Download Makena® (hydroxyprogesterone caproate injection) is supported via

Frequently asked questions
and troubleshooting tips
How do I help my patient obtain copay assistance?
If your patient feels her out-of-pocket cost is too high, she may be
eligible to participate in the Copay Assistance Program, which helps
lower the out-of-pocket cost of Makena® (hydroxyprogesterone
caproate injection) (applies to copays, coinsurance, and deductibles)
for patients who qualify.
•T
o 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 at no cost
through the Makena Patient Assistance Program.
• When submitting the patient’s prescription, be sure to check “Patient
does not have insurance” when completing a Makena ePrescription
or in Step 1 of the prescription form
Eligibility for Assistance Programs
Eligibility criteria include:
• Patient meets the FDA-approved indication (pregnant with a singleton
with a history of singleton spontaneous preterm birth <37 weeks
of gestation)1
In compliance with federal regulations, patients insured by a governmentfunded program (e.g., Medicaid, TRICARE, etc.) are not eligible.
My patient’s insurance company requires a prior
authorization. Can Makena Care Connection help?
As with many specialty injectable drugs, some insurance plans
may require a prior authorization for Makena; therefore, you may be
contacted by the Makena Care Connection, the assigned pharmacy,
and/or the insurance plan with questions regarding prior authorization
for Makena.
• Submit a prior authorization through eMakena at iAssist.com for the
convenience of submitting quickly, in one place
How does my patient obtain Makena refills?
About one week before a patient is due for a refill, her pharmacy will
call her to confirm shipment and collect payment. If your patient does
not receive this call, have her call the pharmacy directly, which is listed
on the patient’s current Makena box. If she is unable to locate the
pharmacy name, have her 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
hcp.com/pi.
My patient doesn’t speak English. Can the Makena Care
Connection help?
The Makena Care Connection recognizes the diverse patient population
that may need information related to their Makena prescription. We
are pleased to offer translation services in approximately 20 different
languages to help with the processing of their prescription.
Reference: 1. Makena® (hydroxyprogesterone caproate injection) prescribing information,
AMAG Pharmaceuticals, 2016.
Marketed by AMAG Pharmaceuticals, Inc.
Waltham, MA 02451
©2016 AMAG Pharmaceuticals, Inc. 17-722-1 06/16
Makena (hydroxyprogesterone caproate injection)
is supported via the Makena Care Connection
®
®
STEP 1
STEP 2
STEP 3
Healthcare provider
submits an ePrescription
at iAssist.com or a fax
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
pharmacy for
processing
The pharmacy
verifies insurance
coverage, collects the
patient’s out-of-pocket
cost, and ships
the product
If prescribing through eMakena,
visit iAssist.com to check your
patient’s status. If submitting
the prescription form via fax,
you should receive a confirmation
of receipt via fax within a few
minutes. If you do not receive
this communication, please
contact the Makena Care
Connection to find out if your
patient’s prescription has
been received.
—or—
Submit online
through
eMakena at
iAssist.com
The results of the investigation
will be relayed to both you and
your patient over the phone.
• If the patient cannot afford
her out-of-pocket cost,
she should ask the Makena
Care Coordinator about
financial assistance
FAX
Once the 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 pharmacy will
call the office to confirm the
shipping address and ensure
that the office will be open on
the scheduled delivery date
Submit a fax
form at
1-800-847-3418
Makena (hydroxyprogesterone caproate injection) 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 back cover for important safety information
and attached full prescribing information for
Makena (hydroxyprogesterone caproate injection).
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
When in doubt, ask
STEP 1 — Complete Patient and Insurance Information (Please Include Copies of Front and Back of Insurance Cards)
Jane
Smith
First Name
Last Name
123 Main Street
Address
New York
Home Phone #
(212) 555-9109
Cell Phone #
1/2/79
Healthplan USA
123456789
Best Time to Contact
2/2/77
XXXXXXXXXXX
Policy ID #
(212) 555-4040
Primary Language if Not English:
Date of Birth
Cardholder Name
Date of Birth
Email
spouse
Primary Insurance Phone #
none
PBM Phone #
Robert Smith
E
L
Primary Medical Insurance
Work Phone #
(212) 555-3030
Group #
Healthplan USA
[email protected]
BIN #
937654
ID #
ZIP
(212) 555-5678
9–5pm
XXXXXX
Prescription Drug Insurer/Pharmacy Benefit Manager (PBM)
10101
State
(212) 555-1234
STEP 1
Patient does not have insurance.
