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hydroxyprogesterone caproate injection
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Makena 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 Makena 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 Makena 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.
2 DOSAGE AND ADMINISTRATION
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. Makena is a clear, yellow solution. Do not use if solid particles appear or if the solution is cloudy.
Instructions for administration:
Discard any unused product 5 weeks after first use.
3 DOSAGE FORMS AND STRENGTHS
Makena (250 mg/mL) is a sterile solution of hydroxyprogesterone caproate in castor oil for injection. Each 5 mL multidose vial contains 1250 mg hydroxyprogesterone caproate.
Do not use Makena in women with any of the following conditions:
5 WARNINGS AND PRECAUTIONS
5.1 Thromboembolic Disorders
Discontinue Makena 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 Makena 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 Makena.
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).
Monitor women who have a history of clinical depression and discontinue Makena if clinical depression recurs.
Carefully monitor women who develop jaundice while receiving Makena 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 (5).
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 Makena 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 [See Clinical Studies (14.1).]
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 Makena group and 32.7% of the control group. Table 3 lists adverse reactions that occurred in ≥2% of subjects and at a higher rate in the Makena group than in the control group.
In the clinical trial, 2.2% of subjects receiving Makena were reported as discontinuing therapy due to adverse reactions compared to 2.6% of control subjects. The most common adverse reactions that led to discontinuation in both groups were urticaria and injection site pain/swelling (1% each).
Pulmonary embolus in one subject and injection site cellulitis in another subject were reported as serious adverse reactions in Makena-treated subjects.
7 DRUG INTERACTIONS
No drug-drug interaction studies were conducted with Makena.
Drugs Metabolized by CYP1A2, CYP2A6 and CYP2B6
The metabolism of drugs metabolized by CYP1A2 (such as theophylline, tizadine, clozapine), CYP2A6 (such as acetaminophen, halothane, nicotine) and CYP2B6 (such as efavirenz, bupropion, methadone) may be increased during treatment with Makena [See Clinical Pharmacology (12.3)] .
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category B: There are no adequate and well-controlled studies of Makena use in women during the first trimester of pregnancy. Data from a vehicle (placebo)-controlled clinical trial of 310 pregnant women who received Makena at weekly doses of 250 mg by intramuscular injection in their second and third 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 Makena.
Reproduction studies have been performed in mice and rats at doses up to 95 and 5, respectively, times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Makena.
Makena administration produced embryolethality in rhesus monkeys but not in cynomolgus monkeys exposed to 1 and 10 times the human dose equivalent every 7 days between days 20 and 146 of gestation. There were no teratogenic effects in either species.
8.2 Labor and Delivery
Makena is not intended for use to stop active preterm labor. The effect of Makena in active labor is unknown.
8.3 Nursing Mothers
Discontinue Makena 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
Makena 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. [See Clinical Studies (14).]
8.5 Geriatric Use
Makena 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 Makena in patients with renal impairment.
There have been no reports of adverse events associated with overdosage of Makena in clinical trials. In the case of overdosage, the patient should be treated symptomatically.
The active pharmaceutical ingredient in Makena is hydroxyprogesterone caproate.
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 a molecular weight of 428.60. Hydroxyprogesterone caproate exists as white to practically white crystals or powder with a melting point of 120°-124°C.
The structural formula is:
Makena is a clear, yellow, sterile, non-pyrogenic solution for intramuscular injection. Each 5 mL multidose vial contains 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).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Hydroxyprogesterone caproate is a synthetic progestin. The mechanism by which hydroxyprogesterone caproate reduces the risk recurrent preterm birth is not known.
Absorption: Peak serum levels of hydroxyprogesterone caproate appeared after 3-7 days in non-pregnant female subjects following a single intramuscular injection of 1000 mg hydroxyprogesterone caproate. Based on pharmacokinetic analysis of five non-pregnant female subjects who received a single intramuscular administration of 1000 mg hydroxyprogesterone caproate, the mean (±SD) Cmax is estimated to be 27.8 (±5.3) ng/mL, and the Tmax is estimated to be 4.6 (±1.7) days. The elimination half-life of hydroxyprogesterone caproate was 7.8 (±3.0) days. Once-weekly intramuscular administration of 1000 mg hydroxyprogesterone caproate to non-pregnant women resulted in trough concentration of 60.0 (±14) ng/mL after 13 weeks. The pharmacokinetics of the 250 mg dose of hydroxyprogesterone caproate has not been evaluated.
