Ostrolut

Estradiol Benzoate:

• Ostrolut information
• Ostrolut indications
• Ostrolut warnings
• Ostrolut intake guidelines
• Ostrolut dosage
• Ostrolut overdose
• Ostrolut missed dose
• Ostrolut side effects
• Ostrolut drug reactions
• Ostrolut (Estradiol Benzoate) reviews

Ostrolut information

Ostrolut (Estradiol Benzoate) is a female sex hormone that regulates many functions in the female organism. This medicine is currently available under the form of tablets in two concentrations - 1 mg and 2 mg, respectively.

Ostrolut indications

Ostrolut (Estradiol Benzoate) is used for the treatment of menopausal symptoms such as vaginal dryness, irritation or burning, or hot flushes - other symptoms that are not listed here may be treated with this medicine as well. Also, this pharmaceutical preparation can be used as a prophylactic agent for the prevention of a medical condition known as osteoporosis in both female and male patients. In some cases, this medicine may also be employed in conjunction with other drugs as part of the treatment for certain types of cancer, both in the case of women and men.

There may be other uses for Ostrolut (Estradiol Benzoate), which are not covered in this leaflet. If you are interested to find out more about the possible uses of this product, it is recommended that you consult with a pharmacist or a specialized physician.

Ostrolut warnings

Ostrolut (Estradiol Benzoate) should not be administered to patients that are suffering from any type of disorder involving blood clots, or from circulatory / cardiac disorders. Patients who present an undiagnosed, abnormal vaginal bleeding may not start taking this medicine until they undergo medical examination and receive their physician's approval. Also, patients that have uterine cancer, breast cancer or any type of hormone-dependant cancer may not start a treatment with Ostrolut (Estradiol Benzoate).

Before you start a therapy course with this drug, it is strongly advised to inform your personal physician of any health problems you may be suffering from. In particular, affections such as hypertension, heart disease, angina, high triglyceride / cholesterol levels, renal or hepatic disease, asthma, migraines, epilepsy (or any other disorder involving seizures), diabetes or gallbladder disease should be mentioned, as well as past surgical procedures such as a hysterectomy. Patients suffering from these conditions may require special dosage adjustments or monitoring during the treatment.

Ostrolut (Estradiol Benzoate) may not be administered during pregnancy. Also, for the duration of the therapy you will need to employ an effective, non-hormonal contraceptive method.

Pharmaceutical products based on Estradiol (including Ostrolut (Estradiol Benzoate)) increase the patients' risk of developing an affection known as endometrial hyperplasia. This can be countered by administration of progestin medication. It is recommended that you consult with your doctor for more information.

Ostrolut intake guidelines

You need to take Ostrolut (Estradiol Benzoate) exactly as directed by your health care specialist. You may take the tablets with a glass of water or with food to reduce stomach upset; however you may not chew, crush or break the tablets.

While following a treatment course with Ostrolut (Estradiol Benzoate) you will need to undergo regular medical examination, typically on a monthly basis. Also, you will need to regularly self-examine your breasts for the presence of lumps.

Ostrolut dosage

Your health care specialist will determine the Ostrolut (Estradiol Benzoate) dosage appropriate for your case by taking into consideration a number of factors, most of which are characteristic to you; as such, your medication dosage is very likely to be different from that of other patients'. Because of that, you should never use the Ostrolut (Estradiol Benzoate) dosage that has been prescribed to another patient - you may not obtain the desired results unless you employ the medication dosage best suited for your situation.

At the same time, your physician will inform you regarding the duration of the Ostrolut (Estradiol Benzoate) therapy and the number of daily intakes. Make sure that you understand all of his or her indications. If you have trouble understanding or remembering any of the dosage directions, you should ask your physician to assist you by providing additional information.

Ostrolut overdose

If an overdose with Ostrolut (Estradiol Benzoate) is suspected, immediately contact the nearest hospital as the patient may need emergency medical assistance. The most common signs of an overdose are vaginal bleeding, nausea and vomiting.

Ostrolut missed dose

In the event that you miss taking one of your Ostrolut (Estradiol Benzoate) doses, take it when you remember before returning to your normal dosing schedule. However, you should skip taking the missed dose if it is almost time for another dose of the medicine. Consult with your physician if you have missed two or more intakes.

