Page 30 - Makena Auto-Injector Patient Storybook
P. 30

 3 DOSAGE FORMS AND STRENGTHS
Subcutaneous injection: 275 mg/1.1 mL clear yellow solution in single-use auto-injector. Intramuscular injection: 250 mg/mL clear yellow solution in single-dose vials.
Intramuscular injection: 1250 mg/5 mL (250 mg/mL) clear yellow solution in multiple-dose vials.
4 CONTRAINDICATIONS
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).
5.5 Depression
Monitor women who have a history of clinical depression and discontinue Makena if clinical depression recurs.
5.6 Jaundice
Carefully monitor women who develop jaundice while receiving Makena and consider whether the benefit of use warrants continuation.
of membranes
7 D•RURGepIrNoTdEuRctAivCeTsIyOsNteSm and breast disorders: Cervical dilation, shortened cervix
continuing until 37 weeks of gestation or delivery, whichever occurred first.
No studies have been conducted to examine the pharmacokinetics of Makena in patients with hepatic
gesta[tSioeenCalnindiccaol nStuinduieisng(1u4.n1t)i.l]37 weeks of gestation or delivery, whichever occurred first. [See Clinical [See Clinical Studies (14.1).]
impairmeTnht.eMaackteinvaeispehxtaernmsivaeclyemuetitacbaoliziendgarnedhiepnatticinimMpaairmkentamiasy hreydducreoxthyeperlimogineatsiotenrone
Studies (14.1).]
Certain pregnancy-related fetal and maternal complications or events were
Certain pregnancy-related fetal and maternal complications or events were
of Makena.
Certaniunmperiecgalnlyanincyre-raeseladteindthfeMtaal kaenda-tmreatteedrnsuabljecotsmaps lcicoamtpioanresd otorceovnteronlts were numerically increased numerically increased in the Makena-treated subjects as compared to control
caproate.
subjects, including miscarriage and stillbirth, admission for preterm labor,
in thesuMbjaekcetsn, ian-ctlruedaintegdmsisucbajrericatgse ansdcsotimllbpirathre, dadtmoiscsoiontrfolr spurebtejermctsla,bionrc, luding miscarriage and stillbirth,
10 11
OVERDOSAGE
preeclampsia or gestational hypertension, gestational diabetes, and admispsreioecnlafmoprspiareortegremstatliaobnoalr,hyppreretecnlsaimonp, sgieastaotirongaelsdtiabtieotnesa,lanhdypertension, gestational diabetes, and
The chemical name for hydroxyprogesterone caproate is pregn-4-ene-3,20-
oligohydramnios (Tables 1 and 2). oligohoylidgroahmydnraiomsni(oTsa(bTleabsle1s a1 nadnd22))..
There have been no reports of adverse events associated with overdosage of Makena in clinical trials.
Table 1 Selected Fetal Complications Table 1 Selected Fetal Complications
dione, 17[(1-oxohexyl)oxy]. It has an empirical formula of C27H40O4 and a
1N = Total number of subjects enrolled prior to 20 weeks 0 days 2 N = Total number of subjects enrolled prior to 20 weeks 0 days
The structural formula is:
2N = Total number of subjects at risk ≥ 20 weeks N = Total number of subjects at risk ≥ 20 weeks
The structural formula is:
7
8
conducted with Makena.
