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Prescribing Makena (hydroxyprogesterone caproate injection) via the Makena Care Connection ® ® STEP 1 STEP 2 STEP 3 Healthcare provider faxes the completed Makena Prescription Form to the Makena Care Connection at 1-800-847-3413 The Makena Care Connection investigates the patient’s insurance benefits, and if approved, sends the Makena prescription to a specialty pharmacy for processing The specialty pharmacy verifies insurance coverage, collects the patient’s copay, and ships the product You should receive a confirmation of receipt via fax within a few minutes. If you do not receive this communication from the Makena Care Connection, please call 1-800-847-3418 and ask if your patient’s prescription has been received. The results of the investigation will be relayed to both you and your patient over the phone. • If the patient cannot afford her copay, she should ask the Makena Care Coordinator for financial assistance Once the specialty pharmacy receives approval from the patient’s insurance company, the pharmacy will call the patient to arrange for payment and delivery. • If the patient does not respond to this phone call, the pharmacy will not ship the medication • If Makena is to be shipped to the healthcare provider’s office, the specialty pharmacy will call the office to confirm the shipping address and ensure that the office will be open on the scheduled delivery date 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. Please see attached full prescribing information for Makena. Makena® Prescription Form To ensure enrollment, please fax to the Makena Care Connection® (1-800-847-3413) Telephone 1-800-847-3418 • www.makena.com STEP 1 STEP 1 — Complete Patient and Insurance Information (Please include copies of front and back of insurance cards) Jane Smith First Name D. Last Name MI Healthplan USA XXXXXX Prescription Drug Insurer/Pharmacy Benefit Manager (PBM) 123458789 123 Main Street Address 937854 ID # New York NY City 10101 State ZIP (2126 555-1234 (2126 555-5878 Home Phone # Work Phone # (2126 555-9109 Cell Phone # 9–5pm [email protected] Best Time to Contact 1/02/79 Email (2126 555-3030 Group # PBM Phone # Healthplan USA Robert Smith Primary Medical Insurance XXXXXXXXXXX Date of Birth Policy ID # E L (2126 555-4040 spouse Primary Insurance Phone # Relationship to Cardholder Date of Birth Secondary Medical Insurance Known allergies: none Date of Birth Cardholder Name Policy ID # Patient does not have insurance Secondary Insurance Phone # By signing this Authorization, I authorize my health plans, physicians, and pharmacy providers to disclose my personal health information, including, but not limited to, information relating to my medical condition, treatment, care management, and health insurance, as well as all information provided on this form and any prescription (“Protected Health Information”), to Ther-Rx Corporation — the Makena Care Connection — and its representatives, agents, and contractors (collectively “Ther-Rx”) for the following purposes: (1) to establish my eligibility for benefits; (2) to communicate with my healthcare providers and me about my medical care; (3) to facilitate the provision of products, supplies, or services by a third party including, but not limited to specialty pharmacies; (4) to register me in any applicable product registration program required for my treatment; and (5) to contact me with branded support materials related to my treatment. I understand that my Protected Health Information disclosed under this authorization may be redisclosed by Ther-Rx and is no longer protected by federal privacy laws. I am aware that my pharmacy may disclose information related to the processing and dispensing of Makena that contains Protected Health Information, and that my pharmacy may receive remuneration for that information. I understand that I may refuse to sign this Authorization and that my treatment, payment, enrollment, or eligibility for benefits is not conditioned on my signing this Authorization. I understand that I am entitled to a copy of this Authorization. I understand that I may cancel this Authorization at any time by mailing a letter requesting such cancellation to Ther-Rx Corporation, 2730 S. Edmonds Lane #300, Lewisville, TX 75067, but that this cancellation will not apply to any information already used or disclosed through this Authorization. This Authorization expires five (5) years from the date signed below. M A X Patient or Legal Guardian Signature: Does the patient meet FDA-approved indication (current pregnancy is singleton and patient has a history of singleton spontaneous preterm birth less than 37 weeks ✓Yes of gestation)? No X E STEP 4 — Complete and Sign Makena Rx Johnson, Allen Prescriber’s Name (Last, First) Current Gestational Age: New York City General OB Practice Name Date recorded: 5/1/13 Other: ✓No Yes ZIP (2126 555-1113 Office Fax # ✓18-g needle & 3 mL syringe 5 ✓21-g, 1½" needle 5 # XXXXXXX Office Tax ID # Lucy Taylor (2126 555-1114 Office Contact(s) Direct Phone # (2126 555-1115 [email protected] After-hours Phone # Email Preferred method of communication? # Preferred Injection Setting: Healthcare Provider Office ✓Makena @ Home by Walgreens Infusion Services, if approved by insurance Phone ✓Fax Dispense As Written/Do Not Substitute ✓ • Calls from the Makena Care Connection will display as “MCC” or a “972” area code on Caller ID • The specialty pharmacy’s number may show as an “unknown” number STEP 2 By signing the HIPAA waiver, the patient allows the Makena Care Connection to communicate with the HCP, insurer, and specialty pharmacy on her behalf. If the patient does not sign the HIPAA waiver, the Makena Care Connection will not have the ability to check the patient’s status with the specialty pharmacy. If your patient is not present when you are completing the Makena Prescription Form, please fax the form to the Makena Care Connection. You can obtain the patient’s signature during her next visit and refax the form to the Makena Care Connection. This waiver is required to participate in the financial assistance