhage, proven sepsis, or necrotizing enterocolitis. Although the proportion of neonates who experienced or more events was numerically lower in the 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. Figure One. 14.2 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 follow-up safety study. Of 348 eligible offspring, 79.9% enrolled: 194 children of 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Do not use hydroxyprogesterone caproate injection in women with any of the following conditions:Current or history of thrombosis or thromboembolic disordersKnown or suspected breast cancer, other hormone-sensitive cancer, or history of these conditionsUndiagnosed abnormal vaginal bleeding unrelated to pregnancyCholestatic jaundice of pregnancyLiver tumors, benign or malignant, or active liver diseaseUncontrolled hypertension. Current or history of thrombosis or thromboembolic disorders. Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions. Undiagnosed abnormal vaginal bleeding unrelated to pregnancy. Cholestatic jaundice of pregnancy. Liver tumors, benign or malignant, or active liver disease. Uncontrolled hypertension. Current or history of thrombosis or thromboembolic disorders (4)Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions (4)Undiagnosed abnormal vaginal bleeding unrelated to pregnancy (4)Cholestatic jaundice of pregnancy (4)Liver tumors, benign or malignant, or active liver disease (4)Uncontrolled hypertension (4). Current or history of thrombosis or thromboembolic disorders (4). Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions (4). Undiagnosed abnormal vaginal bleeding unrelated to pregnancy (4). Cholestatic jaundice of pregnancy (4). Liver tumors, benign or malignant, or active liver disease (4). Uncontrolled hypertension (4).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Hydroxyprogesterone caproate injection is progestin indicated to reduce the risk of preterm birth in women with singleton pregnancy who have history of singleton spontaneous preterm birth. The effectiveness of hydroxyprogesterone caproate injection is based on improvement in the proportion of women who delivered 37 weeks of gestation. There are no controlled trials demonstrating direct clinical benefit, such as improvement in neonatal mortality and morbidity.Limitation of use: While there are many risk factors for preterm birth, safety and efficacy of hydroxyprogesterone caproate injection has been demonstrated only in women with prior spontaneous singleton preterm birth. It is not intended for use in women with multiple gestations or other risk factors for preterm birth.. Administer intramuscularly at dose of 250 mg (1 mL) once weekly, in the upper outer quadrant of the gluteus maximus (2.1)Begin treatment between 16 weeks, days and 20 weeks, days of gestationContinue administration once weekly until week 37 (through 36 weeks, days) of gestation or delivery, whichever occurs first (2.1) Administer intramuscularly at dose of 250 mg (1 mL) once weekly, in the upper outer quadrant of the gluteus maximus (2.1). Begin treatment between 16 weeks, days and 20 weeks, days of gestation. Continue administration once weekly until week 37 (through 36 weeks, days) of gestation or delivery, whichever occurs first (2.1) 2.1 Dosing. Administer intramuscularly at dose of 250 mg (1 mL) once weekly (every days) in the upper outer quadrant of the gluteus maximus by healthcare providerBegin treatment between 16 weeks, days and 20 weeks, days of gestationContinue administration once weekly until week 37 (through 36 weeks, days) of gestation or delivery, whichever occurs first Administer intramuscularly at dose of 250 mg (1 mL) once weekly (every days) in the upper outer quadrant of the gluteus maximus by healthcare provider. Begin treatment between 16 weeks, days and 20 weeks, days of gestation. Continue administration once weekly until week 37 (through 36 weeks, days) of gestation or delivery, whichever occurs first 2.2 Preparation and Administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Hydroxyprogesterone caproate injection is clear, yellow solution. The solution must be clear at the time of use; replace vial if visible particles or crystals are present. Hydroxyprogesterone caproate injection single-dose vials are only for intramuscular injection with syringe into the upper outer quadrant of the gluteus maximus, rotating the injection site to the alternate side from the previous week, using the following preparation and administration procedure: Clean the vial top with an alcohol swab before use.Draw up mL of drug into 3 mL syringe with an 18 gauge needle.Change the needle to 21 gauge 1/2 inch needle.After preparing the skin, inject in the upper outer quadrant of the gluteus maximus. The solution is viscous and oily. Slow injection (over one minute or longer) is recommended.Applying pressure to the injection site may minimize bruising and swelling.. Clean the vial top with an alcohol swab before use.. Draw up mL of drug into 3 mL syringe with an 18 gauge needle.. Change the needle to 21 gauge 1/2 inch needle.. After preparing the skin, inject in the upper outer quadrant of the gluteus maximus. The solution is viscous and oily. Slow injection (over one minute or longer) is recommended.. Applying pressure to the injection site may minimize bruising and swelling.