DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS In vitro drug-drug interaction studies were conducted with hydroxyprogesterone caproate. 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. [See Clinical Pharmacology (12.3).] No in vivo drug-drug interaction studies were conducted with Hydroxyprogesterone Caproate Injection.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Hydroxyprogesterone Caproate Injection single-dose vials (for intramuscular injection)Hydroxyprogesterone Caproate Injection (NDC 67457-967-01) is supplied as mL of sterile preservative-free clear yellow solution in single-dose glass vial.Each mL vial contains hydroxyprogesterone caproate USP, 250 mg/mL (25% w/v), in castor oil USP (30.6% v/v) and benzyl benzoate USP (46% v/v).Single unit carton: Contains one mL single-dose vial of Hydroxyprogesterone Caproate Injection containing 250 mg of hydroxyprogesterone caproate.Store at 20 25C (68 77F). Do not refrigerate or freeze.Caution: Protect vial from light. Store vial in its box. Store upright.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS For the most serious adverse reactions to the use of progestins, see Warnings and Precautions (5). oIn 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oIn 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). 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 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-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 Caproaten/NControln/NMiscarriage (< 20 weeks)N Total number of subjects enrolled prior to 20 weeks days 5/2090/107Stillbirth (>= 20 weeks)N Total number of subjects at risk >= 20 weeks 6/3052/153Table Selected Maternal ComplicationsPregnancy ComplicationHydroxyprogesterone CaproateN 310%ControlN 153%Admission for preterm laborOther than delivery admission. 16.013.8Preeclampsia or gestational hypertension8.84.6Gestational diabetes5.64.6Oligohydramnios3.61.3Common 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 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 group than in the control group.Table Adverse Reactions Occurring in >= 2% of Hydroxyprogesterone Caproate-Treated Subjects and at Higher Rate than Control SubjectsPreferred TermHydroxyprogesterone CaproateN 310%ControlN 153%Injection site pain34.832.7Injection site swelling17.17.8Urticaria12.311.1Pruritus7.75.9Injection 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 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-treated subjects.. 6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use of hydroxyprogesterone caproate. 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.oBody as whole: Local injection site reactions (including erythema, urticaria, rash, irritation, hypersensitivity, warmth); fatigue; fever; hot flashes/flushesoDigestive disorders: VomitingoInfections: Urinary tract infectionoNervous system disorders: Headache, dizzinessoPregnancy, puerperium and perinatal conditions: Cervical incompetence, premature rupture of membranesoReproductive system and breast disorders: Cervical dilation, shortened cervixoRespiratory disorders: Dyspnea, chest discomfortoSkin: Rash. oBody as whole: Local injection site reactions (including erythema, urticaria, rash, irritation, hypersensitivity, warmth); fatigue; fever; hot flashes/flushes. oDigestive disorders: Vomiting. oInfections: Urinary tract infection. oNervous system disorders: Headache, dizziness. oPregnancy, puerperium and perinatal conditions: Cervical incompetence, premature rupture of membranes. oReproductive system and breast disorders: Cervical dilation, shortened cervix. oRespiratory disorders: Dyspnea, chest discomfort. oSkin: Rash.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Hydroxyprogesterone caproate has not been adequately evaluated for carcinogenicity.No reproductive or developmental toxicity or impaired fertility was observed in multigenerational study in rats. Hydroxyprogesterone caproate administered intramuscularly, at gestational exposures up to times the recommended human dose, had no adverse effects on the parental (F0) dams, their developing offspring (F1), or the latter offsprings ability to produce viable, normal second (F2) generation.