program(s). A patient is clinically eligible for Makena if she is: Pregnant with a singleton with a history of singleton spontaneous preterm birth <37 weeks of gestation, and starting Makena therapy between 160 and 206 weeks. If the patient is currently on the compounded form of HPC (“17P”) and is changing to Makena mid-therapy, please check the “patient is currently on 17P” box. Please ship Makena to: Ther-Rx has contracted with Walgreens Infusion Services to provide patients with home administration of FDA-approved Makena. This service is available for patients whose insurance plan covers Makena and home administration of therapy through Walgreens Infusion Services. The Makena Care Connection will coordinate directly with Walgreens Infusion Services to process the Makena prescription and the request for home administration via Makena @Home. Desired Start Date: Prescriber 8/28/13 ✓ Patient Date: Makena prescriptions will be processed as quickly as possible. Please submit the patient’s Makena Prescription Form as early as possible to ensure timely initiation of therapy. Email I certify that this therapy is medically necessary and that this information is accurate to the best of my knowledge. X Prescriber’s Signature: Please inform your patient to expect a phone call from the Makena Care Connection and/or the specialty pharmacy STEP 4 XXXXXXXXXX Office Phone # refills for a complete course of therapy Sig: Inject 1 mL IM each week days Medicaid Provider # State 4 0 weeks XXXXXXXXXX Rx: Makena (hydroxyprogesterone caproate injection) 250 mg/mL, 5 mL multidose vial ✓ Dispense 1 vial, followed by 8 NPI # 10101 Timely communication is critical STEP 3 Is the patient currently on compounded HPC (“17P”)? NY (2126 555-1112 5/1/13 Date: ICD-9 Code: ✓v23.41 (pregnancy with a history of preterm labor) 9878 Elm Street Address Self Relationship to Patient: STEP 3 — Patient Eligibility If your patient does not have insurance, check the uninsured box — she may be eligible to participate in the Makena Patient Assistance Program. Relationship to Cardholder P STEP 2 — Read and Sign Patient Authorization Complete the Makena prescription form. When submitting the prescription to the Makena Care Connection, be sure to include a copy of both sides of the patient’s insurance card(s). Cardholder Name 2/02/77 No secondary insurance Primary language if not English: BIN # 5/1/13 DAW Many insurance companies will not approve Makena prior to 14, or even 15, weeks’ gestation. If your patient’s prescription is submitted prior to 14 weeks’ gestation, the Makena Care Connection will hold her prescription until she reaches 14 weeks’ gestation, when the prescription will be processed. This helps increase the likelihood that Makena will be approved by the insurance company for treatment to begin as indicated between 16 weeks, 0 days and 20 weeks, 6 days of gestation, as well as avoiding duplicative paperwork. STEP 5 — Read and Sign Prescriber Authorization I authorize Sonexus Health to be my designated agent and to act as my business associate (as defined in 45 CFR 160.103) to use and disclose any information about any of my patients enrolled with the Makena Care Connection to the insurer of such patients and/or my patient, and to obtain any information about such patients, including any Protected Health Information (as defined in 45 CFR 160.103) from the insurer, including eligibility and other benefit coverage information, for my payment and/or healthcare operation purposes. Sonexus Health may de-identify any and all Protected Health Information of my patients, provided that the de-identification complies with the requirements set forth in 45 CFR 164.514(b). As my business associate, Sonexus Health is required to comply with, and by its signature hereto, agrees that it will comply with, the applicable requirements of 45 CFR 164.504(e) regarding business associates, and that it will safeguard any Protected Health Information that it obtains on my behalf, and will use and disclose this information only for the purposes specified herein or as otherwise permitted by law. X Prescriber’s Signature: Fax completed form and insurance cards (front and back) to: 1-800-847-3413 Date: 5/1/13 Please see next page for important safety information and attached full prescribing information for Makena (hydroxyprogesterone caproate injection). When in doubt, ask Please contact the Makena Care Connection® directly if you or the patient are ever in doubt regarding the status of the Makena prescription. Makena Care Connection 1-800-847-3418 or [email protected] If you know which specialty pharmacy is dispensing your patient’s prescription, you can call it directly. Accredo Health Group, Inc. 888-608-9010 Aetna Specialty Pharmacy® 866-782-2779 Cigna Specialty Pharmacy Services 800-351-3606 CuraScript, Inc. 877-223-0835 CVS Caremark Specialty Pharmacy 800-237-2767 Exactus 866-458-9246 ICORE Specialty Pharmacy 866-554-2673 800-350-8119 Important safety information for Makena® (hydroxyprogesterone caproate injection) • Do not use Makena 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 • Makena should be discontinued if thrombosis or thromboembolism occurs • Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use of Makena or with other products containing castor oil • Women receiving Makena should be monitored if they: – Are prediabetic or diabetic – Have conditions that may be affected by fluid retention, such as preeclampsia, epilepsy, cardiac or renal dysfunction – Have a history of clinical depression; Makena should be discontinued if depression recurs – Develop jaundice; consider whether benefit of use warrants continuation – Develop hypertension • Certain pregnancy-related fetal and maternal complications or events were numerically increased in Makena-treated subjects as compared to placebo subjects, including miscarriage (2.4% vs. 0%) and stillbirth (2% vs. 1.3%), admission for preterm labor (16% vs. 13.8%), preeclampsia or gestational hypertension (8.8% vs. 4.6%), gestational diabetes (5.6% vs. 4.6%), and oligohydramnios (3.6% vs. 1.3%) • The most common adverse reactions reported