Hydroxyprogesterone Caproate
DRUG DESCRIPTION
THE ACTIVE PHARMACEUTICAL INGREDIENT IN MAKENA IS HYDROXYPROGESTERONE CAPROATE.
THE CHEMICAL NAME FOR HYDROXYPROGESTERONE CAPROATE IS PREGN-4-ENE-3,20DIONE, 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:
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).
INDICATIONS
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.
DOSAGE AND ADMINISTRATION
DOSING
" 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
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.
DISCARD ANY UNUSED PRODUCT 5 WEEKS AFTER FIRST USE.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
MAKENA (250 MG/ML) IS A STERILE SOLUTION OF HYDROXYPROGESTERONE CAPROATE IN CASTOR OIL FOR INJECTION. EACH 5 ML MULTIDOSE VIAL CONTAINS 1250 MG HYDROXYPROGESTERONE CAPROATE.
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.
MANUFACTURED BY: HOSPIRA, INC. MCPHERSON, KS 67460. MARKETED BY: THER-RX CORPORATION CHESTERFIELD, MO 63005. REVISED: 08/2013
SIDE EFFECTS
FOR THE MOST SERIOUS ADVERSE REACTIONS TO THE USE OF PROGESTINS, SEE WARNINGS AND PRECAUTIONS.
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]
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
N/N CONTROL
N/N
MISCARRIAGE ( < 20 WEEKS)1 5/209 0/107
STILLBIRTH ( ? 20 WEEKS)2 6/305 2/153
TABLE 2 : SELECTED MATERNAL COMPLICATIONS
PREGNANCY COMPLICATION MAKENA
N=310
% CONTROL
N=153
%
ADMISSION FOR PRETERM LABOR1 16 13.8
PREECLAMPSIA OR GESTATIONAL HYPERTENSION 8.8 4.6
GESTATIONAL DIABETES 5.6 4.6
OLIGOHYDRAMNIOS 3.6 1.3
COMMON ADVERSE REACTIONS
THE MOST COMMON ADVERSE REACTION WAS INJECTION SITE PAIN, WHICH WAS REPORTED AFTER AT LEAST ONE INJECTION BY 34.8% OF THE MAKENA GROUP AND 32.7% OF THE CONTROL GROUP. TABLE 3 LISTS ADVERSE REACTIONS THAT OCCURRED IN ? 2% OF SUBJECTS AND AT A HIGHER RATE IN THE MAKENA GROUP THAN IN THE CONTROL GROUP.
TABLE 3 : ADVERSE REACTIONS OCCURRING IN ? 2% OF MAKENA-TREATED SUBJECTS AND AT A HIGHER RATE THAN CONTROL SUBJECTS
PREFERRED TERM MAKENA
N=310
% CONTROL
N=153
%
INJECTION SITE PAIN 34.8 32.7
INJECTION SITE SWELLING 17.1 7.8
URTICARIA 12.3 11.1
PRURITUS 7.7 5.9
INJECTION SITE PRURITUS 5.8 3.3
NAUSEA 5.8 4.6
INJECTION SITE NODULE 4.5 2
DIARRHEA 2.3 0.7
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.
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
READ THE MAKENA (HYDROXYPROGESTERONE CAPROATE INJECTION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS "
DRUG INTERACTIONS
IN VITRO DRUG-DRUG INTERACTION STUDIES WERE CONDUCTED WITH MAKENA. [SEE CLINICAL PHARMACOLOGY] NO IN VIVO DRUG-DRUG INTERACTION STUDIES WERE CONDUCTED WITH MAKENA.
PRECAUTIONS
THROMBOEMBOLIC DISORDERS
DISCONTINUE MAKENA IF AN ARTERIAL OR DEEP VENOUS THROMBOTIC OR THROMBOEMBOLIC EVENT OCCURS.
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.
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.
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).
DEPRESSION
MONITOR WOMEN WHO HAVE A HISTORY OF CLINICAL DEPRESSION AND DISCONTINUE MAKENA IF CLINICAL DEPRESSION RECURS.
JAUNDICE
CAREFULLY MONITOR WOMEN WHO DEVELOP JAUNDICE WHILE RECEIVING MAKENA AND CONSIDER WHETHER THE BENEFIT OF USE WARRANTS CONTINUATION.
HYPERTENSION
CAREFULLY MONITOR WOMEN WHO DEVELOP HYPERTENSION WHILE RECEIVING MAKENA AND CONSIDER WHETHER THE BENEFIT OF USE WARRANTS CONTINUATION.
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].
NONCLINICAL TOXICOLOGY
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.
USE IN SPECIFIC POPULATIONS
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.
LABOR AND DELIVERY
MAKENA IS NOT INTENDED FOR USE TO STOP ACTIVE PRETERM LABOR. THE EFFECT OF MAKENA IN ACTIVE LABOR IS UNKNOWN.
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.
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]
GERIATRIC USE
MAKENA IS NOT INTENDED FOR USE IN POSTMENOPAUSAL WOMEN. SAFETY AND EFFECTIVENESS IN POSTMENOPAUSAL WOMEN HAVE NOT BEEN ESTABLISHED.
RENAL IMPAIRMENT
NO STUDIES HAVE BEEN CONDUCTED TO EXAMINE THE PHARMACOKINETICS OF MAKENA IN PATIENTS WITH RENAL IMPAIRMENT.
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.
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.
OVERDOSE
THERE IS NO SPECIFIC TREATMENT FOR INLYTA OVERDOSE.