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.. 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) Pharmacokinetic Parameters for Hydroxyprogesterone CaproateBlood was drawn daily for days (1) starting 24 hours after the first dose between Weeks 16-20 (Group 1), (2) after dose between Weeks 24-28 (Group 2), or (3) after dose between Weeks 32-36 (Group 3)Group(N)Cmax (ng/mL)Tmax (days)Reported as median (range)AUC(0-t) = days(ng.hr/mL)Group (N 6)5.0 (1.5)5.5 (2.0-7.0)571.4 (195.2)Group (N 8)12.5 (3.9)1.0 (0.9-1.9)1269.6 (285.0)Group (N 11)12.3 (4.9)2.0 (1.0-3.0)1268.0 (511.6)For all three groups, peak concentration (Cmax) and area under the curve (AUC(1-7 days)) of the mono-hydroxylated metabolites were approximately 3-8-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.. 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 10-12 weeks gestation, approximately 50% of dose was recovered in the feces and approximately 30% recovered in the urine.. Drug Interactions. Cytochrome 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 14.1Clinical 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 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).A total of 463 pregnant women were randomized to receive either hydroxyprogesterone caproate (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-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)Delivery OutcomeHydroxyprogesterone CaproateFour hydroxyprogesterone caproate-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).(N 310)%Control(N 153)%Treatment Difference and 95% Confidence IntervalAdjusted for interim analysis.< 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%]Compared to controls, treatment with hydroxyprogesterone caproate 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. 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-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 arm, there was no overall survival difference demonstrated in this clinical trial.Table Fetal Losses and Neonatal DeathsComplicationHydroxyprogesterone CaproateN 306Four of the 310 hydroxyprogesterone caproate-treated subjects were lost to follow-up and stillbirth or neonatal status could not be determinedn (%)Percentages are based on the number of enrolled subjects and not adjusted for time on drugControlN 153n (%)Miscarriages 20 weeks gestationPercentage adjusted for the number of at risk subjects (n 209 for hydroxyprogesterone caproate, = 107 for control) enrolled at 20 weeks gestation. (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 composite neonatal morbidity/mortality index evaluated adverse outcomes in live births. 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 arm (11.9% vs. 17.2%), the number of adverse outcomes was limited and the difference between arms was not statistically significant.. Figure Proportion of Women Remaining Pregnant as Function of Gestational Age. 14.2Infant 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-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:oCurrent or history of thrombosis or thromboembolic disordersoKnown or suspected breast cancer, other hormone-sensitive cancer, or history of these conditionsoUndiagnosed abnormal vaginal bleeding unrelated to pregnancyoCholestatic jaundice of pregnancyoLiver tumors, benign or malignant, or active liver diseaseoUncontrolled hypertension. oCurrent or history of thrombosis or thromboembolic disorders. oKnown or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions. oUndiagnosed abnormal vaginal bleeding unrelated to pregnancy. oCholestatic jaundice of pregnancy. oLiver tumors, benign or malignant, or active liver disease. oUncontrolled hypertension. oCurrent or history of thrombosis or thromboembolic disorders (4)oKnown or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions (4)oUndiagnosed abnormal vaginal bleeding unrelated to pregnancy (4)oCholestatic jaundice of pregnancy (4)oLiver tumors, benign or malignant, or active liver disease (4)oUncontrolled hypertension (4). oCurrent or history of thrombosis or thromboembolic disorders (4). oKnown or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions (4). oUndiagnosed abnormal vaginal bleeding unrelated to pregnancy (4). oCholestatic jaundice of pregnancy (4). oLiver tumors, benign or malignant, or active liver disease (4). oUncontrolled hypertension (4).

DESCRIPTION SECTION.

