Hydroxyprogesterone caproate: Difference between revisions

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{{DrugProjectFormSinglePage
{{DrugProjectFormSinglePage
|authorTag={{anusha}}
|authorTag={{AJ}}
|genericName=Hydroxyprogesterone
|genericName=Hydroxyprogesterone caproate
|aOrAn=a
|aOrAn=a
|drugClass=progestin
|drugClass=[[progestin]] and [[endocrine|endocrine-metabolic]] agent
|indicationType=treatment
|indicationType=treatment
|indication=indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.
|indication=indicated to reduce the [[risk]] of [[preterm birth]] in women with a singleton [[pregnancy]] who have a history of singleton [[preterm birth|spontaneous preterm birth]]
|adverseReactions=injection site reactions (pain [35%], [[swelling]] [17%], pruritus [6%], nodule [5%]), [[urticaria]] (12%), [[pruritus]] (8%), [[nausea]] (6%), and [[diarrhea]] (2%).
|adverseReactions=[[injection site reactions]], [[pain]], [[swelling]], [[pruritus]], [[nodule]], [[urticaria]], [[nausea]], and [[diarrhea]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=Used 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.
|fdaLIADAdult=* Used to reduce the [[risk]] of [[preterm birth]] in women with a singleton [[pregnancy]] who have a history of singleton [[preterm birth|spontaneous preterm birth]]. The effectiveness of Hydroxyprogesterone caproate is based on improvement in the proportion of women who [[delivery|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.
* Limitation of use: While there are many risk factors for [[preterm birth]], [[safety]] and [[efficacy]] of Hydroxyprogesterone caproate 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====
====Dosing Information====
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
* Administer [[intramuscularly]] at a dose of 250 mg (1 mL) once weekly (every 7 days) by a healthcare provider
Continue administration once weekly until week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever occurs first.
* Begin treatment between 16 weeks, 0 days and 20 weeks, 6 days of [[gestation]]
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Hydroxyprogesterone caproate in adult patients.
Continue administration once weekly until week 37 (through 36 weeks, 6 days) of [[gestation]] or [[delivery]], whichever occurs first.
|offLabelAdultNoGuideSupport=Amenorrhea
 
Endometrial carcinoma
=====Preparation and Administration=====
Estrogen measurement, Endogenous; Diagnosis
 
|fdaLIADPed=safety and effectiveness have not been demonstrated in pediatric patients younger than 16 years.
* Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Hydroxyprogesterone caproate is a clear, yellow solution. Do not use if solid particles appear or if the solution is cloudy.
safety and efficacy have only been demonstrated in women with a prior spontaneous singleton preterm birth.
 
not to be used in women with multiple gestations or other risk factors for preterm birth.
* Instructions for administration:
 
:* Clean the vial top with an alcohol swab before use.
:* Draw up 1 mL of drug into a 3 mL syringe with an 18 gauge needle.
:* Change the needle to a 21 gauge 1 1/2 inch needle.
:* 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.
:* Applying pressure to the injection site may minimize bruising and swelling.
Discard any unused product 5 weeks after first use.
|offLabelAdultGuideSupport=* There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Hydroxyprogesterone caproate in adult patients.
|offLabelAdultNoGuideSupport=* [[Amenorrhea]]
* [[Endometrial carcinoma]]
* [[Estrogen]] measurement, [[Endogenous]]; [[Diagnosis]]
|fdaLIADPed=There is limited information regarding <i>FDA-Label Guideline-Supported Use</i> of Hydroxyprogesterone caproate in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Hydroxyprogesterone caproate in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Hydroxyprogesterone caproate in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Hydroxyprogesterone caproate in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Hydroxyprogesterone caproate in pediatric patients.
|contraindications=Current or history of thrombosis or thromboembolic disorders
|contraindications=* Do not use Hydroxyprogesterone caproate in women with any of the following conditions:
* Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions
:* Current or history of [[thrombosis]] or [[thromboembolic disorders]]
* Undiagnosed abnormal vaginal bleeding unrelated to pregnancy
:* Known or suspected [[breast cancer]], other [[breast cancer|hormone-sensitive cancer]], or history of these conditions
* Cholestatic jaundice of pregnancy
:* Undiagnosed abnormal [[vaginal bleeding]] unrelated to [[pregnancy]]
* Liver tumors, benign or malignant, or active liver disease
:* [[Cholestatic jaundice of pregnancy]]
* Uncontrolled hypertension
:* [[Liver Tumors|Liver tumors]], [[Hepatocellular carcinoma|benign]] or [[Hepatocellular carcinoma|malignant]], or [[liver disease|active liver disease]]
:* [[hypertension|Uncontrolled hypertension]]
|warnings=====Thromboembolic Disorders====
|warnings=====Thromboembolic Disorders====
Discontinue Makena if an arterial or deep venous thrombotic or thromboembolic event occurs.
* Discontinue Hydroxyprogesterone caproate if an [[arterial]] or [[deep vein thrombosis|deep venous thrombotic]] or [[thromboembolic event]] occurs.