in ≥2% of subjects and at a higher rate in the Makena group than in the control group were injection site reactions (pain [35% vs. 33%], swelling [17% vs. 8%], pruritus [6% vs. 3%], and nodule [5% vs. 2%]), urticaria (12% vs. 11%), pruritus (8% vs. 6%), nausea (6% vs. 5%), and diarrhea (2% vs. 1%) Prescription Solutions OptumRx 888-293-9309 RightSource Specialty Pharmacy 800-486-2668 Walgreens Specialty Pharmacy 888-347-3416 Full prescribing information attached here. If missing, please visit http://www.makena.com/pages/hcp/pi/. If you have questions about your patient’s administration of therapy through Makena @Home by Walgreens Infusion Services, please call 855-275-9647. Please see additional important safety information on reverse side. Marketed by Ther-Rx Corporation, Chesterfield, MO 63005 ©2013 Ther-Rx Corporation 17-404-1 11/13 Frequently Asked Questions and Troubleshooting Tips How do I help my patient obtain copay assistance? If your patient feels her copay is too high, she may be eligible to participate in the Copay Assistance Program, which helps lower the out-of-pocket cost of Makena for patients who qualify. • To inquire about copay assistance, your patient should call the Makena Care Connection at 1-800-847-3418 My patient does not have insurance. Can the Makena Care Connection help? Uninsured patients may be eligible to receive Makena free of charge or at a reduced price through the Makena Patient Assistance Program. • When submitting the patient’s prescription, be certain to check “Patient does not have insurance” in Step 1 Eligibility for Assistance Programs Due to federal and/or state regulations, participation in any Ther-Rx sponsored program requires the following: • Patient meets the FDA-approved indication (pregnant with a singleton with a history of singleton spontaneous preterm birth <37 weeks of gestation) • Patient is starting Makena therapy between 16 weeks, 0 days and 20 weeks, 6 days • Patient is not insured by a government-funded program (e.g., Medicaid, TRICARE, etc.) My patient’s insurance company requires a prior authorization. Can Makena Care Connection help? The Makena Care Connection will complete as much of the prior authorization as possible if the patient’s insurance company allows. Please note that some insurance companies will only allow the healthcare provider’s office to provide the information necessary to submit a prior authorization. How does my patient obtain Makena refills? About one week before a patient is due for a new Makena vial, her specialty pharmacy will call her to confirm shipment and collect payment. If your patient does not receive this call, have her call the specialty pharmacy directly, which is listed on the patient’s current Makena box. If you are unable to locate the pharmacy name, call the Makena Care Connection to inquire. Important safety information for Makena® (hydroxyprogesterone caproate injection) • Do not use Makena 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 • Makena should be discontinued if thrombosis or thromboembolism occurs • Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use of Makena or with other products containing castor oil • Women receiving Makena should be monitored if they: – Are prediabetic or diabetic – Have conditions that may be affected by fluid retention, such as preeclampsia, epilepsy, cardiac or renal dysfunction – Have a history of clinical depression; Makena should be discontinued if depression recurs – Develop jaundice; consider whether benefit of use warrants continuation – Develop hypertension • Certain pregnancy-related fetal and maternal complications or events were numerically increased in Makena-treated subjects as compared to placebo subjects, including miscarriage (2.4% vs. 0%) and stillbirth (2% vs. 1.3%), admission for preterm labor (16% vs. 13.8%), preeclampsia or gestational hypertension (8.8% vs. 4.6%), gestational diabetes (5.6% vs. 4.6%), and oligohydramnios (3.6% vs. 1.3%) • The most common adverse reactions reported in ≥2% of subjects and at a higher rate in the Makena group than in the control group were injection site reactions (pain [35% vs. 33%], swelling [17% vs. 8%], pruritus [6% vs. 3%], and nodule [5% vs. 2%]), urticaria (12% vs. 11%), pruritus (8% vs. 6%), nausea (6% vs. 5%), and diarrhea (2% vs. 1%) Full prescribing information attached here. If missing, please visit http://www.makena.com/pages/hcp/pi/. Marketed by Ther-Rx Corporation, Chesterfield, MO 63005 ©2013 Ther-Rx Corporation 17-404-1 11/13 • Cholestatic jaundice of pregnancy (4) • Liver tumors, benign or malignant, or active liver disease (4) • Uncontrolled hypertension (4) HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use MAKENA safely and effectively. See full prescribing information for MAKENA. MAKENA® (hydroxyprogesterone caproate injection) for intramuscular use. Initial U.S. Approval: 1956 —————————————-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. Limitation of use: Makena is not intended for use in women with multiple gestations or other risk factors for preterm birth. (1) (1) ————————————-DOSAGE AND ADMINISTRATION———————————— Administer intramuscularly intramuscularly at at aa dose dose of of 250 250 mg mg (1 (1 mL) mL) once once weekly weekly •• Administer Begin treatment treatment between between 16 16 weeks, weeks, 00 days days and and 20 20 weeks, weeks, 66 days days of of gestation gestation •• Begin Continue administration administration once once weekly weekly until until week week 37 37 (through (through 36 36 weeks, weeks, 66 days) days) of of gestation gestation •• Continue or delivery, delivery, whichever whichever occurs occurs first first (2.1) (2.1) or —————————————DOSAGE FORMS AND STRENGTHS——————————mL multidose multidose vial vial (250 (250 mg/mL) mg/mL) contains contains 1250 1250 mg mg hydroxyprogesterone hydroxyprogesterone caproate. caproate. (3) (3) 55 mL —————————————-—-CONTRAINDICATIONS—————————————-—Current or or history history of of thrombosis thrombosis or or thromboembolic thromboembolic disorders disorders (4) (4) •• Current Known or or suspected suspected breast breast