11 DESCRIPTION The active pharmaceutical ingredient in Hydroxyprogesterone Caproate Injection is hydroxyprogesterone caproate, progestin.The chemical name for hydroxyprogesterone caproate is pregn-4-ene-3,20-dione, 17[(1-oxohexyl)oxy]. It has an empirical formula of C27H40O4 and molecular weight of 428.60. Hydroxyprogesterone caproate exists as white to practically white crystals or powder with melting point of 120-124C.The structural formula is:Hydroxyprogesterone Caproate Injection is clear, yellow, sterile, non-pyrogenic solution for intramuscular injection. Each mL single-dose vial for intramuscular use contains hydroxyprogesterone caproate USP, 250 mg/mL (25% w/v), in preservative-free solution containing castor oil USP (30.6% v/v) and benzyl benzoate USP (46% v/v).. Hydroxyprogesterone caproate Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oHydroxyprogesterone Caproate Injection, USP (single-dose vials): Administer intramuscularly at dose of 250 mg (1 mL) once weekly in the upper outer quadrant of the gluteus maximus (2.1)oBegin treatment between 16 weeks, days and 20 weeks, days of gestation (2.1)oContinue administration once weekly until week 37 (through 36 weeks, days) of gestation or delivery, whichever occurs first (2.1). oHydroxyprogesterone Caproate Injection, USP (single-dose vials): Administer intramuscularly at dose of 250 mg (1 mL) once weekly in the upper outer quadrant of the gluteus maximus (2.1). oBegin treatment between 16 weeks, days and 20 weeks, days of gestation (2.1). oContinue administration once weekly until week 37 (through 36 weeks, days) of gestation or delivery, whichever occurs first (2.1). 2.1Dosing oHydroxyprogesterone Caproate Injection (single-dose vials): Administer intramuscularly at dose of 250 mg (1 mL) once weekly (every days) in the upper outer quadrant of the gluteus maximus by healthcare provideroBegin treatment between 16 weeks, days and 20 weeks, days of gestationoContinue administration once weekly until week 37 (through 36 weeks, days) of gestation or delivery, whichever occurs first. oHydroxyprogesterone Caproate Injection (single-dose vials): 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. oBegin treatment between 16 weeks, days and 20 weeks, days of gestation. oContinue 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.Specific instructions for administration by dosage form:Hydroxyprogesterone Caproate Injection single-dose vials (intramuscular use only)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:1.Clean the vial top with an alcohol swab before use.2.Draw up mL of drug into 3 mL syringe with an 18 gauge needle.3.Change the needle to 21 gauge 1/2 inch needle.4.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.5.Applying pressure to the injection site may minimize bruising and swelling.. 1.Clean the vial top with an alcohol swab before use.. 2.Draw up mL of drug into 3 mL syringe with an 18 gauge needle.. 3.Change the needle to 21 gauge 1/2 inch needle.. 4.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.. 5.Applying pressure to the injection site may minimize bruising and swelling.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Intramuscular injection: 250 mg/mL clear yellow solution in single-dose vials.. mL single-dose vial for intramuscular use contains 250 mg of hydroxyprogesterone caproate (3).

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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).Counsel patients that Hydroxyprogesterone Caproate injections may cause pain, soreness, swelling, itching or bruising. Inform the patient to contact her physician if she notices increased discomfort over time, oozing of blood or fluid, or inflammatory reactions at the injection site [see Adverse Reactions (6.1)].

LACTATION SECTION.

8.2 Lactation Risk Summary. Low 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.

MECHANISM OF ACTION SECTION.

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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY . 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Hydroxyprogesterone caproate has not been adequately evaluated for carcinogenicity.No reproductive or developmental toxicity or impaired fertility was observed in multigenerational study in rats. Hydroxyprogesterone caproate administered intramuscularly, at gestational exposures up to times the recommended human dose, had no adverse effects on the parental (F0) dams, their developing offspring (F1), or the latter offsprings ability to produce viable, normal second (F2) generation.

OVERDOSAGE SECTION.

10 OVERDOSAGE There have been no reports of adverse events associated with overdosage of hydroxyprogesterone caproate in clinical trials. In the case of overdosage, the patient should be treated symptomatically.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 67457-967-01HydroxyprogesteroneCaproateInjection, USP250 mg/mL1 mL vialFor IntramuscularUse OnlyRx only1 mL Single-Dose VialSterile1 mL contains:hydroxyprogesteronecaproate 250 mg, benzylbenzoate 46%, and castoroil 31%.See package insert for fullprescribing and patientinformation.Store at 20 to 25C(68 to 77F).Do not refrigerate or freeze.Caution: Protect from light.Store vial in its box.Store upright.Manufactured for: Mylan Institutional LLC Rockford, IL 61103 U.S.A.Made in Spain GBP:967:1C:R2Mylan.com. Hydroxyprogesterone Caproate Injection, USP 250 mg/mL mLvial Carton Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Hydroxyprogesterone caproate 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)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics No specific pharmacodynamic studies were conducted with hydroxyprogesterone caproate.

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) Pharmacokinetic Parameters for Hydroxyprogesterone CaproateBlood was drawn daily for days (1) starting 24 hours after the first dose between Weeks 16-20 (Group 1), (2) after dose between Weeks 24-28 (Group 2), or (3) after dose between Weeks 32-36 (Group 3)Group(N)Cmax (ng/mL)Tmax (days)Reported as median (range)AUC(0-t) = days(ng.hr/mL)Group (N 6)5.0 (1.5)5.5 (2.0-7.0)571.4 (195.2)Group (N 8)12.5 (3.9)1.0 (0.9-1.9)1269.6 (285.0)Group (N 11)12.3 (4.9)2.0 (1.0-3.0)1268.0 (511.6)For all three groups, peak concentration (Cmax) and area under the curve (AUC(1-7 days)) of the mono-hydroxylated metabolites were approximately 3-8-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.. 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 10-12 weeks gestation, approximately 50% of dose was recovered in the feces and approximately 30% recovered in the urine.. Drug Interactions. Cytochrome 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.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary. Hydroxyprogesterone caproate 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-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-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.. Data. Animal Data Reproduction 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.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Dosing (2.1) 02/2018Dosage and Administration, Preparation Administration (2.2) 02/2018.

