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Hydroxyprogesterone Caproate

Pronunciation

(hye droks ee proe JES te rone CAP ro ate)

Index Terms

  • 17OHPC
  • Delautin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Oil, Intramuscular:

Makena: 250 mg/mL (5 mL) [contains benzyl alcohol, benzyl benzoate, castor oil (ricine oil)]

Makena: 250 mg/mL (1 mL) [contains benzyl benzoate, castor oil (ricine oil)]

Solution, Intramuscular:

Generic: 1.25 g/5 mL (5 mL)

Brand Names: U.S.

  • Makena

Pharmacologic Category

  • Progestin

Pharmacology

Hydroxyprogesterone is a synthetic progestin. The mechanism by which hydroxyprogesterone reduces the risk of recurrent preterm birth is not known. Hydroxyprogesterone caproate may induce regressive changes in uterine adenocarcinoma.

Distribution

Extensively bound to plasma proteins including albumin and corticosteroid-binding globulins

Metabolism

Hepatic via CYP3A4 and 3A5; forms metabolites

Excretion

Urine (~30%) and feces (~50%); primarily as metabolites

Time to Peak

Serum: IM: Nonpregnant females: 3 to 7 days; Pregnant females (singleton pregnancies): 1 to 7 days

Half-Life Elimination

Nonpregnant females: ~8 days; Pregnant females (singleton pregnancies): 16.4 ± 3.6 days

Special Populations: Hepatic Function Impairment

Extensively metabolized; hepatic impairment may reduce the elimination of hydroxyprogesterone.

Use: Labeled Indications

Pregnancy indications: Preterm birth (Makena): To reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.

Limitation of use: Safety and efficacy have been demonstrated only in women with a prior spontaneous singleton preterm birth. Use is not intended for women with multiple gestations or other risk factors for preterm birth.

Non-pregnancy indications (generic product): Treatment of advanced (stage III or IV) uterine adenocarcinoma; management of amenorrhea (primary and secondary) and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology (eg, submucous fibroids or uterine cancer); as a test for endogenous estrogen production; production of secretory endometrium and desquamation.

Contraindications

Hypersensitivity to hydroxyprogesterone caproate or any component of the formulation; current or history of thrombosis or thromboembolic disorders; breast cancer or other hormone-sensitive cancer (known, suspected, or history of); undiagnosed abnormal vaginal bleeding unrelated to pregnancy; cholestatic jaundice of pregnancy; liver tumors (benign or malignant) or active liver disease; missed abortion; uncontrolled hypertension; as a diagnostic test for pregnancy.

Documentation of allergenic cross-reactivity for progestins is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Pregnancy indications: Preterm birth (Makena): Pregnant females ≥16 years: IM: 250 mg once weekly (every 7 days). Treatment may begin between 16 weeks 0 days and 20 weeks 6 days of gestation. Continue weekly administration until 37 weeks gestation or until delivery, whichever comes first.

Non-pregnancy indications (generic product):

Amenorrhea (primary and secondary) or abnormal uterine bleeding due to hormonal imbalance: IM:

Single dose therapy: 375 mg as a single dose; begin at any time or

Cyclic therapy schedule: 250 mg on day 15 of each 28-day cycle for 4 cycles (in combination with estradiol valerate); begin cyclic therapy schedule after 4 days of desquamation. If there is no bleeding, begin cyclic therapy schedule 21 days after the 375 mg single dose schedule.

Production of secretory endometrium and desquamation: IM:

Patients not on estrogen therapy: Cyclic therapy schedule: 250 mg on day 15 of each 28-day cycle (in combination with estradiol valerate); may begin at any time; continue until cyclic therapy is no longer required.

Patients currently on estrogen therapy:

Single dose therapy: 375 mg as a single dose; begin at any time or

Cyclic therapy schedule: 250 mg on day 15 of each 28-day cycle (in combination with estradiol valerate); begin cyclic therapy schedule after 4 days of desquamation. If there is no bleeding, begin cyclic therapy schedule 21 days after the 375 mg single dose schedule. Continue until cyclic therapy is no longer required.

Test for endogenous estrogen production: IM: 250 mg as a single dose (bleeding 7 to 14 days after administration indicates endogenous estrogen); may repeat once 4 weeks after initial dose.

Uterine adenocarcinoma (advanced): IM: 1,000 mg one or more times a week (1,000 to 7,000 mg/week); discontinue upon relapse.

Note: While approved for the treatment of advanced adenocarcinoma (stage III or IV) of the uterine corpus, chemotherapy may be preferable to progestin therapy in the management of advanced disease. Based on a systematic review, response to hormonal therapy is inversely proportional to tumor grade (Decruze 2007).

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). However, hydroxyprogesterone caproate is extensively metabolized and hepatic impairment may reduce its elimination.

Administration

Administer IM into the upper outer quadrant of the gluteus maximus.

Makena: Withdraw dose using an 18 gauge needle; inject dose using a 21 gauge 11/2 inch needle. Administer by slow injection (≥1 minute). Solution is viscous and oily; do not use if solution is cloudy or contains solid particles. Apply pressure to injection site to decrease bruising and swelling.

Storage

Makena: Store upright at controlled room temperature of 15°C to 30°C (59°F to 86°F); protect from light. Discard multidose vial within 5 weeks of initial use.

Generic product: Store upright at controlled room temperature of 20°C to 25°C (68°F to 77°F); protect from light. Discard unused product within 28 days of initial use. Storage at low temperatures may result in separation of crystalline material which redissolves with a hot water bath.

