Page 31 - Makena Auto-Injector Patient Storybook

Figure 1 Proportion of Women Remaining Pregnant as a Function of
12.1 Mechanism of Action
Hydroxyprogesterone caproate is a synthetic progestin. The mechanism by which
12 CLINhICydAroLxPypHroAgResMteAroCnOe cLaOprGoaYte reduces the risk of recurrent preterm birth is not known.
12.1 Mechanism of Action
Gestational Age
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.
Hydro1x2y.p2rogesPtehroanremcacpordoaytneaimsaicsyntheticprogestin. Themechanismbywhich hydroxyprogesterone caproate reduces the risk of recurrent preterm birth is not known.
No specific pharmacodynamic studies were conducted with Makena.
12.2 Pharmacodynamics
No sp1e2c.i3fic phaPrmhacromdaycnoakmiincesttiucdsies were conducted with Makena.
12.3 APbhsaormptiaocno: Fkeinmeatliecpsatients with a singleton pregnancy received intramuscular doses of 250 mg Absohrpytdioronx:yFperomgeasleterpoanteiecnatpsrowaittehfaorstihnegrledtounctiporneogfnparnecteyrmrebciertivhesdtarintitnrgambeutwsceuenla1r 6dowseeksso0f 250 mg hydrodxaypsraongde2s0tewroenekesc6adparyosa.tAelfloprathientrsehdaudcbtiolonodofdprarwetnedrmailybifrothr 7stdaarytisngtobeevtawlueaeten 16 weeks 0 days and 2p0hawrmeeakcosk6indetaicys.. All patients had blood drawn daily for 7 days to evaluate pharmacokinetics.
Table 4 Summary of Mean (Standard Deviation) Pharmacokinetic Parameters for Hydroxyprogesterone Caproate
Blood was drawn daily for 7 days (1) starting 24 hours after the first dose between Weeks 16-20 (Group 1), (2) after a dose between Weeks 24-28 (Group 2), or (3) after a dose between Weeks 32-36 (Group 3)
a Reported as median (range)
b t=7days
The rates of fetal losses and neonatal deaths in each treatment arm are
Group (N)
Cmax (ng/mL)
Tmax (days)a
AUC(0-t)b (ng·hr/mL)
Group 1 (N=6)
5.0 (1.5)
5.5 (2.0-7.0)
571.4 (195.2)
Group 2 (N=8)
12.5 (3.9)
1.0 (0.9-1.9)
1269.6 (285.0)
Group 3 (N=11)
12.3 (4.9)
2.0 (1.0-3.0)
1268.0 (511.6)
For all three groups, peak concentration (C ) and area under the curve (AUC
For all three groups, peak concentration (Cmax) amnadx area under the curve (AUC(1-7 days)) of th(e1-7 days)
displayed in Table 6. Due to the higher rate of miscarriages and stillbirths in the
) of the mono-hydroxylated metabolites were approximately 3-8-fold lower than the respective parameters
higher rate of miscarriages and stillbirths in the Makena arm, there was no overall survival difference
mono-hydroxylated metabolites were approximately 3-8-fold lower than the respective
Makena arm, there was no overall survival difference demonstrated in this
for the parent drug, 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 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.
In a single-dose, open-label, randomized, parallel design bioavailability study in 120 healthy post- menopausal women, comparable systemic exposure of hydroxyprogesterone caproate was seen when Makena was administered subcutaneously with the auto-injector (1.1 mL) in the back of the upper arm and when Makena was dosed intramuscularly (1 mL) in the upper outer quadrant of the gluteus maximus.
Distribution: Hydroxyprogesterone caproate binds extensively to plasma proteins including albumin and corticosteroid binding globulins.
Metabolism: In vitro studies have shown that hydroxyprogesterone caproate can be metabolized by human hepatocytes, both by phase 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.
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.
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. 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 (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). At the time of randomization (between 16 weeks, 0 days and 20 weeks, 6 days of gestation), an ultrasound examination had confirmed gestational
clinical trial.
The rates of fetal losses and neonatal deaths in each treatment arm are displayed in Table 6. Due to the
demonstrated in this clinical trial.
Complication
Makena N=306 A n (%)B
Control N=153 n (%) B
Miscarriages <20 weeks gestation C
5 (2.4)
0
Stillbirth
6 (2.0)
2 (1.3)
Antepartum stillbirth
5 (1.6)
1 (0.6)
Intrapartum stillbirth
1 (0.3)
1 (0.6)
Neonatal deaths
8 (2.6)
9 (5.9)
Total Deaths
19 (6.2)
11 (7.2)
age and no known fetal anomaly. Women were excluded for prior progesterone treatment or heparin
Table 6 Fetal Losses and Neonatal Deaths
A Four of the 310 Makena-treated subjects were lost to follow-up and stillbirth or neonatal status could not be determined
B Percentages are based on the number of enrolled subjects and not adjusted for time on drug
C Percentage adjusted for the number of at risk subjects (n=209 for Makena, n=107 for control) enrolled at <20 weeks gestation.