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Hydroxyprogesterone caproate injection is progestin indicated to reduce the risk of preterm birth in women with singleton pregnancy who have history of singleton spontaneous preterm birth. The effectiveness of hydroxyprogesterone caproate injection is based on improvement in the proportion of women who delivered 37 weeks of gestation. There are no controlled trials demonstrating direct clinical benefit, such as improvement in neonatal mortality and morbidity.Limitation of use: While there are many risk factors for preterm birth, safety and efficacy of hydroxyprogesterone caproate injection has been demonstrated only in women with prior spontaneous singleton preterm birth. It is not intended for use in women with multiple gestations or other risk factors for preterm birth.. Hydroxyprogesterone caproate injection is progestin indicated to reduce the risk of preterm birth in women with singleton pregnancy who have history of singleton spontaneous preterm birth (1). The effectiveness of hydroxyprogesterone caproate injection is based on improvement in the proportion of women who delivered 37 weeks of gestation (14). There are no controlled trials demonstrating direct clinical benefit, such as improvement in neonatal mortality and morbidity.Limitation of use: Hydroxyprogesterone caproate injection is not intended for use in women with multiple gestations or other risk factors for preterm birth.(1).

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryHydroxyprogesterone caproate injection is indicated to reduce the risk of preterm birth in women with singleton pregnancy who have history of singleton spontaneous preterm birth. Fetal, neonatal, and maternal risks are discussed throughout labeling. Data from the placebo-controlled clinical trial and the infant follow-up safety study [see Clinical Studies (14.1, 14.2)] did not show difference in adverse developmental outcomes between children of hydroxyprogesterone caproate injection-treated women and children of control subjects. However, these data are insufficient to determine drug-associated risk of adverse developmental outcomes as none of the hydroxyprogesterone caproate injection-treated women received the drug during the first trimester of pregnancy. In animal reproduction studies, intramuscular administration of hydroxyprogesterone caproate to pregnant rats during gestation at doses times the human dose equivalent based on 60-kg human was not associated with adverse developmental outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. DataAnimal DataReproduction studies of hydroxyprogesterone caproate administered to various animal species have been reported in the literature. In nonhuman primates, embryolethality was reported in rhesus monkeys administered hydroxyprogesterone caproate up to 2.4 and 24 times the human dose equivalent, but not in cynomolgus monkeys administered hydroxyprogesterone caproate at doses up to 2.4 times the human dose equivalent, every days between days 20 and 146 of gestation. There were no teratogenic effects in either strain of monkey.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 caproate.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryHydroxyprogesterone caproate injection is indicated to reduce the risk of preterm birth in women with singleton pregnancy who have history of singleton spontaneous preterm birth. Fetal, neonatal, and maternal risks are discussed throughout labeling. Data from the placebo-controlled clinical trial and the infant follow-up safety study [see Clinical Studies (14.1, 14.2)] did not show difference in adverse developmental outcomes between children of hydroxyprogesterone caproate injection-treated women and children of control subjects. However, these data are insufficient to determine drug-associated risk of adverse developmental outcomes as none of the hydroxyprogesterone caproate injection-treated women received the drug during the first trimester of pregnancy. In animal reproduction studies, intramuscular administration of hydroxyprogesterone caproate to pregnant rats during gestation at doses times the human dose equivalent based on 60-kg human was not associated with adverse developmental outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. DataAnimal DataReproduction studies of hydroxyprogesterone caproate administered to various animal species have been reported in the literature. In nonhuman primates, embryolethality was reported in rhesus monkeys administered hydroxyprogesterone caproate up to 2.4 and 24 times the human dose equivalent, but not in cynomolgus monkeys administered hydroxyprogesterone caproate at doses up to 2.4 times the human dose equivalent, every days between days 20 and 146 of gestation. There were no teratogenic effects in either strain of monkey.