MI
NY
City
Known Allergies:
D.
Relationship to Cardholder
Note: If a patient has secondary insurance, please have her provide a copy of the insurance card (front and back).
STEP 2 — Read and Sign Patient Authorization
STEP 2
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 AMAG Pharmaceuticals, Inc. and its subsidiaries, representatives, agents and contractors
including the Makena Care Connection (collectively “AMAG Pharmaceuticals”) 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 educational or treatment support materials and requests for participation in patient programs related to treatment. I understand that my Protected Health Information disclosed under this Authorization may be
redisclosed by AMAG Pharmaceuticals 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 AMAG Pharmaceuticals,
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.
P
X Patient or Legal Guardian Signature:
M
A
Self
Relationship to Patient:
Date:
1/5/16
As a patient who has been prescribed Makena, I have access to My Adherence Program (“Program”), a program designed to help me stay on track with treatment and provide me with educational information throughout my pregnancy.
I understand that my participation in the Program will mean that I may be contacted via phone, email, and mail by representatives of NurseWise, a division of Centene Corporation and business partner of AMAG Pharmaceuticals that
administers the Program. By signing below, I acknowledge that I am voluntarily choosing to participate in this Program and I understand that my failure to enroll in the Program will not affect my treatment with Makena or eligibility
for any benefits that I may be eligible to receive. If I decide to participate in the Program, I understand and agree that the data provided to NurseWise, which may include Protected Health Information will be specifically identifiable
to me or my baby and will be used by NurseWise solely in the provision of the Program. I further understand that any data collected in the provision of those services for uses outside of the Program will be de-identified and will not
be specifically identifiable to me or my baby, and may be used by NurseWise, AMAG Pharmaceuticals or their affiliated companies and agents for their internal business purposes. I further acknowledge and give permission for these
entities to publish such data in an aggregate format in a medical journal or other similar publication. I understand that I may discontinue participation in the Program or withdraw my consent to use my medical information at any
time, by calling 1-844-660-0867; or writing My Adherence Program, c/o NurseWise, 7700 Forsyth Blvd., Clayton, MO 63105.
X Patient or Legal Guardian Signature:
X
E
STEP 3 — Patient Eligibility
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
of gestation)? Please see full prescribing information. ✓Yes
No
Current Gestational Age:
8
weeks
0
days
Is the patient currently receiving Makena?
Is the patient currently receiving compounded HPC (“17P”)?
STEP 4 — Complete and Sign Makena Rx
Johnson, Allen
Date recorded:
Yes
Yes
✓No
✓No
City
General OB
Practice Name
(212) 555-1112
Office Phone #
STEP 4
XXXXXXXXXX
XXXXXXX
NPI #
Office Tax ID #
XXXXXXXXXX
NY
State
10101
ZIP
(212) 555-1113
Rx: Makena (hydroxyprogesterone caproate injection) 250 mg/mL (J1725)
✓Dispense 4 x 1 mL single-dose,
✓18-g needle & 3 mL syringe 4
preservative-free vials
✓21-g, 1½” needle 4 #
(64011-247-02) X 5 refills
Sig: Inject 1 mL IM each week
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. If the patient is currently on the compounded form of IM HPC (“17P”) and
is changing to Makena mid-therapy, please check the “patient is currently receiving compounded 17P” box.
Please note that this form contains both ICD-9 and ICD-10 codes.
Other:
Office Fax #
Medicaid Provider #
Lucy Taylor
Direct Phone #
(212) 555-1115
[email protected]
After-hours Phone #
Preferred Method of Communication
#
(212) 555-1114
Office Contact(s)
Email
Phone
Preferred Injection Setting:
Healthcare Provider Office
✓Makena @ Home by Optum® home nursing
services, if approved by insurance
Makena @ Home
,
if approved by insurance
✓Fax
Email
Please Ship Makena to:
Prescriber
✓ Patient
Desired Start 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. Some insurance companies will not approve Makena
until after the patient reaches 13 weeks’ gestation. If the prescription is submitted prior to 13 weeks’ gestation, the
Makena Care Connection will hold the prescription until the patient reaches 13 weeks’ gestation, when the
prescription will be processed.
Home administration of FDA-approved Makena in the comfort of her home or wherever may be convenient for the
patient may be an option, if approved by her insurer. Select Makena @Home by Optum home nursing services or
alternatively, you can select Makena @Home and write in your preferred home health agency.