Table 3 Adverse Reactions Occurring in ≥ 2% of Makena-Treated Subjects and at a Higher Rate than Control Subjects
  Preferred Term
Makena N=310 %
  Control N=153 %
   Injection site pain
  34.8
 32.7
Injection site swelling
 17.1
  7.8
 Urticaria
 12.3
  11.1
  Pruritus
  7.7
 5.9
Injection site pruritus
 5.8
  3.3
  Nausea
  5.8
 4.6
Injection site nodule
 4.5
  2.0
 Diarrhea
 2.3
  0.7
           In the clinical trial, 2.2% of subjects receiving Makena were reported as
In the clinical trial using intramuscular injection, 2.2% of subjects receiving Makena were reported
discontinuing therapy due to adverse reactions compared to 2.6% of control
as discubojnetcitnsu. Tinhge mthoesrtacpoymmduoneatdoveardsevererascetiornesatchtaiot lnesd tcoodmispcoanrteinduatotio2n.6in% of control subjects. The most
commbotnh agrdovueprssweere aucrttiicoanrisa tahnadtinlejedcttiondsiistecopnaitnin/suwaetliloingi(n1%boetahchg)r.oups were urticaria and injection site
pain/swelling (1% each).
Pulmonary embolus in one subject and injection site cellulitis in another subject
Pulmowneareryrepeomrtbedolausseirniouosnaedvseursbejerecatcationnds injMecatkioena-striteeatecdesllublijteisctsi.n another subject were reported as
serious adverse reactions in Makena-treated subjects.
6.2 Postmarketing Experience
Two Tchlienifcoalllowsitnugdaiedsverwseerreactcionsdhuacvteebdeeninidehnetiafiltehdyduprionsgtp-mosetanpopproavuasl ausle women, comparing Makena adminoifsMtearekednav.iaBescuaubsceutthaenseroeuasctiaonustoa-rienrjepcotortredtovoMluanktaerinlyafraodmainpiospteulraetdionas an intramuscular injection.
of uncertain size, it is not always possible to reliably estimate their frequency or
In the first study, injection site pain occurred in 3/30 (10%) of subjects who used the subcutaneous
establish a causal relationship to drug exposure.
auto-injector vs. 2/30 (7%) of subjects receiving intramuscular injection. In the second study, injection
 Body as a whole: Local injection site reactions (including erythema,
site pain occurred in 20/59 (34%) of subjects who used the subcutaneous auto-injector vs. 5/61 (8%)
urticaria, rash, irritation, hypersensitivity, warmth); fatigue; fever; hot
of subjects receiving intramuscular injection.
flashes/flushes
6.2 Postmarketing Experience
 Digestive disorders: Vomiting
The following adverse reactions have been identified during postapproval use of Makena. Because
 Infections: Urinary tract infection
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
 Nervous system disorders: Headache, dizziness
reliably estimate their frequency or establish a causal relationship to drug exposure.
• BodPyreagnsaancwy,hpouler:peLroiucmalaindjepcetriionnataslitceonredaiticotnios:nCse(rivniclaulding erythema, urticaria, rash, irritation, hypinecrosmenpsetietinvcitey,,pwreamrmatuthre);rufaptiugrue eo;f fmeevmebr;rahnoets flashes/flushes
• DigReesptrivoedudcitsivoerdsyesrtesm: Vaonmd bitrineagst disorders: Cervical dilation, shortened • Infeccetrivoinxs:Urinarytractinfection
• NerRveosupisrastyorsytedmisodrdiseorsr:dDeyrsp:nHeea,acdhaescthdeis,cdoimzzfoinrtess
• Pregnancy, puerperium and perinatal conditions: Cervical incompetence, premature rupture
 Skin: Rash
In vitro drug-drug interaction studies were conducted with Makena. [See • Respiratory disorders: Dyspnea, chest discomfort
Clinical Pharmacology (12.3).] No in vivo drug-drug interaction studies were • Skin: Rash
DRUG INTERACTIONS
  6 ADVERSE REACTIONS 5.76 HAyDpVeErRteSnEsRioEnACTIONS
In vitro drug-drug interaction studies were conducted with Makena. 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 [See Clinical Pharmacology (12.3).] No in vivo drug-drug interaction studies were conducted with Makena.