cancer, cancer, other other hormone-sensitive hormone-sensitive cancer, cancer, or or history history of of these these •• Known conditions (4) (4) conditions Undiagnosed abnormal abnormal vaginal vaginal bleeding bleeding unrelated unrelated to to pregnancy pregnancy (4) (4) •• Undiagnosed Cholestatic jaundice jaundice of of pregnancy pregnancy (4) (4) •• Cholestatic Liver tumors, tumors, benign benign or or malignant, malignant, or or active active liver liver disease disease (4) (4) •• Liver Uncontrolled hypertension hypertension (4) (4) •• Uncontrolled FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Dosing 2.1 2.2 Preparation Preparation and and Administration Administration 2.2 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Thromboembolic Thromboembolic Disorders Disorders 5.1 5.2 Allergic Allergic Reactions Reactions 5.2 5.3 Decrease Decrease in in Glucose Glucose Tolerance Tolerance 5.3 5.4 Fluid Fluid Retention Retention 5.4 5.5 Depression Depression 5.5 5.6 Jaundice Jaundice 5.6 5.7 Hypertension Hypertension 5.7 6 ADVERSE REACTIONS 6.1 Clinical Clinical Trials Trials Experience Experience 6.1 6.2 Postmarketing Postmarketing Experience Experience 6.2 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy 8.1 8.2 Labor Labor and and Delivery Delivery 8.2 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 2.1 Dosing Administer intramuscularly intramuscularly at at aa dose dose of of 250 250 mg mg (1 (1 mL) mL) once once weekly weekly (every (every 77 days) days) by by aa healthcare healthcare provider provider •• Administer Begin treatment treatment between between 16 16 weeks, weeks, 00 days days and and 20 20 weeks, weeks, 66 days days of of gestation gestation •• Begin Continue administration administration once once weekly weekly until until week week 37 37 (through (through 36 36 weeks, weeks, 66 days) days) of of gestation gestation or or delivery, delivery, whichever whichever •• Continue 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. Do not use if solid particles appear or if the solution is cloudy. Instructions for administration: 1. Clean Clean the the vial vial top top with with an an alcohol alcohol swab swab before before use. use. 1. 2. Draw Draw up up 11 mL mL of of drug drug into into aa 33 mL mL syringe syringe with with an an 18 18 gauge gauge needle. needle. 2. 3. Change Change the the needle needle to to aa 21 21 gauge gauge 1½ 1½ inch inch needle. needle. 3. 4. After After preparing preparing the the skin, skin, inject inject in in the the upper upper outer outer quadrant quadrant of the gluteus maximus. The solution is viscous and 4. oily. Slow Slow injection injection (over (over one one minute minute or or longer) longer) is is recommended. recommended. oily. 5. Applying pressure to the injection site may minimize bruising and and swelling. swelling. 5. Applying pressure to the injection site may minimize bruising Discard any any unused unused product product 55 weeks weeks after after first first use. use. Discard 3 4 DOSAGE FORMS AND STRENGTHS Makena (250 (250 mg/mL) mg/mL) is is aa sterile sterile solution solution of of hydroxyprogesterone hydroxyprogesterone caproate caproate in in castor castor oil oil for for injection. injection. Each Each 55 mL mL multidose multidose Makena vial contains contains 1250 1250 mg mg hydroxyprogesterone hydroxyprogesterone caproate. caproate. vial CONTRAINDICATIONS Do not use Makena in women with any of the following conditions: Current or or history history of of thrombosis thrombosis or or thromboembolic thromboembolic disorders disorders •• Current Known or or suspected suspected breast breast cancer, cancer, other other hormone-sensitive hormone-s •• Known cancer, or history of these conditions Undiagnosed abnormal abnormal vaginal vaginal bleeding bleeding unrelated unrelated to to pregnancy pregnancy •• Undiagnosed Cholestatic jaundice jaundice of of pregnancy pregnancy •• Cholestatic Liver tumors, tumors, benign benign or or malignant, malignant, or or active active liver liver disease disease •• Liver Uncontrolled hypertension hypertension •• Uncontrolled ———————————-WARNINGS AND PRECAUTIONS———————————— Thromboembolic disorders: disorders: Discontinue Discontinue ifif thrombosis thrombosis or or thromboembolism thromboembolism occurs occurs (5.1) (5.1) •• Thromboembolic Allergic reactions: reactions: Consider Consider discontinuing discontinuing ifif allergic allergic reactions reactions occur occur (5.2) (5.2) •• Allergic 2.1 Dosing Decreased glucose glucose tolerance: Monitor Monitor prediabetic and diabetic women receiving Makena (5.3) •• Decreased 2.2 Preparation tolerance: and Administrationprediabetic and diabetic women receiving Makena (5.3) •• Fluid Fluid retention: retention: Monitor Monitor women women with with condi conditions that may be affected by fluid retention, such as as preeclampsia, preeclampsia, epilepsy, epilepsy, cardiac cardiac or or renal renal dysfunction dysfunction (5.4) (5.4) such Depression: Monitor Monitor women women with with aa history history of of clinical clinical depression; depression; discontinue discontinue Makena Makena ifif •• Depression: depression recurs (5.5) (5.5) Disorders depression recurs 5.1 Thromboembolic —————————————-ADVERSE REACTIONS——————————————5.2 Allergic Reactions Decrease in Glucose Tolerance Most5.3 common adverse reactions reported in ≥ 2% 2% of of subjects subjects and and at at aa higher higher rate rate in in the the 5.4 Fluid Makena groupRetention than in in the the control control group group are are injection injection site site reactions reactions (pain (pain [35%], [35%], swelling swelling Makena group than 5.5pruritus Depression [17%], pruritus [6%], nodule nodule [5%]), [5%]), urticaria urticaria (12%), (12%), pruritus pruritus (8%), (8%), nausea nausea (6%), (6%), and and diarrhea diarrhea [17%], [6%], (2%).5.6(6.1) (6.1) Jaundice (2%). 