====Allergic Reactions====
====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.
* [[Allergic reactions]], including [[urticaria]],[[ pruritus]] and [[angioedema]], have been reported with use of Hydroxyprogesterone caproate or with other products containing castor oil. Consider discontinuing the drug if such reactions occur.


====Decrease in Glucose Tolerance====
====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.
* A decrease in [[glucose tolerance]] has been observed in some patients on [[progestin]] treatment. The mechanism of this decrease is not known. Carefully monitor [[diabetic|prediabetic]] and [[diabetic]] women while they are receiving Hydroxyprogesterone caproate.


====Fluid Retention====
====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).
* 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====
====Depression====
Monitor women who have a history of clinical depression and discontinue Makena if clinical depression recurs.
* Monitor women who have a history of clinical [[depression]] and discontinue Hydroxyprogesterone caproate if clinical [[depression]] recurs.


====Jaundice====
====Jaundice====
Carefully monitor women who develop jaundice while receiving Makena and consider whether the benefit of use warrants continuation.
* Carefully monitor women who develop [[jaundice]] while receiving Hydroxyprogesterone caproate and consider whether the benefit of use warrants continuation.


====Hypertension====
====Hypertension====
Carefully monitor women who develop hypertension while receiving Makena and consider whether the benefit of use warrants continuation.
* Carefully monitor women who develop [[hypertension]] while receiving Hydroxyprogesterone caproate and consider whether the benefit of use warrants continuation.
|clinicalTrials=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.
|clinicalTrials=* 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 Hydroxyprogesterone caproate 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.
* Certain [[pregnancy]]-related [[fetal]] and maternal complications or events were numerically increased in the Hydroxyprogesterone caproate-treated subjects as compared to control subjects, including [[miscarriage]] and [[stillbirth]], admission for [[preterm labor]], [[preeclampsia]] or [[gestational hypertension]], [[gestational diabetes]], and [[oligohydramnios]].


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.
[[File:Hydroxprogesterone complication.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


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.
1 N = Total number of subjects enrolled prior to 20 weeks 0 days
|postmarketing=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
2 N = Total number of subjects at risk ≥ 20 weeks
* 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
|drugInteractions=Cytochrome P450 (CYP) enzymes: An in vitro inhibition study using human liver microsomes and CYP isoform-selective substrates indicated that hydroxyprogesterone caproate increased the metabolic rate of CYP1A2, CYP2A6, and CYP2B6 by approximately 80%, 150%, and 80%, respectively. However, in another in vitro study using human hepatocytes under conditions where the prototypical inducers or inhibitors caused the anticipated increases or decreases in CYP enzyme activities, hydroxyprogesterone caproate did not induce or inhibit CYP1A2, CYP2A6, or CYP2B6 activity. Overall, the findings indicate that hydroxyprogesterone caproate has minimal potential for CYP1A2, CYP2A6, and CYP2B6 related drug-drug interactions at the clinically relevant concentrations.