3/1/16
Dispense As Written/Do Not Substitute ✓
DAW
Date:
1/5/16
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.
Fax completed form and insurance cards (front and back) to: 1-800-847-3413.
1-800-847-3418 or
[email protected]
If prescribing via eMakena, you can log
in at iAssist.com to check the status of
the Makena prescription.
If you know which pharmacy is dispensing
your patient’s prescription, you can call
it directly.
Acaria
800-511-5144
Accredo Health Group, Inc.
888-608-9010
Cigna Tel-Drug Home Delivery
Pharmacy Services
800-351-3606
CVS Caremark Specialty Pharmacy
800-237-2767
Exactus
866-458-9246
Humana Pharmacy, Inc.
855-264-0104
Option Care
855-275-9647
Walgreens Specialty Pharmacy
888-347-3416
STEP 5 — Read and Sign Prescriber Authorization
X Prescriber’s Signature:
Makena Care Connection
Prime Therapeutics Specialty
Pharmacy
877-627-6337
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 contact the Makena Care
Connection® directly if you or the patient
are ever in doubt regarding the status of
the Makena prescription.
BriovaRx of Maine, Inc.
855-427-4682
STEP 3
O09.213 Supervision of pregnancy with history of preterm labor, third trimester
O09.219 Supervision of pregnancy with history of preterm labor, unspecified trimester
1/5/16
By signing the HIPAA waiver, the patient allows the Makena Care Connection to communicate with the HCP,
insurer, and 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 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).
By opting in to the My Adherence Program, the patient consents to be paired with a dedicated maternal health
nursing specialist who will help promote compliance through weekly check-ins, educational tools, and support
services, at no cost.
1/5/16
✓ O09.212 Supervision of pregnancy with history of preterm labor, second trimester
9876 Elm Street
New York
Date:
ICD-10 Code:
Prescriber’s Name (Last, First)
Address
Self
Relationship to Patient:
Complete the Makena® (hydroxyprogesterone caproate injection) 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).
If your patient does not have insurance, check the uninsured box—she may be eligible to participate in the
Makena Patient Assistance Program.
Let your patients know that timely communication is important. Tell your patients to expect a phone call from
the Makena Care Connection and/or the pharmacy.
• Calls from the Makena Care Connection will display as “MCC” or a 972 area code on caller ID
• The pharmacy’s number may show as an “unknown” or 800 number
• Makena will not be shipped until payment is collected and the shipping address is verified
Date:
1/5/16
©2016 AMAG Pharmaceuticals, Inc. 17-973-1a
07/16
Please see back cover for important safety information
and attached full prescribing information for Makena
(hydroxyprogesterone caproate injection).
Please see back cover for important
safety information and attached full
prescribing information for Makena
(hydroxyprogesterone caproate injection).
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)
•
•
•
DOSAGE AND ADMINISTRATION
Administer intramuscularly at a dose of 250 mg (1 mL) once weekly
Begin treatment between 16 weeks, 0 days and 20 weeks, 6 days of gestation
Continue administration once weekly until week 37 (through 36 weeks, 6 days) of
gestation or delivery, whichever occurs first (2.1)
DOSAGE FORMS AND STRENGTHS
1 mL single dose vial contains 250 mg of hydroxyprogesterone caproate. 5 mL
multidose vial (250 mg/mL) contains 1250 mg hydroxyprogesterone caproate. (3)
CONTRAINDICATIONS
• Current or history of thrombosis or thromboembolic disorders (4)
•Known or suspected breast cancer, other hormone-sensitive cancer, or history of
these conditions (4)
• Undiagnosed abnormal vaginal bleeding unrelated to pregnancy (4)
• Cholestatic jaundice of pregnancy (4)
• Liver tumors, benign or malignant, or active liver disease (4)
• Uncontrolled hypertension (4)
WARNINGS AND PRECAUTIONS
•Thromboembolic disorders: Discontinue if thrombosis or thromboembolism
occurs (5.1)
• Allergic reactions: Consider discontinuing if allergic reactions occur (5.2)
•Decreased glucose tolerance: Monitor prediabetic and diabetic women receiving
Makena (5.3)
•Fluid retention: Monitor women with conditions that may be affected by fluid
retention, such as preeclampsia, epilepsy, cardiac or renal dysfunction (5.4)
•Depression: Monitor women with a history of clinical depression; discontinue
Makena if depression recurs (5.5)
ADVERSE REACTIONS
Most common adverse reactions reported in ≥ 2% of subjects and at a higher rate in the
Makena group than in the control group are injection site reactions (pain [35%], swelling
[17%], pruritus [6%], nodule [5%]), urticaria (12%), pruritus (8%), nausea (6%), and
diarrhea (2%). (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact AMAG Pharmaceuticals
at 1-877-411-2510 or FDA at 1‑800‑FDA‑1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Pregnancy: Controlled studies show no increase in congenital anomalies, including
genital abnormalities in male or female infants, from exposure during pregnancy to
hydroxyprogesterone caproate. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient
labeling.