Ostrolut side effects

Side effects of a treatment with Ostrolut (Estradiol Benzoate) include nausea and vomiting, loss of appetite, swelling of the breasts, sex drive changes, impotence (in the case of men), abnormal vaginal bleeding, vaginal dryness, discomfort or pain, break-through bleeding, menstrual period changes, jaundice, sudden weakness or numbness, breast lumps. These are not all the signs and symptoms that may appear. It is best that you check with your doctor at any point during the course of your therapy if anything unusual occurs.

Although uncommon, allergic reactions to Ostrolut (Estradiol Benzoate) are possible. It is strongly recommended that you cease taking the medicine and contact your personal health care provider if you begin experiencing any of the characteristic symptoms - breathing difficulties, swelling of the throat, lips, tongue or face, rashes and hives.

Ostrolut drug reactions

Ostrolut (Estradiol Benzoate) may interact with Phenobarbital, Phenytoin, Ritonavir, Cimetidine, Carbamazepine, Rifampin, blood thinning agents such as Warfarin or with antibiotics (Clarithromycin, Erythromycin, Ketoconazole or Itraconazole). Also, this product may interact with the herbal remedy St. John's wort. These are not all the possible drug reactions; it is best that you tell your prescriber about any other drugs you are currently taking prior to starting your treatment. In most cases, an adjustment to the medication dosage will ensure the safety of the treatment, reducing the risk of accidental interactions.

Hydroxyprogesterone Caproate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Ostrolut (Hydroxyprogesterone Caproate) reviews

1 INDICATIONS AND USAGE

Ostrolut (Hydroxyprogesterone Caproate) is a progestin indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The effectiveness of Ostrolut (Hydroxyprogesterone Caproate) is based on improvement in the proportion of women who delivered < 37 weeks of gestation. There are no controlled trials demonstrating a 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 Ostrolut (Hydroxyprogesterone Caproate) has been demonstrated only in women with a prior spontaneous singleton preterm birth. It is not intended for use in women with multiple gestations or other risk factors for preterm birth.

Ostrolut (Hydroxyprogesterone Caproate) is a progestin indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.

Limitation of use: Ostrolut (Hydroxyprogesterone Caproate) is not intended for use in women with multiple gestations or other risk factors for preterm birth. (1)

2 DOSAGE AND ADMINISTRATION

• Administer intramuscularly at a dose of 250 mg once weekly
• Begin treatment between 16 weeks, 0 days and 20 weeks, 6 days of gestation
• Continue administration once weekly until week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever occurs first (2.1)

2.1 Dosing

• Administer intramuscularly at a dose of 250 mg (1 mL) once weekly (every 7 days) by a healthcare provider
• Begin treatment between 16 weeks, 0 days and 20 weeks, 6 days of gestation
• Continue administration once weekly until week 37 (through 36 weeks, 6 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. Ostrolut (Hydroxyprogesterone Caproate) is a clear, yellow solution. Do not store for long periods of time at low temperatures as this may cause the solution to appear cloudy due to crystallization. The solution must be clear at the time of use, replace vial if visible particles are present. Do not refrigerate.

Instructions for administration:

• Clean the vial top with an alcohol swab before use.
• Draw up 1 mL of drug into a 3 mL syringe with an 18 gauge needle.
• Change the needle to a 21 gauge 1½ 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.

If the 5 mL multidose vial is used, discard any unused product 5 weeks after first use.

3 DOSAGE FORMS AND STRENGTHS

Ostrolut (Hydroxyprogesterone Caproate) (250 mg/mL) is a sterile solution of hydroxyprogesterone caproate in castor oil for injection. Each 1 mL single dose vial contains 250 mg Ostrolut (Hydroxyprogesterone Caproate). Each 5 mL multidose vial contains 1250 mg Ostrolut (Hydroxyprogesterone Caproate).

1 mL single dose vial contains 250 mg of Ostrolut (Hydroxyprogesterone Caproate).