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 caproate. 8.2 Lactation. Risk SummaryLow levels of progestins are present in human milk with the use of progestin-containing products, including hydroxyprogesterone caproate. Published studies have reported no adverse effects of progestins on the breastfed child or on milk production.. 8.4 Pediatric Use. Hydroxyprogesterone caproate injection is not indicated for use in women under 16 years of age. Safety and effectiveness in patients less than 16 years of age have not been established. small number of women under age 18 years were studied; safety and efficacy are expected to be the same in women aged 16 years and above as for users 18 years and older [see Clinical Studies 14 )]. 8.6 Hepatic Impairment. No studies have been conducted to examine the pharmacokinetics of hydroxyprogesterone caproate injection in patients with hepatic impairment. Hydroxyprogesterone caproate injection is extensively metabolized and hepatic impairment may reduce the elimination of hydroxyprogesterone caproate injection.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Do not use hydroxyprogesterone caproate injection in women with any of the following conditions:Current or history of thrombosis or thromboembolic disordersKnown or suspected breast cancer, other hormone-sensitive cancer, or history of these conditionsUndiagnosed abnormal vaginal bleeding unrelated to pregnancyCholestatic jaundice of pregnancyLiver tumors, benign or malignant, or active liver diseaseUncontrolled hypertension. Current or history of thrombosis or thromboembolic disorders. Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions. Undiagnosed abnormal vaginal bleeding unrelated to pregnancy. Cholestatic jaundice of pregnancy. Liver tumors, benign or malignant, or active liver disease. Uncontrolled hypertension. Thromboembolic disorders: Discontinue if thrombosis or thromboembolism occurs (5.1)Allergic reactions: Consider discontinuing if allergic reactions occur (5.2) Decreased glucose tolerance: Monitor prediabetic and diabetic women receiving hydroxyprogesterone caproate injection (5.3)Fluid retention: Monitor women with conditions that may be affected by fluid retention, such as preeclampsia, epilepsy, cardiac or renal dysfunction (5.4) Depression: Monitor women with history of clinical depression; discontinue hydroxyprogesterone caproate injection if depression recurs (5.5) Thromboembolic disorders: Discontinue if thrombosis or thromboembolism occurs (5.1). Allergic reactions: Consider discontinuing if allergic reactions occur (5.2) Decreased glucose tolerance: Monitor prediabetic and diabetic women receiving hydroxyprogesterone caproate injection (5.3). Fluid retention: Monitor women with conditions that may be affected by fluid retention, such as preeclampsia, epilepsy, cardiac or renal dysfunction (5.4) Depression: Monitor women with history of clinical depression; discontinue hydroxyprogesterone caproate injection if depression recurs (5.5) 5.1 Thromboembolic Disorders. Discontinue hydroxyprogesterone caproate injection if an arterial or deep venous thrombotic or thromboembolic event occurs.. 5.2 Allergic Reactions. Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use of hydroxyprogesterone caproate injection or with other products containing castor oil. Consider discontinuing the drug if such reactions occur.. 5.3 Decrease in Glucose Tolerance. decrease in glucose tolerance has been observed in some patients on progestin treatment. The mechanism of this decrease is not known. Carefully monitor prediabetic and diabetic women while they are receiving hydroxyprogesterone caproate injection.. 5.4 Fluid Retention. Because progestational drugs may cause some degree of fluid retention, carefully monitor women with conditions that might be influenced by this effect (e.g., preeclampsia, epilepsy, migraine, asthma, cardiac or renal dysfunction).. 5.5 Depression. Monitor women who have history of clinical depression and discontinue hydroxyprogesterone caproate injection if clinical depression recurs.. 5.6 Jaundice. Carefully monitor women who develop jaundice while receiving hydroxyprogesterone caproate injection and consider whether the benefit of use warrants continuation.. 5.7 Hypertension. Carefully monitor women who develop hypertension while receiving hydroxyprogesterone caproate injection and consider whether the benefit of use warrants continuation.