Revised 04/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Preparation and Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Thromboembolic Disorders
5.2 Allergic Reactions
5.3 Decrease in Glucose Tolerance
5.4 Fluid Retention
5.5 Depression
5.6 Jaundice
5.7 Hypertension
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Labor and Delivery
10
11
12
13
14
15
16
17
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
2.1Dosing
• Administer intramuscularly at a dose of 250 mg (1 mL) once weekly (every 7 days) by a
healthcare provider
• Begin treatment between 16 weeks, 0 days and 20 weeks, 6 days of gestation
• Continue administration once weekly until week 37 (through 36 weeks, 6 days) of gestation or
delivery, whichever occurs first
2.2 Preparation and Administration
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. Makena is a clear, yellow solution. Do not use
if solid particles appear or if the solution is cloudy.
Instructions for administration:
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 multidose vial is used, discard any unused product 5 weeks after first use.
3
DOSAGE FORMS AND STRENGTHS
Makena (250 mg/mL) is a sterile solution of hydroxyprogesterone caproate in castor oil for injection.
Each 1 mL single dose vial contains 250 mg hydroxyprogesterone caproate. Each 5 mL multidose vial
contains 1250 mg hydroxyprogesterone caproate.
4CONTRAINDICATIONS
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
5
WARNINGS AND PRECAUTIONS
5.1 Thromboembolic Disorders
Discontinue Makena if an arterial or deep venous thrombotic or thromboembolic event occurs.
5.2 Allergic Reactions
Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use of Makena or
with other products containing castor oil. Consider discontinuing the drug if such reactions occur.
5.3 Decrease in Glucose Tolerance
A decrease in glucose tolerance has been observed in some patients on progestin treatment. The
mechanism of this decrease is not known. Carefully monitor prediabetic and diabetic women while they
are receiving Makena.
5.4 Fluid Retention
Because progestational drugs may cause some degree of fluid retention, carefully monitor women
with conditions that might be influenced by this effect (e.g., preeclampsia, epilepsy, migraine, asthma,
cardiac or renal dysfunction).
5.5Depression
Monitor women who have a history of clinical depression and discontinue Makena if clinical depression
recurs.
5.6Jaundice
Carefully monitor women who develop jaundice while receiving Makena and consider whether the
benefit of use warrants continuation.
5.7Hypertension
Carefully monitor women who develop hypertension while receiving Makena and consider whether the
benefit of use warrants continuation.
6
ADVERSE REACTIONS
For the most serious adverse reactions to the use of progestins, see Warnings and Precautions (5).
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug
and may not reflect the rates observed in practice.
In a vehicle (placebo)-controlled clinical trial of 463 pregnant women at risk for spontaneous preterm
delivery based on obstetrical history, 310 received 250 mg of Makena and 153 received a vehicle
formulation containing no drug by a weekly intramuscular injection beginning at 16 to 20 weeks of
gestation and continuing until 37 weeks of gestation or delivery, whichever occurred first.1 [See Clinical
Studies (14.1).]
Certain pregnancy-related fetal and maternal complications or events were numerically increased
in the Makena-treated subjects as compared to control subjects, including miscarriage and stillbirth,
admission for preterm labor, preeclampsia or gestational hypertension, gestational diabetes, and
oligohydramnios (Tables 1 and 2).
*
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
CLINICAL STUDIES
14.1 Clinical Trial to Evaluate Reduction of Risk of Preterm Birth
14.2 Infant Follow-Up Safety Study
REFERENCES
HOW SUPPLIED/STORAGE AND HANDLING
PATIENT COUNSELING INFORMATION
Sections or subsections omitted from the full prescribing information are not listed
Table 2 Selected Maternal Complications
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Hydroxyprogesterone caproate is a synthetic progestin. The mechanism by which hydroxyprogesterone
caproate reduces the risk of recurrent preterm birth is not known.
