gestation ( 14 ). there are no controlled trials demonstrating a direct clinical benefit, such as improvement in neonatal mortality and morbidity. limitation of use : makena is not intended for use in women with multiple gestations or other risk factors for preterm birth. ( 1 )

erance 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). 5.5 depression monitor women who have a history of clinical depression and discontinue makena if clinical depression recurs. 5.6 jaundice carefully monitor women who develop jaundice while receiving makena and consider whether the benefit of use warrants continuation. 5.7 hypertension carefully monitor women who develop hypertension while receiving makena and consider whether the benefit of use warrants continuation.

¢ 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. makena is a 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: makena single-dose or multi-dose vials (intramuscular use only) makena single-dose or multi-dose vials are only for intramuscular injection with a 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 1 ml of drug into a 3 ml syringe with an 18 gauge needle. 3. change the needle to a 21 gauge 1½ 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. if the 5 ml multi-dose vial is used, discard any unused product 5 weeks after first use. makena auto-injector (subcutaneous use only) makena auto-injector is a single-use, pre-filled, disposable device containing a 27 gauge, 0.5 inch needle that delivers one dose subcutaneously in the back of the upper arm. because makena auto-injector is preservative-free, once the cap is removed the device should be used immediately or discarded. rotate the injection site to the alternate arm from the previous week. do not use in areas where the skin is tender, bruised, red, scaly, raised, thick, or hard. avoid areas with scars, tattoos, or stretch marks. the solution is viscous and oily. the auto-injector takes approximately 15 seconds to deliver the dose; when the viewing window is fully blocked (completely orange), the full dose has been administered. the “instructions for use” contains detailed steps for administering the subcutaneous injection using the auto-injector [see dosage and administration ( 2.3 )] . read the “instructions for use” carefully before administering makena auto-injector. 2.3 instructions for use (makena auto-injector) 2.3 ifu-1 2.3 ifu-2 2.3 ifu-3

ical 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. [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). table 1 selected fetal complications 1 n = total number of subjects enrolled prior to 20 weeks 0 days 2 n = total number of subjects at risk ≥ 20 weeks pregnancy complication makena control n/n n/n miscarriage (< 20 weeks) 1 5/209 0/107 stillbirth (≥ 20 weeks) 2 6/305 2/153 table 2 selected maternal complications 1 other than delivery admission. pregnancy complication makena n=310 % control n=153 % admission for preterm labor 1 16.0 13.8 preeclampsia or gestational hypertension 8.8 4.6 gestational diabetes 5.6 4.6 oligohydramnios 3.6 1.3 common adverse reactions: the most common adverse reaction with intramuscular injection was injection site pain, which was reported after at least one injection by 34.8% of the 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. table 3 adverse reactions occurring in ≥ 2% of makena-treated subjects and at a higher rate than control subjects preferred term makena n=310 % control n=153 % injection site pain 34.8 32.7 injection site swelling 17.1 7.8 urticaria 12.3 11.1 pruritus 7.7 5.9 injection site pruritus 5.8 3.3 nausea 5.8 4.6 injection site nodule 4.5 2.0 diarrhea 2.3 0.7 in the clinical trial using intramuscular injection, 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. two clinical studies were conducted in healthy post-menopausal women, comparing makena administered via subcutaneous auto-injector to makena administered as an intramuscular injection. in the first study, injection site pain occurred in 3/30 (10%) of subjects who used the subcutaneous auto-injector vs. 2/30 (7%) of subjects receiving intramuscular injection. in the second study, injection site pain occurred in 20/59 (34%) of subjects who used the subcutaneous auto-injector vs. 5/61 (8%) of subjects receiving intramuscular injection. 6.2 postmarketing experience the following adverse reactions have been identified during postapproval use of makena. 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

.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 7 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 makena 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. 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 ) ]. 8.6 hepatic impairment no studies have been conducted to examine the pharmacokinetics of makena in patients with hepatic impairment. makena is extensively metabolized and hepatic impairment may reduce the elimination of makena.

timated 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 7 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.

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 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, 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.

lated 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 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.

63 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/m 2 . 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 5 proportion ofs 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 (18 4 , 22 0 , 34 3 and 36 4 weeks). 2 adjusted for interim analysis. delivery outcome makena 1 (n=310) % control (n=153) % treatment difference and 95% confidence interval 2 <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%] 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. 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 makena arm, there was no overall survival difference demonstrated in this clinical trial. 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. 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) 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. 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.

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.

e baby in the past. makena is not intended for use to stop active preterm labor. it is not known if makena is safe and effective in women who have other risk factors for preterm birth. makena is not for use in women under 16 years of age. who should not receive makena? makena should not be used if you have: • blood clots or other blood clotting problems now or in the past • breast cancer or other hormone-sensitive cancers now or in the past • unusual vaginal bleeding not related to your current pregnancy • yellowing of your skin due to liver problems during your pregnancy • liver problems, including liver tumors • high blood pressure that is not controlled what should i tell my healthcare provider before receiving makena? before you receive makena, tell your healthcare provider about all of your medical conditions, including if you have: • a history of allergic reaction to hydroxyprogesterone caproate, castor oil, or any of the other ingredients in makena. see the end of this patient information leaflet for a complete list of ingredients in makena. • diabetes or pre-diabetes. • epilepsy (seizures). • migraine headaches. • asthma. • heart problems. • kidney problems. • depression. • high blood pressure. tell your healthcare provider about all the medicines you take , including prescription and over-the-counter 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 medicine. how should i receive makena? • do not give yourself makena injections. a healthcare provider will give you the makena injection 1 time each week (every 7 days) either: • in the back of your upper arm as an injection under the skin (subcutaneous), or • in the upper outer area of the buttocks as an injection into the muscle (intramuscular). • you will start receiving makena 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 makena injections 1 time each week until week 37 (through 36 weeks and 6 days) of your pregnancy or when your baby is delivered, whichever comes first. what are the possible side effects of makena? makena 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 the touch • leg pain that gets worse when you bend your foot call your healthcare provider right away if you get any of the symptoms above during treatment with makena. • 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 during treatment with makena. • decrease in glucose (blood sugar) tolerance . your healthcare provider will need to monitor your blood sugar while taking makena if you have diabetes or pre-diabetes. • your body may hold too much fluid (fluid retention). • depression. • yellowing of your skin and the whites of your eyes (jaundice). • high blood pressure. the most common side effects of makena include: • pain, swelling, itching 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 other side effects that may happen more often in women who receive makena include: • 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) 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. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store makena? • makena auto-injector for subcutaneous use : • store the auto-injector at room temperature between 68°f to 77°f (20°c to 25°c). • do not refrigerate or freeze. • protect the auto-injector from light. • store the auto-injector in its box. • makena vial for intramuscular use : • store the vial at room temperature between 68°f to 77°f (20°c to 25°c). • do not refrigerate or freeze. • protect the vial from light. • store the vial in its box in an upright position. keep makena and all medicines out of the reach of children. general information about the safe and effective use of makena. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use makena for a condition for which it was not prescribed. do not give makena to other people, even if they have the same symptoms 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 your healthcare provider or pharmacist for information about makena that is written for health professionals. what are the ingredients in makena? active ingredient : hydroxyprogesterone caproate inactive ingredients : castor oil and benzyl benzoate. 5 ml multi-dose vials also contain benzyl alcohol (a preservative). distributed by: amag pharmaceuticals, inc. makena is a registered trademark of amag pharmaceuticals, inc for more information, go to www.makena.com or call amag pharmaceuticals customer service at the toll-free number 1-877-411-2510.