In vitro data indicated that therapeutic concentration of hydroxyprogesterone caproate is not likely to inhibit the activity of CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
[[File:table2.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|FDAPregCat=B
|useInPregnancyFDA=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 infants 2, 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.
====Common Adverse Reactions====


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.
* The most common adverse reaction was [[Injection site reaction|injection site pain]], which was reported after at least one injection by 34.8% of the Hydroxyprogesterone caproate 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 Hydroxyprogesterone caproate group than in the control group.
|useInLaborDelivery=Makena is not intended for use to stop active preterm labor. The effect of Makena in active labor is unknown.
|useInNursing=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
|useInPed=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.
|useInGeri=Makena is not intended for use in postmenopausal women. Safety and effectiveness in postmenopausal women have not been established.
|useInRenalImpair=No studies have been conducted to examine the pharmacokinetics of Makena in patients with renal impairment.
|useInHepaticImpair=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.
|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====
[[File:table3.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


Clean the vial top with an alcohol swab before use.
* In the [[clinical trial]], 2.2% of subjects receiving Hydroxyprogesterone caproate 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 reaction|injection site pain]]/[[swelling]] (1% each).
Draw up 1 mL of drug into a 3 mL syringe with an 18 gauge needle.
Change the needle to a 21 gauge 1 1/2 inch needle.
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.
Applying pressure to the injection site may minimize bruising and swelling.
Discard any unused product 5 weeks after first use.
|drugBox=[[File:hydroxyprogesterone caproate structure.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|mechAction=Hydroxyprogesterone caproate is a synthetic progestin. The mechanism by which hydroxyprogesterone caproate reduces the risk recurrent preterm birth is not known.
|PD=No specific pharmacodynamic studies were conducted with Makena.
|PK=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.
* [[Pulmonary embolus]] in one subject and [[Injection site reaction|injection site]] [[cellulitis]] in another subject were reported as serious adverse reactions in Hydroxyprogesterone caproate-treated subjects.
|postmarketing=* The following adverse reactions have been identified during postapproval use of Hydroxyprogesterone caproate. 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.


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.
* 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]], [[Cervical|shortened cervix]]
* Respiratory disorders:
:* [[Dyspnea]], [[chest discomfort]]
* Skin:
:* [[Rash]]
|drugInteractions=* [[Cytochrome P450]] (CYP) enzymes: An in vitro inhibition study using human [[liver]] [[microsomes]] and CYP isoform-selective substrates indicated that hydroxyprogesterone caproate increased the metabolic rate of [[CYP1A2]], [[CYP2A6]], and [[CYP2B6]] by approximately 80%, 150%, and 80%, respectively. However, in another in vitro study using human [[hepatocytes]] under conditions where the prototypical inducers or inhibitors caused the anticipated increases or decreases in CYP enzyme activities, hydroxyprogesterone caproate did not induce or inhibit [[CYP1A2]], [[CYP2A6]], or [[CYP2B6]] activity. Overall, the findings indicate that hydroxyprogesterone caproate has minimal potential for [[CYP1A2]], [[CYP2A6]], and [[CYP2B6]] related drug-drug interactions at the clinically relevant concentrations.


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.
* 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]].
|clinicalStudies=Clinical Trial to Evaluate Reduction of Risk of Preterm Birth
|FDAPregCat=B
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).
|useInPregnancyFDA=* There are no adequate and well-controlled studies of Hydroxyprogesterone caproate use in women during the [[first trimester of pregnancy]]. Data from a vehicle ([[placebo]])-controlled [[clinical trial]] of 310 [[pregnant]] women who received Hydroxyprogesterone caproate at weekly doses of 250 mg by [[intramuscular injection]] in their [[pregnancy|second and third trimesters]]1, as well as long-term (2-5 years) follow-up safety data on 194 of their infants 2, did not demonstrate any [[teratogenic]] risks to infants from in utero exposure to Hydroxyprogesterone caproate.


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.
* 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.