5.7 Hypertension To report SUSPECTED ADVERSE REACTIONS, contact Ther-Rx Corporation at 1-877-567-7676 or FDA at 1 800 FDA 1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience IN SPECIFIC POPULATIONS—-—————————————————————-—-USE 6.2 Postmarketing Experience Pregnancy: Controlled Controlled studies studies show show no no increase increase in in congenital congenital anomalies, anomalies, including including genital genital Pregnancy: abnormalities in male or female infants, from exposure during pregnancy to hydroxy-progesterone caproate. (8.1) (8.1) one caproate. 8.1 Pregnancy See 8.2 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Labor and Delivery 8. 8. 8. 8. 8. Revised 08/2013 Pulm reac 13 14 14 are frequ 8.3 Nursing Nursing Mothers Mothers 8.3 8.4 Pediatric Pediatric Use Use 8.4 8.5 Geriatricintramuscularly Use 8.5 Geriatric Use • Administer at a dose of 250 mg (1 mL) once weekly (every 7 days) by a healthcare provider 8.6 Renal Impairment • Begin treatment between 16 weeks, 0 days and 20 weeks, 6 days of gestation 8.6 Renal Impairment • Continue once weekly until week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever 8.7 Hepaticadministration Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism Mechanism of of Action Action 12.1 12.2 Pharmacodynamics 1. Clean the vial top with an alcohol swab before use. 12.2 Pharmacodynamics 2. Draw up 1 mL of drug into a 3 mL syringe with an 18 gauge needle. 12.3 Pharmacokinetics 12.3 Pharmacokinetics 3. Change the needle to a 21 gauge 1½ inch needle. 13 NONCLINICAL TOXICOLOGY 4. After preparing the skin, inject in the upper outer quadrant 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Fertility 13.1oily.Carcinogenesis, Impairment of Slow injection (overMutagenesis, one minute or longer) is recommended. 14 CLINICAL STUDIES 5. Applying pressure to the injection site may minimize bruising and swelling. Discard unusedTrial product weeks after Reduction first use. 14.1any Clinical to5Evaluate Evaluate of Risk Risk of of Preterm Preterm Birth Birth 14.1 Clinical Trial to Reduction of 14.2 Infant Infant Follow-Up Follow-Up Safety Safety Study Study 14.2 Makena (250 mg/mL) is a sterile solution of hydroxyprogesterone caproate in castor oil for injection. Each 5 mL multidose 15vialREFERENCES contains 1250 mg hydroxyprogesterone caproate. 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION who as w Rep 10 ti • Current or history of thrombosis or thromboembolic disorders • Known or suspected breast cancer, other hormone-s *Sections or subsections from the full prescribing • Undiagnosed abnormalomitted vaginal bleeding unrelated to pregnancy information are not listed 5 6 • Cholestatic jaundice of pregnancy • Liver tumors, benign or malignant, or active liver disease Pulmonary embolus hypertension in one one subject subject and and injection injection site site cellulitis cellulitis in in another another subject subject were were reported reported as as serious serious adverse adverse • Uncontrolled Pulmonary embolus in reactions in Makena-treated Makena-treated subjects. subjects. reactions in WARNINGS AND PRECAUTIONS 5.1 Thromboembolic Disorders postapproval use of of Makena. Makena. Because these these reactions reactions Discontinue Makena if an arterial or deep venous thrombotic or thromboembolic event occurs. postapproval use Because are reported reported voluntarily voluntarily from from aa population population of of uncertain uncertain size size are 5.2 Allergic Reactions frequency or or establish establish aa causal causal relationship relationship to to drug drug exposure. exposure. frequency Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use of Makena or with other Body as aa whole: whole: Local injection site reactions (including (including erythema, products containing castor oil. injection Considersite discontinuing the drugerythema, if such reactions occur. as Local reactions •• Body warmth); fatigue; fatigue; fever; hot hot flashes/flushes flashes/flushes warmth); 5.3 Decrease in Glucosefever; Tolerance • • A decrease in glucose tolerance has been observed in some patients on progestin treatment. The mechanism of this Urinary tract infection infection decrease is not known. Carefully monitor prediabetic and diabetic women while they are receiving Makena. Urinary tract •• Headache, dizziness dizziness Headache, •• 5.4 Fluid Retention Cervical incompetence, premature rupture of membranes membranes • Because of fluid incompetence, retention, carefully monitor women with conditions that premature rupture of • progestational drugs may cause some degreeCervical Reproductive system and (e.g., breastpreeclampsia, disorders: Cervical Cervical dilation, shortened cervix might•• beReproductive influenced bysystem this effect epilepsy, migraine, asthma, cardiac or renal dysfunction). and breast disorders: dilation, shortened cervix Respiratory disorders: disorders: 5.5 Depression •• Respiratory Rash Monitor who have a history of clinical depression and discontinue Makena if clinical depression recurs. Rash •• women 5.6 Jaundice drug-drug interaction studiesjaundice were conducted conducted withMakena Makena.and [See Clinical Pharmacology (12.3).] Carefullydrug-drug monitor women who develop while receiving consider whether the benefit (12.3).] of use warrants interaction studies were with Makena. [See Clinical Pharmacology drug-drug interaction interaction studies studies were were conducted conducted with with Makena. Makena. continuation. drug-drug 5.7 Hypertension Carefully monitor women who develop hypertension while receiving Makena and consider whether the benefit of use There are are no no adequate adequate and and well-controlled well-controlled studies studies of of Makena Makena use use in in women women during during warrants continuation. There of pregnancy. pregnancy. Data Data from from aa vehicle vehicle (placebo)-controlled (placebo)-controlled clinical clinical trial trial of of 310 310 pregnant pregnant women women of ADVERSE REACTIONS whothe received Makenaadverse at weekly weekly doses of ofto250 250 mg by intramuscular injection in their their second and third third trimesters11 who received Makena at doses injection in and Warnings andsecond Precautions (5). trimesters For most serious reactions the mg useby of intramuscular progestins, see as well well as as long-term (2-5 (2-5 