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 I 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 a dose was recovered in the feces and approximately 30% recovered in the urine.
Renal Impairment: The effect of renal impairment on the pharmacokinetics of Makena has not been evaluated.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Makena has not been evaluated.
Cytochrome P450 (CYP) enzymes: An in vitro 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. The clinical implication of this in vitro metabolic acceleration is not well understood.
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.
The metabolic induction potential of hydroxyprogesterone caproate has not been evaluated.
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 a multigenerational study in rats. Makena 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 (placebo)-controlled clinical trial, the safety and effectiveness of Makena 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 Makena (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 4.
Compared to controls, treatment with Makena 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 Makena. 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.
The rates of fetal and neonatal deaths in each treatment arm are displayed in Table 5. Due to the higher rate of miscarriages and stillbirths in the Makena 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 Makena arm (11.9% vs. 17.2%), the number of adverse outcomes was limited and the difference between arms was not statistically significant.
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
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
Makena (NDC 64011-243-01) is supplied as 5 mL of a sterile solution in a multidose glass vial.
Each 5 mL vial contains 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 Makena (250 mg/mL) containing 1250 mg of hydroxyprogesterone caproate.
Store at controlled room temperature [15°-30°C (59°-86°F)]. Use within 5 weeks after first use.
Caution: Protect vial from light. Store vial in its box. Store upright.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information).
Counsel patients that Makena 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)] .
Read this Patient Information Leaflet before you receive Makena. 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 Makena?
Makena is a prescription hormone medicine (progestin) used in women who are pregnant and who have delivered a baby too early (preterm) in the past. Makena is used in these women to help lower the risk of having a preterm baby again.
Makena is for women who:
How well does Makena work?
Makena 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 Makena gave birth preterm (before 37 weeks of pregnancy), compared to about 55 of 100 women who did not receive Makena. Another study of Makena is going on to see whether Makena reduces the number of babies who have serious problems shortly after birth or who die.
It is not known whether Makena is safe and effective in women who have other risk factors for preterm birth.
It is not known whether Makena is safe and effective in women less than 16 years old.
Makena is not intended for use to stop active preterm labor.
Who should not receive Makena?
Makena should not be used if you:
What should I tell my healthcare provider before receiving Makena?
Before you receive Makena, tell your healthcare provider if you have:
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
Makena may affect the way other medicines work, and other medicines may affect how Makena 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 Makena?
Makena comes in ready-to-use vials. There are 5 doses of medicine in each vial. Your healthcare professional should give you only one dose (1 mL) of Makena as prescribed each week.
Makena should be used within 5 weeks after the first use.
It is very important that you do not miss a dose of Makena 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 Makena?
Makena may cause serious side effects, including:
The most common side effects of Makena include:
Call your healthcare provider if you have the following at your injection site:
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 Makena. 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 Makena compared to women who did not receive Makena, including:
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 Makena?
General information about the safe and effective use of Makena.
Medicines are sometimes prescribed for purposes other than those mentioned in the Patient Information Leaflets. Do not take Makena for conditions for which it was not prescribed. Do not give Makena to other people, even if they have the same condition you have. It may harm them.
This leaflet summarizes the most important information about Makena. If you would like more information, talk with your healthcare provider. You can ask for information about Makena that is written for healthcare professionals.
For more information, go to www.makena.com or call Ther-Rx Corporation Customer Service at the toll free number 1-877-567-7676.
To refill a prescription or to check on prescription status, call the Makena Care Connection at the toll free number 1-800-847-3418.
What are the ingredients in Makena?
Active ingredient: hydroxyprogesterone caproate
Inactive ingredients: castor oil, benzyl benzoate, and benzyl alcohol (a preservative)
PRINCIPAL DISPLAY PANEL
1250 mg/5 mL
FOR INTRAMUSCULAR USE
5 mL multidose vial
Revised: 02/2011 Ther-Rx Corporation
Reproduced with permission of U.S. National Library of Medicine
Copyright © 2018
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