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.
* Hydroxyprogesterone caproate 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.
xxx
|useInLaborDelivery=* Hydroxyprogesterone caproate is not intended for use to stop active [[preterm labor]]. The effect of Hydroxyprogesterone caproate in active [[labor]] is unknown.
1 Four Makena-treated subjects were lost to follow-up. They were counted as deliveries at their gestational ages at time of last contact (184, 220, 343 and 364 weeks).
|useInNursing=* Discontinue Hydroxyprogesterone caproate 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]]
2 Adjusted for interim analysis.
|useInPed=* Hydroxyprogesterone caproate 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.
|useInGeri=* Hydroxyprogesterone caproate is not intended for use in [[postmenopausal]] women. Safety and effectiveness in [[postmenopausal]] women have not been established.
|useInRenalImpair=No studies have been conducted to examine the [[pharmacokinetics]] of Hydroxyprogesterone caproate in patients with [[renal impairment]].
|useInHepaticImpair=* No studies have been conducted to examine the pharmacokinetics of Hydroxyprogesterone caproate in patients with hepatic impairment. Hydroxyprogesterone caproate is extensively metabolized and [[hepatic impairment]] may reduce the elimination of Hydroxyprogesterone caproate.
|administration=* Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Hydroxyprogesterone caproate is a clear, yellow solution. Do not use if solid particles appear or if the solution is cloudy.


Table 4 Proportion of Subjects Delivering at < 37, < 35  and < 32 Weeks Gestational Age (ITT Population)
====Instructions for administration====
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.
xxx
Figure 1 Proportion of Women Remaining Pregnant as a Function of Gestational Age
 
The rates of fetal 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.
xxxxx
A Four of the 310 Makena-treated subjects were lost to follow-up and stillbirth or neonatal status could not be determined
B 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
|howSupplied=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.
|storage=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.
|packLabel=Patient Information
 
Makena (mah-KEE-na)
(hydroxyprogesterone caproate injection) 250 mg/mL
 
Read this Patient Information Leaflet before you receive Makena. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
 
What is Makena?
 
Makena is a prescription hormone medicine (progestin) used in women who are pregnant and who have delivered a baby too early (preterm) in the past. Makena is used in these women to help lower the risk of having a preterm baby again.
 
Makena is for women who:
 
Are pregnant with one baby
Have had a preterm delivery of one baby in the past
How well does Makena work?
 
Makena was studied in women who were at risk for having a preterm baby because they had previously given birth to a preterm baby. In the main study, about 37 of 100 women who received Makena gave birth preterm (before 37 weeks of pregnancy), compared to about 55 of 100 women who did not receive Makena. Another study of Makena is going on to see whether Makena reduces the number of babies who have serious problems shortly after birth or who die.
 
It is not known whether Makena is safe and effective in women who have other risk factors for preterm birth.


It is not known whether Makena is safe and effective in women less than 16 years old.
* Clean the vial top with an [[alcohol]] swab before use.
* Draw up 1 mL of drug into a 3 mL [[syringe]] with an 18 gauge needle.
* Change the needle to a 21 gauge 1 1/2 inch needle.
* 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.
* Applying pressure to the [[injection site]] may minimize [[bruising]] and [[swelling]].
* Discard any unused product 5 weeks after first use.
|drugBox={{Drugbox2
| Verifiedfields = changed
| verifiedrevid = 477198932
| IUPAC_name = [(8''R'',9''S'',10''R'',13''S'',14''S'',17''R'')-17-acetyl-10,13-dimethyl-<br>3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-<br>1H-cyclopenta[a]phenanthren-17-yl] hexanoate
| image = Hydroxyprogesterone caproate.png


Makena is not intended for use to stop active preterm labor.
<!--Clinical data-->
| tradename = 
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B            / C / D / X -->
| pregnancy_category = 
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!--            / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL        / P      / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC                  / Rx-only  / Schedule I, II, III, IV, V -->
| legal_status = 
| routes_of_administration =


Who should not receive Makena?
<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 
| metabolism = 
| elimination_half-life = 
| excretion =


Makena should not be used if you:
<!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 630-56-8
| ATC_prefix = 
| ATC_suffix = 
| PubChem = 169870
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = 
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 148552