RISKS.

Risk Summary. Hydroxyprogesterone caproate 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-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-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.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION Hydroxyprogesterone Caproate Injection, USP(hye drox ee proe jes ter one kap roe ate)vial for intramuscular useRead this Patient Information Leaflet before you receive Hydroxyprogesterone Caproate Injection. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.What is Hydroxyprogesterone Caproate InjectionHydroxyprogesterone Caproate Injection is prescription hormone medicine (progestin) used in women who are pregnant and who have delivered baby too early (preterm) in the past. Hydroxyprogesterone Caproate is used in these women to help lower the risk of having preterm baby again. It is not known if Hydroxyprogesterone Caproate Injection reduces the number of babies who are born with serious medical conditions or die shortly after birth. Hydroxyprogesterone Caproate Injection is for women who: oAre pregnant with one baby. oHave had preterm delivery of one baby in the past.Hydroxyprogesterone Caproate Injection is not intended for use to stop active preterm labor.It is not known if Hydroxyprogesterone Caproate Injection is safe and effective in women who have other risk factors for preterm birth. Hydroxyprogesterone Caproate Injection is not for use in women under 16 years of age.Who should not receive Hydroxyprogesterone Caproate InjectionHydroxyprogesterone Caproate Injection should not be used if you have: oblood clots or other blood clotting problems now or in the past obreast cancer or other hormone-sensitive cancers now or in the past ounusual vaginal bleeding not related to your current pregnancy oyellowing of your skin due to liver problems during your pregnancy oliver problems, including liver tumors ohigh blood pressure that is not controlledWhat should tell my healthcare provider before receiving Hydroxyprogesterone Caproate InjectionBefore you receive Hydroxyprogesterone Caproate Injection, tell your healthcare provider about all of your medical conditions, including if you have: oa history of allergic reaction to hydroxyprogesterone caproate, castor oil, or any of the other ingredients in Hydroxyprogesterone Caproate Injection. See the end of this Patient Information leaflet for complete list of ingredients in Hydroxyprogesterone Caproate Injection.odiabetes or pre-diabetes. oepilepsy (seizures). omigraine headaches. oasthma. oheart problems. okidney problems. odepression. ohigh blood pressure. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Hydroxyprogesterone Caproate Injection may affect the way other medicines work, and other medicines may affect how Hydroxyprogesterone Caproate Injection works. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should receive Hydroxyprogesterone Caproate Injection oDo not give yourself Hydroxyprogesterone Caproate injections. healthcare provider will give you the Hydroxyprogesterone Caproate injection time each week (every days)oin the upper outer area of the buttocks as an injection into the muscle (intramuscular). oYou will start receiving Hydroxyprogesterone Caproate injections anytime from 16 weeks and days of your pregnancy, up to 20 weeks and days of your pregnancy.oYou will continue to receive Hydroxyprogesterone Caproate injections time each week until week 37 (through 36 weeks and days) of your pregnancy or when your baby is delivered, whichever comes first.What are the possible side effects of Hydroxyprogesterone Caproate Injection Hydroxyprogesterone Caproate Injection may cause serious side effects, including: oBlood clots. Symptoms of blood clot may include:oleg swellingoredness in your legoa spot on your leg that is warm to the toucholeg pain that gets worse when you bend your footCall your healthcare provider right away if you get any of the symptoms above during treatment with Hydroxyprogesterone Caproate Injection.oAllergic reactions. Symptoms of an allergic reaction may include:ohivesoitchingoswelling of the faceCall your healthcare provider right away if you get any of the symptoms above during treatment with Hydroxyprogesterone Caproate Injection. oDecrease in glucose (blood sugar) tolerance. Your healthcare provider will need to monitor your blood sugar while taking Hydroxyprogesterone Caproate Injection if you have diabetes or pre-diabetes.oYour body may hold too much fluid (fluid retention)oDepression oYellowing of your skin and the whites of your eyes (jaundice)oHigh blood pressureThe most common side effects of Hydroxyprogesterone Caproate Injection include:opain, swelling, itching or hard bump at the injection siteohivesoitchingonauseaodiarrheaCall your healthcare provider if you have the following at your injection site:oincreased pain over timeooozing of blood or fluidoswellingOther side effects that may happen more often in women who receive Hydroxyprogesterone Caproate Injection include:oMiscarriage (pregnancy loss before 20 weeks of pregnancy) oStillbirth (fetal death occurring during or after the 20th week of pregnancy) oHospital admission for preterm labor oPreeclampsia (high blood pressure and too much protein in your urine) oGestational hypertension (high blood pressure caused by pregnancy) oGestational diabetes oOligohydramnios (low amniotic fluid levels)Tell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of Hydroxyprogesterone Caproate Injection. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store Hydroxyprogesterone Caproate InjectionoHydroxyprogesterone Caproate Injection vial for intramuscular use: oStore the vial at room temperature between 68o 77oF (20o 25oC).oDo not refrigerate or freeze.oProtect the vial from light.oStore the vial in its box in an upright position.Keep Hydroxyprogesterone Caproate Injection and all medicines out of the reach of children.General information about the safe and effective use of Hydroxyprogesterone Caproate Injection.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Hydroxyprogesterone Caproate Injection for condition for which it was not prescribed. Do not give Hydroxyprogesterone Caproate Injection to other people, even if they have the same symptoms you have. lt may harm them.This leaflet summarizes the most important information about Hydroxyprogesterone Caproate Injection. lf you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Hydroxyprogesterone Caproate Injection that is written for health professionals.What are the ingredients in Hydroxyprogesterone Caproate InjectionActive ingredient: hydroxyprogesterone caproateInactive ingredients: castor oil and benzyl benzoate.Manufactured for: Mylan Institutional LLC, Rockford, IL 61103 U.S.A.Manufactured by: Gadea Biopharma S.L.U. division of Albany Molecular Research Inc. (AMRI)Parque Tecnologico de Leon-C/Nicostrato. Vela, s/n 24009 Leon, SpainFor more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).This Patient Information has been approved by the U.S. Food and Drug Administration.Manufactured for: Mylan Institutional LLC Rockford, IL 61103 U.S.A.Manufactured by: Gadea Biopharma S.L.U. division of Albany Molecular Research Inc. (AMRI)Parque Tecnologico de Leon-C/Nicostrato. Vela, s/n24009 Leon, SpainRevised: 4/2019GBP:HPCIJS:R2. oAre pregnant with one baby. oHave had preterm delivery of one baby in the past.. oblood clots or other blood clotting problems now or in the past obreast cancer or other hormone-sensitive cancers now or in the past ounusual vaginal bleeding not related to your current pregnancy oyellowing of your skin due to liver problems during your pregnancy oliver problems, including liver tumors ohigh blood pressure that is not controlled. oa history of allergic reaction to hydroxyprogesterone caproate, castor oil, or any of the other ingredients in Hydroxyprogesterone Caproate Injection. See the end of this Patient Information leaflet for complete list of ingredients in Hydroxyprogesterone Caproate Injection.. odiabetes or pre-diabetes. oepilepsy (seizures). omigraine headaches. oasthma. oheart problems. okidney problems. odepression. ohigh blood pressure. oDo not give yourself Hydroxyprogesterone Caproate injections. healthcare provider will give you the Hydroxyprogesterone Caproate injection time each week (every days)oin the upper outer area of the buttocks as an injection into the muscle (intramuscular). oin the upper outer area of the buttocks as an injection into the muscle (intramuscular). oYou will start receiving Hydroxyprogesterone Caproate injections anytime from 16 weeks and days of your pregnancy, up to 20 weeks and days of your pregnancy.. oYou will continue to receive Hydroxyprogesterone Caproate injections time each week until week 37 (through 36 weeks and days) of your pregnancy or when your baby is delivered, whichever comes first.. Hydroxyprogesterone Caproate Injection may cause serious side effects, including: oBlood clots. Symptoms of blood clot may include:. oleg swelling. oredness in your leg. oa spot on your leg that is warm to the touch. oleg pain that gets worse when you bend your foot. oAllergic reactions. Symptoms of an allergic reaction may include:. ohives. oitching. oswelling of the face. oDecrease in glucose (blood sugar) tolerance. Your healthcare provider will need to monitor your blood sugar while taking Hydroxyprogesterone Caproate Injection if you have diabetes or pre-diabetes.. oYour body may hold too much fluid (fluid retention). oDepression oYellowing of your skin and the whites of your eyes (jaundice). oHigh blood pressure. opain, swelling, itching or hard bump at the injection site. ohives. oitching. onausea. odiarrhea. oincreased pain over time. ooozing of blood or fluid. oswelling. oMiscarriage (pregnancy loss before 20 weeks of pregnancy) oStillbirth (fetal death occurring during or after the 20th week of pregnancy) oHospital admission for preterm labor oPreeclampsia (high blood pressure and too much protein in your urine) oGestational hypertension (high blood pressure caused by pregnancy) oGestational diabetes oOligohydramnios (low amniotic fluid levels). oHydroxyprogesterone Caproate Injection vial for intramuscular use: oStore the vial at room temperature between 68o 77oF (20o 25oC).oDo not refrigerate or freeze.oProtect the vial from light.oStore the vial in its box in an upright position.. oStore the vial at room temperature between 68o 77oF (20o 25oC).. oDo not refrigerate or freeze.. oProtect the vial from light.. oStore the vial in its box in an upright position.