5 mL multidose vial (250 mg/mL) contains 1250 mg Ostrolut (Hydroxyprogesterone Caproate). (3)

4 CONTRAINDICATIONS

Do not use Ostrolut (Hydroxyprogesterone Caproate) in women with any of the following conditions:

• 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)

5 WARNINGS AND PRECAUTIONS

• Thromboembolic disorders: Discontinue if thrombosis or thromboembolism occurs
• Allergic reactions: Consider discontinuing if allergic reactions occur (5.2)
• Decreased glucose tolerance: Monitor prediabetic and diabetic women receiving Ostrolut (Hydroxyprogesterone Caproate) (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 a history of clinical depression; discontinue Ostrolut (Hydroxyprogesterone Caproate) if depression recurs (5.5)

5.1 Thromboembolic Disorders

Discontinue Ostrolut (Hydroxyprogesterone Caproate) 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 Ostrolut or with other products containing castor oil. Consider discontinuing the drug if such reactions occur.

5.3 Decrease 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 Ostrolut (Hydroxyprogesterone Caproate).

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.

5.5 Depression

Monitor women who have a history of clinical depression and discontinue Ostrolut (Hydroxyprogesterone Caproate) if clinical depression recurs.

5.6 Jaundice

Carefully monitor women who develop jaundice while receiving Ostrolut and consider whether the benefit of use warrants continuation.

5.7 Hypertension

Carefully monitor women who develop hypertension while receiving Ostrolut (Hydroxyprogesterone Caproate) and consider whether the benefit of use warrants continuation.

6 ADVERSE REACTIONS

For the most serious adverse reactions to the use of progestins, see Warnings and Precautions.

Most common adverse reactions reported in ≥ 2% of subjects and at a higher rate in the Ostrolut (Hydroxyprogesterone Caproate) group than in the control group are 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 AMAG Pharmaceuticals at 1-877-411-2510 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 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 Ostrolut (Hydroxyprogesterone Caproate) 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.¹

Certain pregnancy-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 Ostrolut (Hydroxyprogesterone Caproate) 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 Ostrolut (Hydroxyprogesterone Caproate) group than in the control group.

In the clinical trial, 2.2% of subjects receiving Ostrolut (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 Makena-treated subjects.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Ostrolut (Hydroxyprogesterone Caproate). 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

7 DRUG INTERACTIONS

In vitro drug-drug interaction studies were conducted with Ostrolut (Hydroxyprogesterone Caproate). No in vivo drug-drug interaction studies were conducted with Ostrolut (Hydroxyprogesterone Caproate).

8 USE IN SPECIFIC POPULATIONS

Pregnancy: Controlled studies show no increase in congenital anomalies, including genital abnormalities in male or female infants, from exposure during pregnancy to Ostrolut. (8.1)

8.1 Pregnancy

Pregnancy Category B: There are no adequate and well-controlled studies of Ostrolut (Hydroxyprogesterone Caproate) use in women during the first trimester of pregnancy. Data from a vehicle (placebo)-controlled clinical trial of 310 pregnant women who received Ostrolut (Hydroxyprogesterone Caproate) at weekly doses of 250 mg by intramuscular injection in their second and third trimesters¹, as well as long-term (2-5 years) follow-up safety data on 194 of their infants ², did not demonstrate any teratogenic risks to infants from in utero exposure to Ostrolut (Hydroxyprogesterone Caproate).

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 Ostrolut (Hydroxyprogesterone Caproate).

Ostrolut (Hydroxyprogesterone Caproate) 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.

8.2 Labor and Delivery

Ostrolut is not intended for use to stop active preterm labor. The effect of Ostrolut (Hydroxyprogesterone Caproate) in active labor is unknown.

8.3 Nursing Mothers

Discontinue Ostrolut (Hydroxyprogesterone Caproate) 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.

8.4 Pediatric Use

Ostrolut is not indicated for use in children. Safety and effectiveness in pediatric patients less than 16 years of age have not been established. A 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.

8.5 Geriatric Use

Ostrolut (Hydroxyprogesterone Caproate) is not intended for use in postmenopausal women. Safety and effectiveness in postmenopausal women have not been established.

8.6 Renal Impairment

No studies have been conducted to examine the pharmacokinetics of Ostrolut in patients with renal impairment.