Have now or have had a history of blood clots or other blood clotting problems
<!--Chemical data-->
Have now or have had a history of breast cancer or other hormone-sensitive cancers
| C=27 | H=40 | O=4
Have unusual vaginal bleeding not related to your current pregnancy
| molecular_weight = 428.6041 g/mol
Have yellowing of your skin due to liver problems during your pregnancy
| smiles = O=C4\C=C2/[C@]([C@H]1CC[C@@]3([C@@](OC(=O)CCCCC)(C(=O)C)CC[C@H]3[C@@H]1CC2)C)(C)CC4
Have liver problems, including liver tumors
| InChI = 1/C27H40O4/c1-5-6-7-8-24(30)31-27(18(2)28)16-13-23-21-10-9-19-17-20(29)11-14-25(19,3)22(21)12-15-26(23,27)4/h17,21-23H,5-16H2,1-4H3/t21-,22+,23+,25+,26+,27+/m1/s1
Have uncontrolled high blood pressure
| InChIKey = DOMWKUIIPQCAJU-LJHIYBGHBI
What should I tell my healthcare provider before receiving Makena?
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C27H40O4/c1-5-6-7-8-24(30)31-27(18(2)28)16-13-23-21-10-9-19-17-20(29)11-14-25(19,3)22(21)12-15-26(23,27)4/h17,21-23H,5-16H2,1-4H3/t21-,22+,23+,25+,26+,27+/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DOMWKUIIPQCAJU-LJHIYBGHSA-N
}}
|mechAction=* Hydroxyprogesterone caproate is a synthetic [[progestin]]. The mechanism by which hydroxyprogesterone caproate reduces the risk recurrent preterm birth is not known.
|structure=* The active pharmaceutical ingredient in Hydroxyprogesterone caproate is hydroxyprogesterone caproate.


Before you receive Makena, tell your healthcare provider if you have:
* 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.


An allergy to hydroxyprogesterone caproate, castor oil, or any of the other ingredients in Makena. See the end of this patient leaflet for a complete list of the ingredients in Makena.
The structural formula is:
Diabetes or prediabetes
Epilepsy
Migraine headaches
Asthma
Heart problems
Kidney problems
Depression
High blood pressure
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.


Makena may affect the way other medicines work, and other medicines may affect how Makena works.
[[File:Hydroxprogesterone structure.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|PD=No specific pharmacodynamic studies were conducted with Hydroxyprogesterone caproate.
|PK======Absorption:=====


Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medication.
* 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.


How should I receive Makena?
=====Distribution:=====


Do not give yourself Makena injections. A healthcare professional will give you the Makena injection into your hip area (upper outer area of the buttocks) once a week (every 7 days).
* Hydroxyprogesterone caproate binds extensively to [[plasma proteins]] including albumin and [[corticosteroid]] binding [[globulins]].
You will start receiving Makena injections anytime from 16 weeks and 0 days of your pregnancy up to 20 weeks and 6 days of your pregnancy.
You will continue to receive Makena injections once weekly until week 37 of your pregnancy or when your baby is delivered, whichever happens first.
Makena comes in ready-to-use vials. There are 5 doses of medicine in each vial. Your healthcare professional should give you only one dose (1 mL) of Makena as prescribed each week.


Makena should be used within 5 weeks after the first use.
=====Metabolism:=====


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.
* 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.


What are the possible side effects of Makena?
=====Excretion:=====


Makena may cause serious side effects, including:
* 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]].
|clinicalStudies======Clinical Trial to Evaluate Reduction of Risk of Preterm Birth=====


Blood clots. Symptoms of a blood clot may include:
* In a multicenter, randomized, double-blind, vehicle (placebo)-controlled clinical trial, the safety and effectiveness of Hydroxyprogesterone caproate 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 [[preterm birth|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).
Leg swelling
Redness in your leg
A spot on your leg that is warm to touch
Leg pain that worsens when you bend your foot
Allergic reactions. Symptoms of an allergic reaction may include:
Hives
Itching
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
* A total of 463 [[pregnant]] women were randomized to receive either Hydroxyprogesterone caproate (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 Hydroxyprogesterone caproate-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.
Hives
Itching
Nausea
Diarrhea
Call your healthcare provider if you have the following at your injection site:


Increased pain over time
* 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.
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.
[[File:table4.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


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:
:* Four Hydroxyprogesterone caproate-treated subjects were lost to follow-up. They were counted as deliveries at their [[gestational]] ages at time of last contact (184, 220, 343 and 364 weeks).
:* Adjusted for interim analysis.