Common Adverse Reactions:
The most common adverse reaction was injection site pain, which was reported after at least one
injection by 34.8% of the Makena group and 32.7% of the control group. Table 3 lists adverse
reactions that occurred in ≥ 2% of subjects and at a higher rate in the Makena group than in the
control group.
akena is a clear, yellow, sterile, non-pyrogenic solution for intramuscular injection. Each 1 mL
M
single dose vial contains hydroxyprogesterone caproate USP, 250 mg/mL (25% w/v), in castor
oil USP (30.6% v/v) and benzyl benzoate USP (46% v/v). 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).
Table 3 Adverse Reactions Occurring in ≥ 2% of Makena-Treated Subjects and at a
Higher Rate than Control Subjects
In the clinical trial, 2.2% of subjects receiving Makena were reported as discontinuing therapy due
to adverse reactions compared to 2.6% of control subjects. The most common adverse reactions
that led to discontinuation in both groups were urticaria and injection site pain/swelling (1% each).
Pulmonary embolus in one subject and injection site cellulitis in another subject were reported as
serious adverse reactions in Makena-treated subjects.
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
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.
postmenopausal women have not been established.
Safety and effectiveness in
12.2 Pharmacodynamics
No specific pharmacodynamic studies were conducted with Makena.
12.3 Pharmacokinetics
Absorption: Peak serum levels of hydroxyprogesterone caproate appeared after 3-7 days in nonpregnant female subjects following a single intramuscular injection of 1000 mg hydroxyprogesterone
caproate. Based on pharmacokinetic analysis of five non-pregnant female subjects who received
a single intramuscular administration of 1000 mg hydroxyprogesterone caproate, the mean (±SD)
Cmax is estimated to be 27.8 (±5.3) ng/mL, and the Tmax is estimated to be 4.6 (±1.7) days. The
elimination half-life of hydroxyprogesterone caproate was 7.8 (±3.0) days. Once-weekly intramuscular
administration of 1000 mg hydroxyprogesterone caproate to non-pregnant women resulted in trough
concentration of 60.0 (±14) ng/mL after 13 weeks. The pharmacokinetics of the 250 mg dose of
hydroxyprogesterone caproate has not been evaluated.
Distribution: Hydroxyprogesterone caproate binds extensively to plasma proteins including albumin
and corticosteroid binding globulins.
Metabolism: In vitro studies have shown that hydroxyprogesterone caproate can be metabolized
by human hepatocytes, both by phase I and phase II reactions. Hydroxyprogesterone caproate
undergoes extensive reduction, hydroxylation and conjugation. The conjugated metabolites include
sulfated, glucuronidated and acetylated products. In vitro data indicate that the metabolism of
hydroxyprogesterone caproate is predominantly mediated by CYP3A4 and CYP3A5. The in vitro
data indicate that the caproate group is retained during metabolism of hydroxyprogesterone caproate.
Excretion: Both conjugated metabolites and free steroids are excreted in the urine and feces, with
the conjugated metabolites being prominent. Following intramuscular administration to pregnant
women at 10-12 weeks gestation, approximately 50% of a dose was recovered in the feces and
approximately 30% recovered in the urine.
Specific Populations
Renal Impairment: The effect of renal impairment on the pharmacokinetics of Makena has not been
evaluated.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Makena has not
been evaluated.
Drug Interactions
Cytochrome P450 (CYP) enzymes: An in vitro inhibition study using human liver microsomes and CYP
isoform-selective substrates indicated that hydroxyprogesterone caproate increased the metabolic
rate of CYP1A2, CYP2A6, and CYP2B6 by approximately 80%, 150%, and 80%, respectively.
However, in another in vitro study using human hepatocytes under conditions where the prototypical
inducers or inhibitors caused the anticipated increases or decreases in CYP enzyme activities,
hydroxyprogesterone caproate did not induce or inhibit CYP1A2, CYP2A6, or CYP2B6 activity.
Overall, the findings indicate that hydroxyprogesterone caproate has minimal potential for CYP1A2,
CYP2A6, and CYP2B6 related drug-drug interactions at the clinically relevant concentrations.
In vitro data indicated that therapeutic concentration of hydroxyprogesterone caproate is not likely to
inhibit the activity of CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Hydroxyprogesterone caproate has not been adequately evaluated for carcinogenicity.
No reproductive or developmental toxicity or impaired fertility was observed in a multigenerational
study in rats. 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)
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.
Four Makena-treated subjects were lost to follow-up. They were counted as deliveries at
their gestational ages at time of last contact (184, 220, 343 and 364 weeks).