years) years) follow-up follow-up safety safety data data on on 194 194 of of their their infants infants22 as 6.1 Clinicallong-term Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical Reproduction studiesbe have beencompared performedtoin inthemice mice and ratsclinical at doses doses upofto toanother 95 and anddrug 5, respectively, respectively, times the human Reproduction studies have been performed rats at up 95 5, trials of a drug cannot directly ratesand in the trials and may nottimes reflectthe thehuman rates observed in practice. monkeys but not in cynomolgus monkeys exposed to 1 and notforinspontaneous cynomolgus monkeys exposedbased to 1 and In a vehicle (placebo)-controlled clinical trial of 463 pregnantmonkeys women atbutrisk preterm delivery on 10 times times the the human dose equivalent every days between between days 20 and and 146 of of gestation. gestation. There were no no teratogenic 10 human dose equivalent every days 20 146 were obstetrical history, 310 received 250 mg of 77Makena and 153days received a vehicle formulationThere containing noteratogenic 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). Table 1 Selected Fetal Complications Pregnancy Complication Makena Control n/N n/Nthan fectiveness in in pediatric pediatric patients patients less less than 16 16 years years of of age age have have fectiveness not been established. A small number of women under age 18 years were studied; safety and efficacy efficacy are are expected expected to to 1 not been established. small number of women under5/209 age 18 years were studied; safety0/107 and Miscarriage (< 20Aweeks) [See Clinical Studies (14).] be the same in women aged 16 years and above as for users 18 years and older. be the same in women aged2 16 years and above as for users 18 years and older. [See Clinical Studies (14).] 6/305 2/153 Stillbirth (≥ 20 weeks) 1 2 Allergic reactions, reactions, including including urticaria, urticaria, pruritus pruritus and and angi angi Allergic 12 12 12 N = Total number of subjects enrolled prior to 20 weeks 0 days N = Total number of subjects at risk ≥ 20 weeks Table 2 Selected Maternal Complications not b be th is ex form whit Mak hydr (46% Abso der chever ltidose reated 6/305 Stillbirth ( 20 weeks) abetes, and oligohydramnios (Tables 1 and 2). 2/153 N = Total number of subjects enrolled prior to 20 weeks 0 days 2 N = Total number of subjects at risk 20 weeks Table 2 Selected Maternal Complications 1 5/209 Makena N=310 6/305 % 1 N =Admission Total number of subjects prior to 20 weeks 0 days 1 16.0 for preterm laborenrolled 2 N = Total number of subjects at risk 20 weeks Preeclampsia or gestational hypertension 8.8 Miscarriage (< 20 weeks)1 Pregnancy Complication Stillbirth ( 20 weeks)2 Control 0/107 N=153 2/153 % 13.8 4.6 GestationalMothers diabetes 5.6 4.6 8.3 Nursing Oligohydramnios 3.6 1.3 8.4 Pediatric Use 8.5 1 Geriatric Use Other than delivery admission. 16.0 13.8 forReactions: preterm labor1 8.6 Admission Renal Impairment Common Adverse Preeclampsia or gestational hypertension 8.8 was reported after at least 4.6 The common adverse reaction was injection site pain, which one injection by 34.8% of 8.7most Hepatic Impairment the Makena groupdiabetes and 32.7% of the control group. Table 3 lists 5.6 adverse reactions that occurred Gestational 4.6in ≥ 2% of subjects and at a higher rate in the Makena group than in the control group. Oligohydramnios 3.6 Subjects and at a1.3 Higher Rate than Table 3 Adverse Reactions Occurring in ≥ 2% of Makena-Treated 1 Control Subjects 12.1 Mechanism of Action Makena Control Common Adverse Reactions: Preferred Term N=310was reported after at leastN=153 12.2 The mostPharmacodynamics common adverse reaction was injection site pain, which 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 12.3 Pharmacokinetics Injection site pain 34.8 32.7 Injection site swelling 17.1of Fertility 13.1 Carcinogenesis, Mutagenesis, Impairment Urticaria 12.3 7.8 11.1 14.1 Clinical Trial to Evaluate Reduction of Risk Pruritus 7.7of Preterm Birth 14.2 InfantInjection Follow-Up Safety Study site pruritus 5.8 5.9 3.3 32.7 4.6 7.8 2.0 11.1 0.7 5.9 In the clinical trial, 2.2% of subjects receiving Makena were reported as discontinuing therapy due to adverse reactions Injection site pruritus 5.8 reactions that led to discontinuation in both groups compared to 2.6% of control subjects. The most common adverse were urticaria Nausea and injection site pain/swelling (1% each). 5.8 4.6 Injection site pain Nausea Injection site swelling Injection site nodule Urticaria Diarrhea 34.8 5.8 17.1 4.5 12.3 2.3 Pulmonary embolus in one serious adverse Injection sitesubject noduleand injection site cellulitis in another 4.5 subject were reported as2.0 reactions in Makena-treated subjects. Diarrhea 2.3 0.7 6.2 Postmarketing Experience The following reactions have receiving been identified during postapproval use of Makena. Because these reactions In the clinicaladverse trial, 2.2% of subjects Makena are reportedto voluntarily from asubjects. population uncertain size,adv it is not always possible to reliably estimate their compared 2.6% of control Theofmost common frequency or establish a causal drugeach). exposure. were urticaria and injection site relationship pain/swellingto(1% • 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 Makena. [See Clinical Pharmacology (12.3).] No in vivo drug-drug interaction studies were conducted with Makena. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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 infants2, 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. 8.7 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. 10 OVERDOSAGE 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. 11 DESCRIPTION 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: H3 C O O CH3 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%] 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, 220, 343 and 364 weeks). 2 Adjusted for interim analysis. 