8.7 Hepatic Impairment

No studies have been conducted to examine the pharmacokinetics of Ostrolut (Hydroxyprogesterone Caproate) in patients with hepatic impairment. Ostrolut (Hydroxyprogesterone Caproate) is extensively metabolized and hepatic impairment may reduce the elimination of Ostrolut (Hydroxyprogesterone Caproate).

10 OVERDOSAGE

There have been no reports of adverse events associated with overdosage of Ostrolut (Hydroxyprogesterone Caproate) in clinical trials. In the case of overdosage, the patient should be treated symptomatically.

11 DESCRIPTION

The active pharmaceutical ingredient in Ostrolut (Hydroxyprogesterone Caproate) is Ostrolut (Hydroxyprogesterone Caproate).

The chemical name for Ostrolut (Hydroxyprogesterone Caproate) is pregn-4-ene-3,20-dione, 17[(1-oxohexyl)oxy]. It has an empirical formula of C₂₇H₄₀O₄ and a molecular weight of 428.60. Ostrolut (Hydroxyprogesterone Caproate) exists as white to practically white crystals or powder with a melting point of 120°-124°C.

The structural formula is:

Ostrolut (Hydroxyprogesterone Caproate) is a clear, yellow, sterile, non-pyrogenic solution for intramuscular injection. Each 1 mL single dose vial contains Ostrolut (Hydroxyprogesterone Caproate) USP, 250 mg/mL (25% w/v), in castor oil USP (30.6% v/v) and benzyl benzoate USP (46% v/v). Each 5 mL multidose vial contains Ostrolut (Hydroxyprogesterone Caproate) USP, 250 mg/mL (25% w/v), in castor oil USP (28.6% v/v) and benzyl benzoate USP (46% v/v) with the preservative benzyl alcohol NF (2% v/v).

Chemical Structure for Ostrolut (Hydroxyprogesterone Caproate)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ostrolut is a synthetic progestin. The mechanism by which Ostrolut (Hydroxyprogesterone Caproate) reduces the risk of recurrent preterm birth is not known.

12.2 Pharmacodynamics

No specific pharmacodynamic studies were conducted with Ostrolut (Hydroxyprogesterone Caproate).

12.3 Pharmacokinetics

Absorption: Female patients with a singleton pregnancy received intramuscular doses of 250 mg Ostrolut for the reduction of preterm birth starting between 16 weeks 0 days and 20 weeks 6 days. All patients had blood drawn daily for 7 days to evaluate pharmacokinetics.

For all three groups, peak concentration (C_max) 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, Ostrolut (Hydroxyprogesterone Caproate). While di-hydroxylated and tri-hydroxylated metabolites were also detected in human plasma to a 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 Ostrolut (Hydroxyprogesterone Caproate), as evaluated from 4 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: Ostrolut (Hydroxyprogesterone Caproate) binds extensively to plasma proteins including albumin and corticosteroid binding globulins.

Metabolism: In vitro studies have shown that Ostrolut (Hydroxyprogesterone Caproate) can be metabolized by human hepatocytes, both by phase I and phase II reactions. Ostrolut (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 Ostrolut (Hydroxyprogesterone Caproate) is predominantly mediated by CYP3A4 and CYP3A5. The in vitro data indicate that the caproate group is retained during metabolism of Ostrolut (Hydroxyprogesterone Caproate).

Excretion: Both conjugated metabolites and free steroids are excreted in the urine and feces, with the conjugated metabolites being prominent. Following intramuscular administration to pregnant women at 10-12 weeks gestation, approximately 50% of a dose was recovered in the feces and approximately 30% recovered in the urine.

Specific Populations

Renal Impairment: The effect of renal impairment on the pharmacokinetics of Ostrolut (Hydroxyprogesterone Caproate) has not been evaluated.

Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Ostrolut (Hydroxyprogesterone Caproate) has not been evaluated.

Drug Interactions

Cytochrome P450 (CYP) enzymes: An in vitro inhibition study using human liver microsomes and CYP isoform-selective substrates indicated that Ostrolut (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, Ostrolut (Hydroxyprogesterone Caproate) did not induce or inhibit CYP1A2, CYP2A6, or CYP2B6 activity. Overall, the findings indicate that Ostrolut (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 Ostrolut (Hydroxyprogesterone Caproate) is not likely to inhibit the activity of CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Ostrolut (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. Ostrolut (Hydroxyprogesterone Caproate) 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.