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Makena is indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. Fetal, neonatal, and maternal risks are discussed throughout labeling. Data from the placebo-controlled clinical trial and the infant follow-up safety study [see Clinical Studies (14.1, 14.2)] did not show a difference in adverse developmental outcomes between children of Makena-treated women and children of control subjects. However, these data are insufficient to determine a drug-associated risk of adverse developmental outcomes as none of the Makena-treated women received the drug during the first trimester of pregnancy. In animal reproduction studies, intramuscular administration of hydroxyprogesterone caproate to pregnant rats during gestation at doses 5 times the human dose equivalent based on a 60-kg human was not associated with adverse developmental outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
Reproduction studies of hydroxyprogesterone caproate administered to various animal species have been reported in the literature. In nonhuman primates, embryolethality was reported in rhesus monkeys administered hydroxyprogesterone caproate up to 2.4 and 24 times the human dose equivalent, but not in cynomolgus monkeys administered hydroxyprogesterone caproate at doses up to 2.4 times the human dose equivalent, every 7 days between days 20 and 146 of gestation. There were no teratogenic effects in either strain of monkey.
Reproduction studies have been performed in mice and rats at doses up to 95 and 5, respectively, times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to hydroxyprogesterone caproate.
8.2 Lactation
Risk Summary
Low levels of progestins are present in human milk with the use of progestin-containing products, including hydroxyprogesterone caproate. Published studies have reported no adverse effects of
For the most serious adverse reactions to the use of progestins, see Warnings
CarefFuollrythme omnoistot srewrioums eadnvewrsheoredaectvioenlosptohthyepuesreteonfspirongewsthinilse, sreecWeaivrinigngMs akena and consider whether
and Precautions (5).
the beandefiPtreocfaustieonws a(5r)r.ants continuation.
 6.1 Clinical Trials Experience 6 A D V E 6 . R 1 S CE l i R n Ei c Aa l C T T r i I a O l s N E S x p e r i e n c e
Because clinical trials are conducted under widely varying conditions, adverse
For thBeecmauossetcslienriicoaul strialdsvaerersceonrdeuacctetidounnsdteor wthiedeulysveaoryfinpgrocgonedsitiinosn,s,saedeveWrsearnings and Precautions (5).
reaction rates observed in the clinical trials of a drug cannot be directly reaction rates observed in the clinical trials of a drug cannot be directly
6.1 cColminpiacraedl TtoritahelsraEtexspinerthiencclineical trials of another drug and may not reflect
progestins on the breastfed child or on milk production.
compared to the rates in the clinical trials of another drug and may not reflect Becatuheseratecslinobicsaerlvetrdiainlspracreticec.onducted under widely varying conditions, adverse reaction rates
10 OVERDOSAGE
the rates observed in practice.
There have been no reports of adverse events associated with overdosage of
observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of
Makena is not indicated for use in women under 16 years of age. Safety and effectiveness in patients less than 16 years of age have not been established. A small number of women under age 18 years
In a vehicle (placebo)-controlled clinical trial of 463 pregnant women at risk In a vehicle (placebo)-controlled clinical trial of 463 pregnant women at risk
Makena in clinical trials. In the case of overdosage, the patient should be
another drug and may not reflect the rates observed in practice.
for spontaneous preterm delivery based on obstetrical history, 310 received 250 for spontaneous preterm delivery based on obstetrical history, 310 received 250
were studied; safety and efficacy are expected to be the same in women aged 16 years and above as
In a vehicle (placebo)-controlled clinical trial of 463 pregnant women at risk for spontaneous preterm
treated symptomatically.
mg of Makena and 153 received a vehicle formulation containing no drug by a mg of Makena and 153 received a vehicle formulation containing no drug by a
for users 18 years and older [see Clinical Studies (14)]. 8.6 Hepatic Impairment
delivewreyekblyasinetdramonuscoublasrteintrjeicatilonhibsetgoirnyn,in3g1a0t 1re6cteoi2v0edwe2e5ks0omf gesotaftiMonaaknedna and 153 received a vehicle weekly intramuscular injection beginning at 16 to 20 weeks of gestation and
1
formucolantiionnuincgounntatiiln3in7 gweneoksdorfugesbtaytiaonwoer edeklliyveirnyt,rawmhiuchsecvuelraorcicnujrercedtiofinrstb. e1 ginning at 16 to 20 weeks of
11 DESCRIPTION
8.4 Pediatric Use
In the case of overdosage, the patient should be treated symptomatically.