SPL UNCLASSIFIED SECTION.

2.1Dosing oHydroxyprogesterone Caproate Injection (single-dose vials): Administer intramuscularly at dose of 250 mg (1 mL) once weekly (every days) in the upper outer quadrant of the gluteus maximus by healthcare provideroBegin treatment between 16 weeks, days and 20 weeks, days of gestationoContinue administration once weekly until week 37 (through 36 weeks, days) of gestation or delivery, whichever occurs first. oHydroxyprogesterone Caproate Injection (single-dose vials): 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. oBegin treatment between 16 weeks, days and 20 weeks, days of gestation. oContinue administration once weekly until week 37 (through 36 weeks, days) of gestation or delivery, whichever occurs first.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS . 8.1 Pregnancy Risk Summary. Hydroxyprogesterone caproate 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-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-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.. Data. Animal Data Reproduction 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 Summary. Low 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 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)].. 8.6Hepatic Impairment No studies have been conducted to examine the pharmacokinetics of hydroxyprogesterone caproate in patients with hepatic impairment. Hydroxyprogesterone caproate is extensively metabolized and hepatic impairment may reduce the elimination of hydroxyprogesterone caproate.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oThromboembolic disorders: Discontinue if thrombosis or thromboembolism occurs (5.1)oAllergic reactions: Consider discontinuing if allergic reactions occur (5.2)oDecreased glucose tolerance: Monitor prediabetic and diabetic women receiving hydroxyprogesterone caproate (5.3)oFluid retention: Monitor women with conditions that may be affected by fluid retention, such as preeclampsia, epilepsy, cardiac or renal dysfunction (5.4)oDepression: Monitor women with history of clinical depression; discontinue hydroxyprogesterone caproate if depression recurs (5.5). oThromboembolic disorders: Discontinue if thrombosis or thromboembolism occurs (5.1). oAllergic reactions: Consider discontinuing if allergic reactions occur (5.2). oDecreased glucose tolerance: Monitor prediabetic and diabetic women receiving hydroxyprogesterone caproate (5.3). oFluid retention: Monitor women with conditions that may be affected by fluid retention, such as preeclampsia, epilepsy, cardiac or renal dysfunction (5.4). oDepression: Monitor women with history of clinical depression; discontinue hydroxyprogesterone caproate if depression recurs (5.5). 5.1 Thromboembolic Disorders Discontinue Hydroxyprogesterone Caproate Injection if an arterial or deep venous thrombotic or thromboembolic event occurs.. 5.2Allergic 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.. 5.3Decrease in Glucose Tolerance A 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.. 5.4Fluid 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).. 5.5Depression Monitor women who have history of clinical depression and discontinue Hydroxyprogesterone Caproate Injection if clinical depression recurs.. 5.6Jaundice Carefully monitor women who develop jaundice while receiving Hydroxyprogesterone Caproate Injection and consider whether the benefit of use warrants continuation.. 5.7Hypertension Carefully monitor women who develop hypertension while receiving Hydroxyprogesterone Caproate Injection and consider whether the benefit of use warrants continuation.