14 CLINICAL STUDIES

14.1 Clinical Trial to Evaluate Reduction of Risk of Preterm Birth

In a multicenter, randomized, double-blind, vehicle -controlled clinical trial, the safety and effectiveness of Ostrolut (Hydroxyprogesterone Caproate) for the reduction of the risk of spontaneous preterm birth was studied in women with a singleton pregnancy (age 16 to 43 years) who had a documented history of singleton spontaneous preterm birth (defined as delivery at less than 37 weeks of gestation following spontaneous preterm labor or premature rupture of membranes).¹ At the time of randomization (between 16 weeks, 0 days and 20 weeks, 6 days of gestation), an ultrasound examination had confirmed gestational age and no known fetal anomaly. Women were excluded for prior progesterone treatment or heparin therapy during the current pregnancy, a history of thromboembolic disease, or maternal/obstetrical complications (such as current or planned cerclage, hypertension requiring medication, or a seizure disorder).

A total of 463 pregnant women were randomized to receive either Ostrolut (Hydroxyprogesterone Caproate) (N=310) or vehicle (N=153) at a dose of 250 mg administered weekly by intramuscular injection starting between 16 weeks, 0 days and 20 weeks, 6 days of gestation, and continuing until 37 weeks of gestation or delivery. Demographics of the Makena-treated women were similar to those in the control group, and included: 59.0% Black, 25.5% Caucasian, 13.9% Hispanic and 0.6% Asian. The mean body mass index was 26.9 kg/m².

The proportions of women in each treatment arm who delivered at < 37 (the primary study endpoint), < 35, and < 32 weeks of gestation are displayed in Table 5.

Compared to controls, treatment with Ostrolut (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 Ostrolut (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 a 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 Makena-treated subjects delivered prior to 25 weeks compared to 4.7% of control subjects; see Figure 1.

Figure 1 Proportion of Women Remaining Pregnant as a Function of Gestational Age

The 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 Ostrolut (Hydroxyprogesterone Caproate) arm, there was no overall survival difference demonstrated in this clinical trial.

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 3 or 4 intraventricular hemorrhage, proven sepsis, or necrotizing enterocolitis. Although the proportion of neonates who experienced 1 or more events was numerically lower in the Ostrolut (Hydroxyprogesterone Caproate) arm (11.9% vs. 17.2%), the number of adverse outcomes was limited and thedifference between arms was not statistically significant.

Figure 1 Proportion of Women Remaining Pregnant as a Function of Gestational Age

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 a follow-up safety study. Of 348 eligible offspring, 79.9% enrolled: 194 children of Makena-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.²

15 REFERENCES

¹Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379-85.

²Northen A, Norman G, Anderson K, et al. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate. Obstet & Gynecol. 2007;110:865-872.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ostrolut (Hydroxyprogesterone Caproate) (NDC 64011-247-02) is supplied as 1 mL of a sterile solution in a single dose glass vial.

Each 1 mL vial contains Ostrolut (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 1 mL single dose vial of Ostrolut (Hydroxyprogesterone Caproate) containing 250 mg of Ostrolut (Hydroxyprogesterone Caproate).

Ostrolut (Hydroxyprogesterone Caproate) (NDC 64011-243-01) is supplied as 5 mL of a sterile solution in a multidose glass vial.

Each 5 mL vial contains Ostrolut (Hydroxyprogesterone Caproate) USP, 250 mg/mL (25% w/v), in castor oil USP (28.6% v/v) and benzyl benzoate USP (46% v/v) with the preservative benzyl alcohol NF (2% v/v).

Single unit carton: Contains one 5 mL multidose vial of Ostrolut (Hydroxyprogesterone Caproate) (250 mg/mL) containing 1250 mg of Ostrolut (Hydroxyprogesterone Caproate).

Store at 20° to 25°C (68° to 77°F). Excursions permitted to 15° – 30°C (59° – 86°F). Do not refrigerate. Use multidose vials within 5 weeks after first use.

Caution: Protect vial from light. Store vial in its box. Store upright.

17 PATIENT COUNSELING INFORMATION

Counsel patients that Ostrolut (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 .