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 100 90 Makena 80 Control 70 60 50 40 30 20 10 O CH3 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 Absorption:PHARMACOLOGY Peak serum levels of hydroxyprogesterone caproate appeared after 3-7 days in non-pregnant female subjects 12.1 Mechanism Action following a single of intramuscular injection of 1000 mg hydroxyprogesterone caproate. Based on pharmacokinetic analysis Hydroxyprogesterone caproate is a synthetic progestin. The intramuscular mechanism byadministration which hydroxyprogesterone caproate reduces of five non-pregnant female subjects who received a single of 1000 mg hydroxyprogesterone the risk of recurrent not known.to be 27.8 (±5.3) ng/mL, and the T is estimated to be 4.6 (±1.7) days. caproate, the meanpreterm (±SD) Cbirth isis estimated The Pharmacodynamics elimination half-life of hydroxyprogesterone caproate was 7.8 (±3.0) days. Once-weekly intramuscular administration 12.2 of 1000 mgpharmacodynamic hydroxyprogesterone caproate non-pregnant women resulted in trough concentration of 60.0 (±14) ng/mL No specific studies weretoconducted with Makena. afterPharmacokinetics 13 weeks. The pharmacokinetics of the 250 mg dos 12.3 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 mgbyhydroxyprogesterone rone caproate can be metabolized human hepatocytes, 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 and conjugation. The conjugated metabolites include sulfated, of 1000 mg hydroxyprogesterone caproate to non-pregnant women resulted in trough concentration of 60.0 (±14) predominantly mediated by CYP3A4 and CYP3A5. The ng/mL in vitro 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 Excretion: Both conjugated metabolites and free steroids are excreted in the urine and feces, with the conjugated metabolites binding globulins. to pregnant women at 10-12 weeks gestation, approximately 50% of a dose was studies recovered in shown the feces approximately 30%caproate recovered themetabolized urine. Metabolism: In vitro have thatand hydroxyprogesterone caninbe by human hepatocytes, both by phase I and phase II reactions. Hydroxyprogesterone caproate undergoes extensive reduction, hydroxylation and conjugation. TheThe conjugated metabolites include sulfated, glucuronidated and acetylated products. In vitro data indicate Renal Impairment: 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: BothP450 conjugated metabolitesAnand free steroids excreted the urine and feces, with the metabolites Cytochrome (CYP) enzymes: inhibitionare study usinginhuman liver microsomes andconjugated CYP isoform-selective being prominent. Following intramuscular administration to pregnant at rate 10-12 gestation, approximately creased the women metabolic of weeks CYP1A2, CYP2A6, and CYP2B6 50% of a dose was recovered in the feces and approximately 30% recovered in the urine. by approximately 80%, 150%, and 80%, respectively. However, in another Specific Populations aused the anticipated increases or decreases in CYP enzyme Renal Impairment: The effect of renal impairment on the pharmacokinetics Makena has not been activity. evaluated. inhibit CYP1A2,of CYP2A6, or CYP2B6 Overall, the has minimal potential for CYP1A2, and CYP2B6 related Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of MakenaCYP2A6, has not been evaluated. drug-drug interactions at the clinically relevant concentrations. Drug Interactions Cytochrome P450 (CYP) enzymes: An in vitro inhibition study using human liver microsomes and CYP isoform-selective of CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4. substrates indicated thatCYP2C19, hydroxyprogesterone caproateand 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 did not induce orevaluated inhibit CYP1A2, CYP2A6, or CYP2B6 activity. Overall, the Hydroxyprogesterone caproate caproate has not been adequately for carcinogenicity. findings indicate that hydroxyprogesterone caproate has minimal potential for CYP1A2, CYP2A6, and CYP2B6 related drug-drug interactions at the clinically relevant concentrations. up to 5 times the recommended human dose, had no adverse Ineffects vitro data of hydroxyprogesterone caproate ability is not to likely to inhibit the activity dams, their concentration developing offspring (F1), or the latter offspring's produce a viable, normal on theindicated parentalthat (F0)therapeutic ofsecond CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. generation. (F2) CYP2C9, 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. Table 4 Proportion of Subjects Delivering at < 37, < 35 and < 32 Weeks Gestational Age (ITT Population) Proportion Remaining Pregnant e 0 16 H 18 20 22 24 26 28 30 32 34 36 38 40 42 228 89 141 55 38 11 0 0 Gestational Age at Delivery (weeks) Number at Risk H H O 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). Makena 3 Control 2 108 56 215 113 296 152 293 148 286 139 281 137 280 129 273 123 259 114 The rates of fetal losses 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. • Are pregnant with one baby • Have had a preterm delivery of one baby in the past Table 5 Fetal Losses and Neonatal Deaths Complication Makena N=306 A n (%) B Control N=153 n (%) B Miscarriages <20 weeks gestation C Stillbirth Antepartum stillbirth Intrapartum stillbirth Neonatal deaths Total Deaths 5 (2.4) 6 (2.0) 5 (1.6) 1 (0.3) 8 (2.6) 19 (6.2) 0 2 (1.3) 1 (0.6) 1 (0.6) 9 (5.9) 11 (7.2) A Four of the 310 Makena-treated subjects were lost to follow-up and stillbirth or neonatal status could not be determined 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 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 B Patient Information Makena (mah-KEE-na) (hydroxyprogesterone caproate injection) 250 mg/mL 15 REFERENCES 1 Meis 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. 