Drug Interactions

Anticoagulants: Progestins may diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

C1 inhibitors: Progestins may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2A6 Substrates (High risk with Inducers): CYP2A6 Inducers (Strong) may increase the metabolism of CYP2A6 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Herbs (Progestogenic Properties) (eg, Bloodroot, Yucca): May enhance the adverse/toxic effect of Progestins. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Pomalidomide: Progestins may enhance the thrombogenic effect of Pomalidomide. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Management: Ulipristal for uterine fibroids (Canadian indication): avoid progestins within 12 days of stopping ulipristal; as emergency contraceptive (U.S. indication): avoid progestins within 5 days of stopping ulipristal. Avoid combination

Adverse Reactions

>10%:

Dermatologic: Urticaria (12%)

Genitourinary: Preterm labor (admission: 16%)

Local: Pain at injection site (35%), swelling at injection site (17%)

1% to 10%:

Cardiovascular: Preeclampsia (9%)

Dermatologic: Pruritus (8%)

Endocrine & metabolic: Gestational diabetes (6%)

Gastrointestinal: Nausea (6%), diarrhea (2%)

Genitourinary: Oligohydramnios (4%)

Local: Local pruritus (6%), injection site nodule (5%)

<1%, postmarketing, and/or case reports: Angioedema, cellulitis at injection site, cervical dilation, cervical shortening, chest discomfort, decreased glucose tolerance, depression, dizziness, dyspnea, fatigue, fever, fluid retention, headache, hypersensitivity reaction, hypertension, hot flash, injection site reaction, jaundice, premature rupture of membranes, pulmonary embolism, skin rash, thromboembolic complications, urinary tract infection, vomiting

Warnings/Precautions

Concerns related to adverse events:

• Hypersensitivity: Hypersensitivity and allergic-like reactions (eg, urticaria, pruritus, angioedema) have been reported. Consider discontinuing if allergic reactions occur.

• Retinal vascular thrombosis: May cause retinal vascular thrombosis; discontinue pending examination if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.

• Thromboembolism: Discontinue if arterial thrombosis, DVT, or thromboembolic events occur. Use is contraindicated with current or history of thrombosis or thromboembolic disorders.

Disease related concerns:

• Carbohydrate intolerance: May have adverse effects on glucose tolerance; use caution in women with prediabetes and diabetes.

• Depression: Use with caution in patients with depression; discontinue if depression occurs.

• Diseases exacerbated by fluid retention: Use with caution in patients with diseases that may be exacerbated by fluid retention, including asthma, epilepsy, preeclampsia, cardiac or renal dysfunction.

• Hepatic impairment: Specific studies have not been conducted; elimination may be decreased. Use is contraindicated with hepatic impairment.

• Hypertension: Monitor women who develop hypertension during therapy; consider risk versus benefit of continuation. Use is contraindicated with uncontrolled hypertension.

• Jaundice: Monitor women who develop jaundice during therapy; consider risk versus benefit of continuation. Use is contraindicated in women with cholestatic jaundice of pregnancy.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

• Castor oil: Some formulations contain castor oil. Discontinue if allergic reactions (eg urticaria, pruritus, angioedema) occur.

Other warnings/precautions:

• Appropriate use: Preterm birth: The effectiveness of hydroxyprogesterone is based on improvement in the proportion of women who delivered at less than 37 weeks of gestation. Clinical benefits related to improved neonatal mortality or morbidity following maternal use have not been demonstrated. Not intended to stop active preterm labor.

• Appropriate use: Uterine adenocarcinoma: While the intramuscular solution is approved for the treatment of stage III or IV adenocarcinoma of the uterine corpus, chemotherapy may be preferable to progestin therapy in the management of advanced disease. Based on a systematic review, response to hormonal therapy is inversely proportional to tumor grade (Decruze 2007).

• Laboratory changes: Use may change the results of some laboratory tests (eg, coagulation factors, tests of hepatic or thyroid function).

• Product selection: Hydroxyprogesterone caproate is available in multiple dosage forms. The Makena brand and the generic product (generic for Delautin) have different indications (Makena pregnancy indications; the generic product has non-pregnancy indications); products are not interchangeable.

Monitoring Parameters

Glucose (in patients with prediabetes or diabetes); blood pressure; signs/symptoms of depression, fluid retention, jaundice, and/or thromboembolic disorders.

Non-pregnancy uses: Papanicolaou smear, pelvic organ and breast exam prior to therapy

Pregnancy Risk Factor

B (Makena)

Pregnancy Considerations

Adverse events observed in some animal reproduction studies. Adverse events were not observed in human studies following second or third trimester exposure; use not studied during first trimester.

Following use of Makena, maternal serum concentrations of hydroxyprogesterone caproate are widely variable and may be decreased in women with increased BMI. Hydroxyprogesterone is metabolized by the placenta and reaches the fetal circulation. In one study, the cord:maternal concentration ratio averaged 0.2. Hydroxyprogesterone caproate was detected in cord blood when delivery occurred ≥44 days after the last injection (Caritis 2012; Hemaue 2008).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience injection site pain, nausea, vomiting, diarrhea, abdominal cramps, bloating, breast soreness, weight gain, weight loss, hair loss, decreased libido, increased libido, lack of appetite, increased appetite, loss of strength and energy, or back pain. Have patient report immediately to prescriber signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit); signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; angina; shortness of breath; tachycardia; or coughing up blood); vision changes; severe headache; severe dizziness; passing out; depression; swelling of hands or feet; severe injection site edema, oozing of blood, or irritation; signs of virilization (in females a deep voice, facial hair, acne, or menstrual changes); abnormal vaginal bleeding; or jaundice (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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