Distributed by:

AMAG Pharmaceuticals, Inc.

Waltham, MA 02451

08/2017

Patient Information

Ostrolut (Hydroxyprogesterone Caproate) (mah-KEE-na)

(hydroxyprogesterone caproate injection) 250 mg/mL

Read this Patient Information Leaflet before you receive Ostrolut (Hydroxyprogesterone Caproate). 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 Ostrolut (Hydroxyprogesterone Caproate)?

Ostrolut (Hydroxyprogesterone Caproate) is a prescription hormone medicine (progestin) used in women who are pregnant and who have delivered a baby too early (preterm) in the past. Ostrolut (Hydroxyprogesterone Caproate) is used in these women to help lower the risk of having a preterm baby again.

Ostrolut (Hydroxyprogesterone Caproate) is for women who:

• Are pregnant with one baby
• Have had a preterm delivery of one baby in the past

How well does Ostrolut (Hydroxyprogesterone Caproate) work?

Ostrolut (Hydroxyprogesterone Caproate) was studied in women who were at risk for having a preterm baby because they had previously given birth to a preterm baby. In the main study, about 37 of 100 women who received Ostrolut (Hydroxyprogesterone Caproate) gave birth preterm (before 37 weeks of pregnancy), compared to about 55 of 100 women who did not receive Ostrolut (Hydroxyprogesterone Caproate). Another study of Ostrolut (Hydroxyprogesterone Caproate) is going on to see whether Ostrolut (Hydroxyprogesterone Caproate) reduces the number of babies who have serious problems shortly after birth or who die.

It is not known whether Ostrolut (Hydroxyprogesterone Caproate) is safe and effective in women who have other risk factors for preterm birth.

It is not known whether Ostrolut (Hydroxyprogesterone Caproate) is safe and effective in women less than 16 years old.

Ostrolut (Hydroxyprogesterone Caproate) is not intended for use to stop active preterm labor.

Who should not receive Ostrolut (Hydroxyprogesterone Caproate)?

Ostrolut (Hydroxyprogesterone Caproate) should not be used if you:

• Have now or have had a history of blood clots or other blood clotting problems
• Have now or have had a history of breast cancer or other hormone-sensitive cancers
• Have unusual vaginal bleeding not related to your current pregnancy
• Have yellowing of your skin due to liver problems during your pregnancy
• Have liver problems, including liver tumors
• Have uncontrolled high blood pressure

What should I tell my healthcare provider before receiving Ostrolut (Hydroxyprogesterone Caproate)?

Before you receive Ostrolut (Hydroxyprogesterone Caproate), tell your healthcare provider if you have:

• An allergy to Ostrolut (Hydroxyprogesterone Caproate), castor oil, or any of the other ingredients in Ostrolut (Hydroxyprogesterone Caproate). See the end of this patient leaflet for a complete list of the ingredients in Ostrolut (Hydroxyprogesterone Caproate).
• Diabetes or prediabetes
• Epilepsy
• Migraine headaches
• Asthma
• Heart problems
• Kidney problems
• Depression
• High blood pressure

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Ostrolut (Hydroxyprogesterone Caproate) may affect the way other medicines work, and other medicines may affect how Ostrolut (Hydroxyprogesterone Caproate) works.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medication.

How should I receive Ostrolut (Hydroxyprogesterone Caproate)?

• Do not give yourself Ostrolut (Hydroxyprogesterone Caproate) injections. A healthcare professional will give you the Ostrolut (Hydroxyprogesterone Caproate) injection into your hip area (upper outer area of the buttocks) once a week (every 7 days).
• You will start receiving Ostrolut (Hydroxyprogesterone Caproate) injections anytime from 16 weeks and 0 days of your pregnancy up to 20 weeks and 6 days of your pregnancy.
• You will continue to receive Ostrolut (Hydroxyprogesterone Caproate) injections once weekly until week 37 of your pregnancy or when your baby is delivered, whichever happens first.

Ostrolut (Hydroxyprogesterone Caproate) comes in ready-to-use vials. There are either 1 or 5 doses of medicine in each vial. Your healthcare professional should give you only one dose (1 mL) of Ostrolut (Hydroxyprogesterone Caproate) as prescribed each week.