2 Northen 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)]. Manufactured by: Hospira, Inc. McPherson, KS 67460 Marketed by: Ther-Rx Corporation Chesterfield, MO 63005 • Have now or have had a history of blood clots or other blood clotting • • • • • • • P H It N D • In • O • S P10072-1 • 08/2013 Have now or have had a history of breast cancer or other hormone• • • • 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 Makena? Before you receive Makena, tell your healthcare provider if you have: • An allergy to hydroxyprogesterone caproate, castor oil, or any of the Read this Patient Information Leaflet before you receive Makena. There other ingredients in Makena. See the end of this patient leaflet for a may be new information. This information does not take the place of talkcomplete list of the ingredients in Makena. ing to your healthcare provider about your medical condition or treatment. • •• Diabetes or prediabetes • Epilepsy What is Makena? • Migraine headaches Makena is a prescription hormone medicine (progestin) used in women who are pregnant and who have delivered a baby too early (preterm) in • Asthma the past. Makena is used in these women to help lower the risk of having • Heart problems a preterm baby again. • •• Kidney problems Makena is for women who: • Depression Arepregnant pregnantwith withone onebaby baby • •Are • High blood pressure Havehad hada apreterm pretermdelivery deliveryofofone onebaby babyininthe thepast past • •Have Tell your healthcare provider about all the medicines you take, including preHow well does Makena work? scription and non-prescription medicines, vitamins, and herbal supplements. Makena was studied in women who were at risk for having a preterm Makena may affect the way other medicines work, and other medicines • affect how Makena works. baby because they had previously given birth to a preterm baby. In the • may main study, about 37 of 100 women who received Makena gave birth • the medicines you take. Keep a list of them to show your health• Know preterm (before 37 weeks of pregnancy), compared to about 55 of 100 care provider and pharmacist when you get a new medication. women who did not receive Makena. Another study of Makena is going •Pain, Pain, swelling, itching, bruisingorora ahard hardbump bumpatatthe theinjection injectionsite site swelling, itching, bruising should I receive Makena? on to see whether Makena reduces the number of babies who have serious • How • Hives • Hives Do not give yourself Makena injections. A healthcare professional problems shortly after birth or who die. will give you the Makena injection into your hip area (upper outer area Itching It is not known whether Makena is safe and effective in women who have • •Itching of the buttocks) once a week (every 7 days). • Nausea • Nausea other risk factors for preterm birth. • You will start receiving Makena injections anytime from 16 weeks and Diarrhea It is not known whether Makena is safe and effective in women less than • •Diarrhea 0 days of your pregnancy up to 20 weeks and 6 days of your pregnancy. 16 years old. • You will continue to receive Makena injections once weekly until week Makena is not intended for use to stop active preterm labor. 37 of yourpain pregnancy or when your baby is delivered, whichever hapIncreased painover overtime time • •Increased Who should not receive Makena? pens first. Oozingofofblood bloodororfluid fluid • •Oozing • Makena should not be used if you: Makena comes in ready-to-use vials. There are 5 doses of medicine in • Swelling • Swelling each vial. Your healthcare professional should give you only one dose Havenow nowororhave havehad hada ahistory historyofofblood bloodclots clotsororother otherblood bloodclotting clotting • •Have (1 mL) of Makena as prescribed each week. problems Makena should be used within 5 weeks after the first use. Havenow nowororhave havehad hada ahistory historyofofbreast breastcancer cancerororother otherhormonehormone• •Have sensitive cancers Haveunusual unusualvaginal vaginalbleeding bleedingnot notrelated relatedtotoyour yourcurrent currentpregnancy pregnancy • •Have • Have yellowing of your skin due to liver problems during your pregnancy • Have yellowing of your skin due to liver problems during your pregnancy • • Have liver problems, including liver tumors • Have liver problems, including liver tumors • Haveuncontrolled uncontrolledhigh highblood bloodpressure pressure • •Have Miscarriage(pregnancy (pregnancyloss lossbefore before2020weeks weeksofofpregnancy) pregnancy) • •Miscarriage • Pain, swelling, itching, bruising or a hard bump at the injection site Stillbirth(fetal (fetaldeath deathoccurring occurringduring duringororafter afterthe the20th 20thweek weekofofpregnancy) pregnancy) • •Stillbirth • Hives Hospitaladmission admissionforforpreterm pretermlabor labor • •Hospital • •Itching Preeclampsia(high (highblood bloodpressure pressureand andtoo toomuch muchprotein proteinininyour yoururine) urine) •AnAnallergy allergytotohydroxyprogesterone hydroxyprogesteronecaproate, caproate,castor castoroil, oil,ororany anyofofthe the • •Preeclampsia • Nausea Gestationalhypertension hypertension(high (highblood bloodpressure pressurecaused causedbybypregnancy) pregnancy) • •Gestational • Diarrhea Gestationaldiabetes diabetes • •Gestational Diabetesororprediabetes prediabetes • •Diabetes Oligohydramnios(low (lowamniotic amnioticfluid fluidlevels) levels) • •Oligohydramnios • • • • • • • M S H P G G O or p • • • • • S S S M wou ncy • 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: • • Blood clots. Symptoms of a blood clot may include: o Leg swelling o Redness in your leg • You will o A spot on your leg that is warm to touch o Leg that worsens you injections bend youronce foot weekly until week • You will pain continue to receivewhen Makena • Allergic reactions. Symptoms of an allergic reaction may include: o Hives o Itching each vial. Your healthcare professional should give you only o 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 Makena 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 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: • 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. 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) How should I store Makena? • Store Makena at room temperature (59° to 86°F or 15° to 30°C) • Store Makena in the original box to protect it from light • Store the Makena box upright • Makena should be used within 5 weeks after the first use • Keep Makena out of the reach of children would like more information, talk with your healthcare provider. You can ask k 17-519