IN A CONTROLLED CLINICAL STUDY WITH INLYTA FOR THE TREATMENT OF PATIENTS WITH RCC, 1 PATIENT INADVERTENTLY RECEIVED A DOSE OF 20 MG TWICE DAILY FOR 4 DAYS AND EXPERIENCED DIZZINESS (GRADE 1).
IN A CLINICAL DOSE FINDING STUDY WITH INLYTA, SUBJECTS WHO RECEIVED STARTING DOSES OF 10 MG TWICE DAILY OR 20 MG TWICE DAILY EXPERIENCED ADVERSE REACTIONS WHICH INCLUDED HYPERTENSION, SEIZURES ASSOCIATED WITH HYPERTENSION, AND FATAL HEMOPTYSIS.
IN CASES OF SUSPECTED OVERDOSE, INLYTA SHOULD BE WITHHELD AND SUPPORTIVE CARE INSTITUTED.
CLINICAL PHARMACOLOGY
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.
PHARMACODYNAMICS
NO SPECIFIC PHARMACODYNAMIC STUDIES WERE CONDUCTED WITH MAKENA (HYDROXYPROGESTERONE CAPROATE INJECTION) .
PHARMACOKINETICS
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 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 (HYDROXYPROGESTERONE CAPROATE INJECTION) HAS NOT BEEN EVALUATED.
HEPATIC IMPAIRMENT: THE EFFECT OF HEPATIC IMPAIRMENT ON THE PHARMACOKINETICS OF MAKENA (HYDROXYPROGESTERONE CAPROATE INJECTION) HAS NOT BEEN EVALUATED.
DRUG INTERACTIONS
CYTOCHROME P450 (CYP) ENZYMES: AN IN VITRO 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. THE CLINICAL IMPLICATION OF THIS IN VITRO METABOLIC ACCELERATION IS NOT WELL UNDERSTOOD.
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.
THE METABOLIC INDUCTION POTENTIAL OF HYDROXYPROGESTERONE CAPROATE HAS NOT BEEN EVALUATED.
CLINICAL STUDIES
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 (HYDROXYPROGESTERONE CAPROATE INJECTION) 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 (HYDROXYPROGESTERONE CAPROATE INJECTION) (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 (HYDROXYPROGESTERONE CAPROATE INJECTION) -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)
DELIVERY OUTCOME MAKENA (HYDROXYPROGESTERONE CAPROATE INJECTION) 1
(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%]
COMPARED TO CONTROLS, TREATMENT WITH MAKENA (HYDROXYPROGESTERONE CAPROATE INJECTION) 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 (HYDROXYPROGESTERONE CAPROATE INJECTION) . 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 (HYDROXYPROGESTERONE CAPROATE INJECTION) -TREATED SUBJECTS DELIVERED PRIOR TO 25 WEEKS COMPARED TO 4.7% OF CONTROL SUBJECTS; SEE FIGURE 1.
FIGURE 1 : PROPORTION OF WOMEN REMAINING PREGNANT AS A FUNCTION OF GESTATIONAL AGE
THE RATES OF FETAL LOSSES AND NEONATAL DEATHS IN EACH TREATMENT ARM ARE DISPLAYED IN TABLE 5. DUE TO THE HIGHER RATE OF MISCARRIAGES AND STILLBIRTHS IN THE MAKENA (HYDROXYPROGESTERONE CAPROATE INJECTION) ARM, THERE WAS NO OVERALL SURVIVAL DIFFERENCE DEMONSTRATED IN THIS CLINICAL TRIAL.
TABLE 5 : FETAL LOSSES AND NEONATAL DEATHS
COMPLICATION MAKENA (HYDROXYPROGESTERONE CAPROATE INJECTION)
N=306A
N (%) B CONTROL
N=153
N (%) B
MISCARRIAGES < 20 WEEKS GESTATION C 5 (2.4) 0
STILLBIRTH 6 (2.0) 2 (1.3)
ANTEPARTUM STILLBIRTH 5 (1.6) 1 (0.6)
INTRAPARTUM STILLBIRTH 1 (0.3) 1 (0.6)
NEONATAL DEATHS 8 (2.6) 9 (5.9)
TOTAL DEATHS 19 (6.2) 11 (7.2)
A COMPOSITE NEONATAL MORBIDITY/MORTALITY INDEX EVALUATED ADVERSE OUTCOMES IN 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 (HYDROXYPROGESTERONE CAPROATE INJECTION) ARM (11.9% VS. 17.2%), THE NUMBER OF ADVERSE OUTCOMES WAS LIMITED AND THE DIFFERENCE BETWEEN ARMS WAS NOT STATISTICALLY SIGNIFICANT.
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 (HYDROXYPROGESTERONE CAPROATE INJECTION) -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
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.
SYNOPSIS:
Adverse Effects and Precautions
As for progestogens in general (see Progesterone).
There may be local reactions at the site of injection. Rarely,
coughing, dyspnoea, and circulatory disturbances may occur
during or immediately after injection of hydroxyprogesterone
caproate but can be avoided by injecting the drug very slow-
ly.
Pregnancy. Abnormalities reported in infants born to moth-
ers who had received hydroxyprogesterone during pregnancy
have included tetralogy of Fallot in one infant, genito-uri-
nary abnormalities in 2 infants and adrenocortical carcino-
ma in one infant.
Interactions
As for progestogens in general (see Progesterone).
Uses and Administration
Hydroxyprogesterone hexanoate is a progestogen structurally
related to progesterone that has been used for habit-
ual abortion and various menstrual disorders. In habitual
abortion associated with proven progesterone deficiency, sug-
gested doses have been 250 to 500 mg weekly by intramuscu-
lar injection during the first half of pregnancy.
Hydroxyprogesterone enanthate has also been used.