Ostrolut (Hydroxyprogesterone Caproate) supplied in multidose 5 mL vials should be used within 5 weeks after the first use.

It is very important that you do not miss a dose of Ostrolut (Hydroxyprogesterone Caproate) and that you continue to receive the medicine once a week. If you miss a dose, talk to your healthcare provider for specific directions on how to get back on schedule.

What are the possible side effects of Ostrolut (Hydroxyprogesterone Caproate)?

Ostrolut (Hydroxyprogesterone Caproate) may cause serious side effects, including:

• Blood clots. Symptoms of a blood clot may include:
  • Leg swelling
  • Redness in your leg
  • A spot on your leg that is warm to touch
  • Leg pain that worsens when you bend your foot
• Allergic reactions. Symptoms of an allergic reaction may include:
  • Hives
  • Itching
  • Swelling of the face
  
  

  Call your healthcare provider right away if you get any of the symptoms above.
  

• Depression
• Yellowing of your skin and the whites of your eyes

The most common side effects of Ostrolut (Hydroxyprogesterone Caproate) include:

• Pain, swelling, itching, bruising or a hard bump at the injection site
• Hives
• Itching
• Nausea
• Diarrhea

Call your healthcare provider if you have the following at your injection site:

• Increased pain over time
• Oozing of blood or fluid
• Swelling

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 Ostrolut (Hydroxyprogesterone Caproate). For more information, ask your healthcare provider or pharmacist.

In a clinical study, certain complications or events associated with pregnancy occurred more often in women who received Ostrolut (Hydroxyprogesterone Caproate) compared to women who did not receive Ostrolut (Hydroxyprogesterone Caproate), including:

• Miscarriage (pregnancy loss before 20 weeks of pregnancy)
• Stillbirth (fetal death occurring during or after the 20th week of pregnancy)
• Hospital admission for preterm labor
• Preeclampsia (high blood pressure and too much protein in your urine)
• Gestational hypertension (high blood pressure caused by pregnancy)
• Gestational diabetes
• Oligohydramnios (low amniotic fluid levels)

Call your healthcare provider for medical advice about side effects or pregnancy complications. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Ostrolut (Hydroxyprogesterone Caproate)?

• Store Ostrolut (Hydroxyprogesterone Caproate) at 20° to 25°C (68° to 77°F). Excursions permitted to 15° – 30°C (59° – 86°F)
• Do Not Refrigerate
• Store Ostrolut (Hydroxyprogesterone Caproate) in the original box to protect it from light
• Store the Ostrolut (Hydroxyprogesterone Caproate) box upright
• Ostrolut (Hydroxyprogesterone Caproate) 5 mL multidose vials should be used within 5 weeks after the first use
• Keep Ostrolut (Hydroxyprogesterone Caproate) out of the reach of children

General information about the safe and effective use of Ostrolut (Hydroxyprogesterone Caproate).

Medicines are sometimes prescribed for purposes other than those mentioned in the Patient Information Leaflets. Do not take Ostrolut (Hydroxyprogesterone Caproate) for conditions for which it was not prescribed. Do not give Ostrolut (Hydroxyprogesterone Caproate) to other people, even if they have the same condition you have. It may harm them.

This leaflet summarizes the most important information about Ostrolut (Hydroxyprogesterone Caproate). If you would like more information, talk with your healthcare provider. You can ask for information about Ostrolut (Hydroxyprogesterone Caproate) that is written for healthcare professionals.

For more information, go to www.makena.com or call AMAG Pharmaceuticals Customer Service at the toll free number 1-877-411-2510.

To refill a prescription or to check on prescription status, call the Ostrolut (Hydroxyprogesterone Caproate) Care Connection at the toll free number 1-800-847-3418.

What are the ingredients in Ostrolut (Hydroxyprogesterone Caproate)?

Active ingredient: Ostrolut (Hydroxyprogesterone Caproate)

Inactive ingredients: castor oil and benzyl benzoate. 5 mL multidose vials also contain benzyl alcohol (a preservative).

Makena®

Ostrolut (Hydroxyprogesterone Caproate) injection

1250 mg/5 mL

(250 mg/mL)

Makena®

Ostrolut (Hydroxyprogesterone Caproate) injection

250 mg/mL

1 mL vial