Miscarriage (pregnancy loss before 20 weeks of pregnancy)
* Compared to controls, treatment with Hydroxyprogesterone caproate reduced the proportion of women who [[delivery|delivered]] [[preterm]] at <37 weeks. The proportions of women [[delivery|delivering]] at <35 and < 32 weeks also were lower among women treated with Hydroxyprogesterone caproate. 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.
Stillbirth (fetal death occurring after the 20th week of pregnancy)
Hospital admission for preterm labor
Preeclampsia (high blood pressure and too much protein in your urine)
Gestational hypertension (high blood pressure caused by pregnancy)
Gestational diabetes
Oligohydramnios (low amniotic fluid levels)
Call your healthcare provider for medical advice about side effects or pregnancy complications. You may report side effects to FDA at 1-800-FDA-1088.


How should I store Makena?
* After adjusting for time in the study, 7.5% of Hydroxyprogesterone caproate-treated subjects delivered prior to 25 weeks compared to 4.7% of control subjects; see Figure 1.


Store Makena at room temperature (59° to 86°F or 15° to 30°C)
[[File:Hydroxprogesterone graph.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Store Makena in the original box to protect it from light
Store the Makena box upright
Makena should be used within 5 weeks after first use.
Keep Makena out of the reach of children
General information about the safe and effective use of Makena.


Medicines are sometimes prescribed for purposes other than those mentioned in the Patient Information Leaflets. Do not take Makena for conditions for which it was not prescribed. Do not give Makena to other people, even if they have the same condition you have. It may harm them.
* The rates of [[fetal]] and [[neonatal]] deaths in each treatment arm are displayed in Table 5. Due to the higher rate of [[miscarriages]] and [[stillbirths]] in the Hydroxyprogesterone caproate arm, there was no overall survival difference demonstrated in this [[clinical trial]].
[[File:table5.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


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.
:* A Four of the 310 Hydroxyprogesterone caproate-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
:* Percentage adjusted for the number of at risk subjects (n=209 for Hydroxyprogesterone caproate, n=107 for control) enrolled at <20 weeks [[gestation]].


For more information, go to www.makena.com or call Lumara Health Customer Service at the toll free number 1-877-567-7676.
* 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 Hydroxyprogesterone caproate arm (11.9% vs. 17.2%), the number of adverse outcomes was limited and the difference between arms was not statistically significant.


To refill a prescription or to check on prescription status, call the Makena Care Connection at the toll free number 1-800-847-3418.
=====Infant Follow-Up Safety Study=====


What are the ingredients in Makena?
* [[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 Hydroxyprogesterone caproate-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.
|howSupplied=Hydroxyprogesterone caproate (NDC 64011-243-01) is supplied as 5 mL of a [[sterile]] solution in a multidose glass vial.


Active ingredient: hydroxyprogesterone caproate
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).


Inactive ingredients: castor oil, benzyl benzoate, and benzyl alcohol (a preservative)
Single unit carton: Contains one 5 mL multidose vial of Hydroxyprogesterone caproate (250 mg/mL) containing 1250 mg of hydroxyprogesterone caproate.
|storage=* Store at controlled room temperature [15°-30°C (59°-86°F)]. Use within 5 weeks after first use.


xxxx
* Caution: Protect vial from light. Store vial in its box. Store upright.
|packLabel=[[File:Hydroxprogesterone drug label.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


Carton Label
Carton Label
Line 314: Line 286:
Chesterfield, MO 63005
Chesterfield, MO 63005
|alcohol=Alcohol-Hydroxyprogesterone caproate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=Alcohol-Hydroxyprogesterone caproate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* Hylutin®
* Prodrox®
* Makena®
}}
}}

Latest revision as of 15:02, 2 April 2015

Hydroxyprogesterone caproate
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Overview

Hydroxyprogesterone caproate is a progestin and endocrine-metabolic agent that is FDA approved for the treatment of indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. Common adverse reactions include injection site reactions, pain, swelling, pruritus, nodule, urticaria, nausea, and diarrhea.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Dosing Information

  • 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. Hydroxyprogesterone caproate is a clear, yellow solution. Do not use if solid particles appear or if the solution is cloudy.
  • Instructions for administration:
  • Clean the vial top with an alcohol swab before use.
  • Draw up 1 mL of drug into a 3 mL syringe with an 18 gauge needle.
  • Change the needle to a 21 gauge 1 1/2 inch needle.
  • 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.
  • Applying pressure to the injection site may minimize bruising and swelling.