DESCRIPTION
The actimveoplheacrmualaceruwticaeliignghrtedoiefn4t i2n 8M.a6k0e.naHisyhdyrdoroxyprorgoegsetesrotenerocnaperocaatep, raoparotegeestxini.sts as white to The chemical name for hydroxyprogesterone caproate is pregn-4-ene-3,20-dione, 17[(1-oxohexyl)
Pregnancy Complication Pregnancy Complication
1
     Makena Makena
    n/N n/N
    Control Control
  n/N n/N
  Miscarriage (< 20 weeks) 1
Miscarriage (< 20 weeks) 2
   5/209 5/209
    0/107 0/107
  Stillbirth (≥ 20 weeks) 2 1 Stillbirth (≥ 20 weeks)
   6/305 6/305
     2/153 2/153
   practically white crystals or powder with a melting point of 120°-124°C.
oxy]. It has an empirical formula of C27H40O4 and a molecular weight of 428.60. Hydroxyprogesterone
   Table 2 Selected Maternal Complications Table 2 Selected Maternal Complications
11Other than delivery admission. Other than delivery admission.
H3C O O
CH 3
caproate exists as white to practically white crystals or powder with a melting point of 120°-124°C.
     O
       Pregnancy Complication Pregnancy Complication
Makena Makena N=310 N=310
 % %
Control Control N=153 N=153
   % %
Admission for preterm labor11 Admission for preterm labor
 16.0 16.0
 13.8 13.8
    Preeclampsia or gestational hypertension Preeclampsia or gestational hypertension
 8.8 8.8
 4.6 4.6
  Gestational diabetes Gestational diabetes
 5.6 5.6
 4.6 4.6
    Oligohydramnios Oligohydramnios
 3.6 3.6
  1.3 1.3
     CH3 HH
H
            Common Adverse Reactions:
Makena is a clear, yellow, sterile, non-pyrogenic solution for intramuscular
Common Adverse Reactions: Common Adverse Reactions:
dose vial for intramuscular use contains hydroxyprogesterone caproate USP, 250 mg/mL (25% w/v), in a preservative-free solution containing castor oil USP (30.6% v/v) and benzyl benzoate USP (46% v/v). Each
O
 Makena is a clear, yellow, sterile, non-pyrogenic solution for intramuscular (vials) or subcutaneous (auto-injector) injection. Each 1.1 mL Makena auto-injector for subcutaneous use and each 1 mL single-
 The most common adverse reaction with intramuscular injection was injection site pain, which was reported
injection. Each 1 mL single dose vial contains hydroxyprogesterone caproate
The most common adverse reaction was injection site pain, which was reported 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
5 mL multi-dose vial contains hydroxyprogesterone caproate USP, 250 mg/mL (25% w/v), in castor oil USP
after at least one injection by 34.8% of the Makena group and 32.7% of the after at least one injection by 34.8% of the Makena group and 32.7% of the
USP, 250 mg/mL (25% w/v), in castor oil USP (30.6% v/v) and benzyl
adversereacotinotnroslgthroautpo.Tccabulrere3dlisintsa≥dv2e%rseorfeascutibojnescthsataoncdcuarrtedaihni≥gh2e%rorfasteubijnecthseMakenagroupthaninthe control group. Table 3 lists adverse reactions that occurred in ≥ 2% of subjects
(28.6%)andbenzylbenzoateUSP(46%v/v)withthepreservativebenzylalcoholNF(2%v/v).
control groupan.d at a higher rate in the Makena group than in the control group. and at a higher rate in the Makena group than in the control group.
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
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