Download Prescribing Makena - Partnership for Prescription Assistance

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
•
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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