Discard any unused product 5 weeks after first use.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

  • There is limited information regarding Off-Label Guideline-Supported Use of Hydroxyprogesterone caproate in adult patients.

Non–Guideline-Supported Use

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Label Guideline-Supported Use of Hydroxyprogesterone caproate in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Hydroxyprogesterone caproate in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydroxyprogesterone caproate in pediatric patients.

Contraindications

  • Do not use Hydroxyprogesterone caproate in women with any of the following conditions:

Warnings

Thromboembolic Disorders

Allergic Reactions

  • Allergic reactions, including urticaria,pruritus and angioedema, have been reported with use of Hydroxyprogesterone caproate 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 Hydroxyprogesterone caproate.

Fluid Retention

Depression

  • Monitor women who have a history of clinical depression and discontinue Hydroxyprogesterone caproate if clinical depression recurs.

Jaundice

  • Carefully monitor women who develop jaundice while receiving Hydroxyprogesterone caproate and consider whether the benefit of use warrants continuation.

Hypertension

  • Carefully monitor women who develop hypertension while receiving Hydroxyprogesterone caproate and consider whether the benefit of use warrants continuation.

Adverse Reactions

Clinical Trials Experience

This image is provided by the National Library of Medicine.

1 N = Total number of subjects enrolled prior to 20 weeks 0 days

2 N = Total number of subjects at risk ≥ 20 weeks

This image is provided by the National Library of Medicine.

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 Hydroxyprogesterone caproate 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 Hydroxyprogesterone caproate group than in the control group.
This image is provided by the National Library of Medicine.
  • In the clinical trial, 2.2% of subjects receiving Hydroxyprogesterone caproate 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).

Postmarketing Experience

  • The following adverse reactions have been identified during postapproval use of Hydroxyprogesterone caproate. 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:
  • Digestive disorders:
  • Infections:
  • Nervous system disorders:
  • Pregnancy, puerperium and perinatal conditions:
  • Skin:

Drug Interactions

  • Cytochrome P450 (CYP) enzymes: An in vitro inhibition study using human liver microsomes and CYP isoform-selective substrates indicated that hydroxyprogesterone caproate increased the metabolic rate of CYP1A2, CYP2A6, and CYP2B6 by approximately 80%, 150%, and 80%, respectively. However, in another in vitro study using human hepatocytes under conditions where the prototypical inducers or inhibitors caused the anticipated increases or decreases in CYP enzyme activities, hydroxyprogesterone caproate did not induce or inhibit CYP1A2, CYP2A6, or CYP2B6 activity. Overall, the findings indicate that hydroxyprogesterone caproate has minimal potential for CYP1A2, CYP2A6, and CYP2B6 related drug-drug interactions at the clinically relevant concentrations.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): B

  • 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.
  • Hydroxyprogesterone caproate 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.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hydroxyprogesterone caproate in women who are pregnant.

Labor and Delivery

  • Hydroxyprogesterone caproate is not intended for use to stop active preterm labor. The effect of Hydroxyprogesterone caproate in active labor is unknown.

Nursing Mothers

  • Discontinue Hydroxyprogesterone caproate 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

  • Hydroxyprogesterone caproate 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.

Geriatic Use

  • Hydroxyprogesterone caproate is not intended for use in postmenopausal women. Safety and effectiveness in postmenopausal women have not been established.

Gender

There is no FDA guidance on the use of Hydroxyprogesterone caproate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Hydroxyprogesterone caproate with respect to specific racial populations.

Renal Impairment

No studies have been conducted to examine the pharmacokinetics of Hydroxyprogesterone caproate in patients with renal impairment.

Hepatic Impairment

  • No studies have been conducted to examine the pharmacokinetics of Hydroxyprogesterone caproate in patients with hepatic impairment. Hydroxyprogesterone caproate is extensively metabolized and hepatic impairment may reduce the elimination of Hydroxyprogesterone caproate.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Hydroxyprogesterone caproate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Hydroxyprogesterone caproate in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Hydroxyprogesterone caproate is a clear, yellow solution. Do not use if solid particles appear or if the solution is cloudy.