Adjusted for interim analysis.
10OVERDOSAGE
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.
1
11DESCRIPTION
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:
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.
2
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
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
15REFERENCES
1
Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alphahydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379-85.
Northen A, Norman G, Anderson K, et al. Follow-up of children exposed in utero to 17 alphahydroxyprogesterone caproate. Obstet & Gynecol. 2007;110:865-872.
2
16
HOW SUPPLIED/STORAGE AND HANDLING
Makena (NDC 64011-247-02) is supplied as 1 mL of a sterile solution in a single dose glass vial.
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.
Table 5 Fetal Losses and Neonatal Deaths
Each 1 mL vial contains hydroxyprogesterone caproate USP, 250 mg/mL (25% w/v), in castor oil USP
(30.6% v/v) and benzyl benzoate USP (46% v/v).
Single unit carton: Contains one 1 mL single dose vial of Makena containing 250 mg of
hydroxyprogesterone caproate.
Makena (NDC 64011-243-01) is supplied as 5 mL of a sterile 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 multidose vials within 5 weeks after
first use.
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
B
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.
Patient Information
Makena (mah-KEE-na)
(hydroxyprogesterone caproate injection) 250 mg/mL
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)].
Distributed by:
AMAG Pharmaceuticals, Inc.
Waltham, MA 02451
04/2016
What is Makena?
Makena is a prescription hormone medicine (progestin) used in women who
are pregnant and who have delivered a baby too early (preterm) in the past.
Makena is used in these women to help lower the risk of having a preterm
baby again.
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 other
ingredients in Makena. See the end of this patient leaflet for a complete list
of the ingredients in Makena.
• Diabetes or prediabetes
• Epilepsy
• Migraine headaches
• Asthma
• Heart problems
• Kidney problems
• Depression
• High blood pressure
Makena is for women who:
• Are pregnant with one baby
• Have had a preterm delivery of one baby in the past
Tell your healthcare provider about all the medicines you take, including
prescription and non-prescription medicines, vitamins, and herbal
supplements.
How well does Makena work?
Makena was studied in women who were at risk for having a preterm baby
because they had previously given birth to a preterm baby. In the main
study, about 37 of 100 women who received Makena gave birth preterm
(before 37 weeks of pregnancy), compared to about 55 of 100 women
who did not receive Makena. Another study of Makena is going on to see
whether Makena reduces the number of babies who have serious problems
shortly after birth or who die.
Makena may affect the way other medicines work, and other medicines may
affect how Makena works.
Read this Patient Information Leaflet before you receive Makena. There may
be new information. This information does not take the place of talking to
your healthcare provider about your medical condition or treatment.
It is not known whether Makena is safe and effective in women who have
other risk factors for preterm birth.
It is not known whether Makena is safe and effective in women less than 16
years old.
Makena is not intended for use to stop active preterm labor.
Who should not receive Makena?
Makena should not be used if you:
• Have now or have had a history of blood clots or other blood clotting
problems
• Have now or have had a history of breast cancer or other hormonesensitive cancers
• Have unusual vaginal bleeding not related to your current pregnancy
• Have yellowing of your skin due to liver problems during your pregnancy
• Have liver problems, including liver tumors
• Have uncontrolled high blood pressure
Know the medicines you take. Keep a list of them to show your healthcare
provider and pharmacist when you get a new medication.
How should I receive Makena?
• Do not give yourself Makena injections. A healthcare professional will
give you the Makena injection into your hip area (upper outer area of the
buttocks) once a week (every 7 days).
• 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 once weekly until week 37 of
your pregnancy or when your baby is delivered, whichever happens first.
Makena comes in ready-to-use vials. There are either 1 or 5 doses of
medicine in each vial. Your healthcare professional should give you only one
dose (1 mL) of Makena as prescribed each week.
Makena supplied in multidose 5 mL vials should be used within 5
weeks after the first use.
It is very important that you do not miss a dose of 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
o A spot on your leg that is warm to touch
o Leg pain that worsens when you bend your foot
• Allergic reactions. Symptoms of an allergic reaction may include:
o Hives
o Itching
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.
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 5 mL multidose vials should be used within 5 weeks after the
first use
• Keep Makena 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
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 AMAG Pharmaceuticals
Customer Service at the toll free number 1-877-411-2510.
To refill a prescription or to check on prescription status, call the 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 and benzyl benzoate. 5 mL multidose vials
also contain benzyl alcohol (a preservative)