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 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
Makena auto-injector (for subcutaneous injection)
Makena auto-injector (NDC 64011-301-03) is supplied as 1.1 mL of a clear yellow sterile preservative- free solution in an auto-injector containing a pre-filled syringe. Each 1.1 mL auto-injector 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 1.1 mL single-patient-use auto-injector of Makena containing 275 mg of hydroxyprogesterone caproate.
Store at 20° to 25°C (68° to 77°F). Do not refrigerate or freeze.
Caution: Protect auto-injector from light. Store auto-injector in its box.
Makena single- and multi-dose vials (for intramuscular injection)
Makena (NDC 64011-247-02) is supplied as 1 mL of a sterile preservative-free clear yellow solution in a single-dose glass vial.
Each 1 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 1 mL single-dose vial of Makena containing 250 mg of hydroxyprogesterone caproate.
Makena (NDC 64011-243-01) is supplied as 5 mL of a sterile clear yellow solution in a multi-dose 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 multi-dose vial of Makena (250 mg/mL) containing 1250 mg of hydroxyprogesterone caproate.
Store at 20° to 25°C (68° to 77°F). Do not refrigerate or freeze. Use multi-dose vials within 5 weeks after first use.
Caution: Protect vial from light. Store vial in its box. Store upright.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the 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)].
as current or planned cerclage, hypertension requiring medication, or a seizure
therapy during the current pregnancy, a history of thromboembolic disease, or maternal/obstetrical
disorder).
complications (such as current or planned cerclage, hypertension requiring medication, or a seizure disordAetro).tal 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
A total of 463 pregnant women were randomized to receive either Makena (N=310) or vehicle (N=153)
intramuscular injection starting between 16 weeks, 0 days and 20 weeks, 6 days
at a dose of 250 mg administered weekly by intramuscular injection starting between 16 weeks,
of gestation, and continuing until 37 weeks of gestation or delivery.
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
Demographics of the Makena-treated women were similar to those in the control group, and included:
control group, and included: 59.0% Black, 25.5% Caucasian, 13.9% Hispanic
59.0% Black, 25.5% Caucasian, 13.9% Hispanic and 0.6%2 Asian. The mean body mass index was
and 0.6% Asian. The mean body mass index was 26.9 kg/m .
26.9 kg/m2.
The proportions of women in each treatment arm who delivered at < 37 (the
The proportions of women in each treatment arm who delivered at < 37 (the primary study endpoint),
primary study endpoint), < 35, and < 32 weeks of gestation are displayed in
< 35, and < 32 weeks of gestation are displayed in Table 5.
Table 5.
Table 5 Proportion of Subjects Delivering at < 37, < 35 and < 32 Weeks Gestational Age (ITT Population)
1 Four Makena-treated subjects were lost to follow-up. They were counted as deliveries at their gestational ages at time of last contact (184, 220, 343 and 364 weeks).
2 Adjusted for interim analysis.
CompCaormedpatorecdotontcronlstr,otlrse,atrtematemnetnwt iwthitMh Makaeknenaarreeducedttheepprorpooprotirotnioonfof women who delivered preterm at < 3w7owmeenkwsh.oTdhelipverorepdoprrtieotenrsmoaftw<o3m7 ewneedkes.liTveherinpgropaotr<tio3n5s oafnwdo<m3en2 weeks also were lower among womedneltirvearitnegdawt <ith35Mankde<na3.2Twhekuspaplseor wboeruenldoswoerf athmeoncgonwfiodmeennctereinatedrvwailtsh for the treatment difference at < 3M5 aknedna<. 3T2hewuepepkersbwoeunredscolof stheetocoznefirdoe.nIcnecilnutseirovnalos fozretrhoe itnreatcmoenfit dence interval would indicate the treatmdeifnfetrdenifcferaetn<c3e5isanndo<t s3t2awtiseteicksalwlyerseigcnloifisecatonzt.erCoo. Imncplausreiodn tof ztheeroointhaer gestational ages evaluated, the nucmonbfiedrenocfepirnetteervrmal wbiortuhlds iantd<ica3t2e twheterekastmweanst dlimiffieteredn.ce 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.
Distributed by:
02/2018 ver 1.2
AMAG Pharmaceuticals, Inc. Waltham, MA 02451
Delivery Outcome
Makena1 (N=310) %
Control (N=153) %
Treatment difference and 95% Confidence Interval2
<37 weeks
37.1
54.9
-17.8% [-28.0%, -7.4%]
<35 weeks
21.3
30.7
-9.4% [-19.0%, -0.4%]
<32 weeks
11.9
19.6
-7.7% [-16.1%, -0.3%]