Instructions for administration

  • Clean the vial top with an alcohol swab before use.
  • Draw up 1 mL of drug into a 3 mL syringe with an 18 gauge needle.
  • Change the needle to a 21 gauge 1 1/2 inch needle.
  • 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.
  • Applying pressure to the injection site may minimize bruising and swelling.
  • Discard any unused product 5 weeks after first use.

Monitoring

There is limited information regarding Hydroxyprogesterone caproate Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Hydroxyprogesterone caproate and IV administrations.

Overdosage

There is limited information regarding Hydroxyprogesterone caproate overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

Template:Px
Hydroxyprogesterone caproate
Systematic (IUPAC) name
[(8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-
3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-
1H-cyclopenta[a]phenanthren-17-yl] hexanoate
Identifiers
CAS number 630-56-8
ATC code ?
PubChem 169870
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 428.6041 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Pregnancy cat.

?

Legal status
Routes ?

Mechanism of Action

  • Hydroxyprogesterone caproate is a synthetic progestin. The mechanism by which hydroxyprogesterone caproate reduces the risk recurrent preterm birth is not known.

Structure

  • The active pharmaceutical ingredient in Hydroxyprogesterone caproate 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:

This image is provided by the National Library of Medicine.

Pharmacodynamics

No specific pharmacodynamic studies were conducted with Hydroxyprogesterone caproate.

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:
Metabolism:
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.

Nonclinical Toxicology

There is limited information regarding Hydroxyprogesterone caproate Nonclinical Toxicology in the drug label.

Clinical Studies

Clinical Trial to Evaluate Reduction of Risk of Preterm Birth
  • A total of 463 pregnant women were randomized to receive either Hydroxyprogesterone caproate (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 Hydroxyprogesterone caproate-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.
This image is provided by the National Library of Medicine.
  • Four Hydroxyprogesterone caproate-treated subjects were lost to follow-up. They were counted as deliveries at their gestational ages at time of last contact (184, 220, 343 and 364 weeks).
  • Adjusted for interim analysis.
  • Compared to controls, treatment with Hydroxyprogesterone caproate 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 Hydroxyprogesterone caproate. 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 Hydroxyprogesterone caproate-treated subjects delivered prior to 25 weeks compared to 4.7% of control subjects; see Figure 1.
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  • The rates of fetal and neonatal deaths in each treatment arm are displayed in Table 5. Due to the higher rate of miscarriages and stillbirths in the Hydroxyprogesterone caproate arm, there was no overall survival difference demonstrated in this clinical trial.
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  • A Four of the 310 Hydroxyprogesterone caproate-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
  • Percentage adjusted for the number of at risk subjects (n=209 for Hydroxyprogesterone caproate, n=107 for control) enrolled at <20 weeks gestation.
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 Hydroxyprogesterone caproate-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.

How Supplied

Hydroxyprogesterone caproate (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 Hydroxyprogesterone caproate (250 mg/mL) containing 1250 mg of hydroxyprogesterone caproate.

Storage

  • 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.

Images

Drug Images

{{#ask: Page Name::Hydroxyprogesterone caproate |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

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Carton Label

NDC 64011-243-01

Makena® hydroxyprogesterone caproate injection

1250 mg/5 mL (250 mg/mL)

FOR INTRAMUSCULAR USE

5 mL multidose vial Rx ONLY

Store at controlled room temperature 15°-30°C (59°-86°F).

Caution: Protect from light. Store vial in its box. Store upright. Use within 5 weeks after first use.

Each mL contains: hydroxyprogesterone caproate 250 mg, benzyl benzoate 46%, castor oil 28.6%, and benzyl alcohol 2%, as preservative.

See package insert for full prescribing and patient information.

Lumara Health

P8009 6/14

Marketed by Lumara Health™ Chesterfield, MO 63005 {{#ask: Label Page::Hydroxyprogesterone caproate |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Hydroxyprogesterone caproate Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Hydroxyprogesterone caproate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

  • Hylutin®
  • Prodrox®
  • Makena®

Look-Alike Drug Names

There is limited information regarding Hydroxyprogesterone caproate Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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