Hydroxyprogesterone Caproate Injection USP 1.25g/5ml Taj Pharma

Hydroxyprogesterone Caproate Injection USP 250mg/1ml, 500mg/2ml, 1.25g/5ml Taj Pharma

Composition
a) Hydroxyprogesterone Caproate Injection USP 250mg/1ml.
Each ml contains:
Hydroxyprogesterone Caproate 250mg
Excipients q.s.

b) Hydroxyprogesterone Caproate Injection USP 500mg/2ml.
Each ml contains:
Hydroxyprogesterone Caproate 250mg
Excipients q.s.

c) Hydroxyprogesterone Caproate Injection USP 1.25g/5ml.
Each ml contains:
Hydroxyprogesterone Caproate 250mg
Excipients q.s.

Description
Hydroxyprogesterone is a form of progestin, a manmade form of a female hormone called progesterone.
Hydroxyprogesterone is used to lower the risk of premature birth in a woman who has already had one premature baby. Hydroxyprogesterone will not stop premature labor that has already begun.
Hydroxyprogesterone is not for use in women who are pregnant with more than one baby (twins, triplets, etc).

Dosage form
Oil, Intramuscular

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

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 of age: Note: Treatment may begin between 16 weeks 0 days and 20 weeks 6 days of gestation. Continue weekly administration until 37 weeks (through 36 weeks, 6 days) gestation or until delivery, whichever comes first.

IM (vial): 250 mg once weekly (every 7 days).

SubQ (auto-injector): 275 mg once weekly (every 7 days).

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:
Pediatric Preterm birth, prevention: Adolescents ≥16 years: Makena: IM: 250 mg every 7 days; treatment should be initiated between 16 weeks 0 days and 20 weeks 6 days of gestation; can be continued up to 37 weeks gestation (ie, 36 weeks 6 days) or until delivery, whichever occurs first.

Administration

IM: Generic product (nonpregnancy indications): For IM use only. Administer IM into the upper outer quadrant of the gluteus maximus.

vial: For IM use only. Withdraw dose using an 18-gauge needle; inject dose using a 21-gauge 1¹/₂ inch needle. Administer IM by slow injection (≥1 minute) into the upper outer quadrant of the gluteus maximus; alternate injection sites. 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.

SubQ:

Auto-injector: For subcutaneous use only. Use immediately once cap is removed. Administer in the back of either upper arm; solution is viscous and oily and requires ~15 seconds to deliver the dose; rotate injection sites weekly. Do not inject if skin is tender, bruised, red, scaly, raised, thick or hard; avoid areas with scars, tattoos or stretch marks. Apply light pressure with gauze or cotton ball to injection site if bleeding occurs; do not rub. See manufacturer’s instructions for use for additional administration information.

Usual Adult Dose for Premature Labor

Treatment should begin between 16 weeks, 0 days and 20 weeks, 6 days of gestation:

Intramuscularly (IM): 250 mg IM once every 7 day in the upper outer quadrant of the gluteus maximus

Subcutaneously: 275 mg subcutaneously once every 7 days in the back of either upper arm

Duration: Continue administration once a week until week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever occurs first

Comments:
-Efficacy of this drug 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.

Use: To reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.

Usual Pediatric Dose for Premature Labor

16 years or older:
Treatment should begin between 16 weeks, 0 days and 20 weeks, 6 days of gestation:

Intramuscularly (IM): 250 mg IM once every 7 day in the upper outer quadrant of the gluteus maximus

Subcutaneously: 275 mg subcutaneously once every 7 days in the back of either upper arm

Duration: Continue administration once a week until week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever occurs first

Use: To reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Contraindicated in active liver disease

Precautions

CONTRAINDICATIONS:
-Current or history of thrombosis or thromboembolic disorders
-Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions
-Undiagnosed abnormal vaginal bleeding unrelated to pregnancy
-Cholestatic jaundice of pregnancy
-Liver tumors, benign or malignant, or active liver disease
-Uncontrolled hypertension

Safety and efficacy have not been established in patients younger than 16 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Administration advice:
For IM or subcutaneous administration once every 7 days by a healthcare provider

Subcutaneous Auto-injector:
-Administer 275 mg (1.1 mL) subcutaneously in the back of either upper arm; rotate injection to alternate arms weekly
-Auto-injector takes approximately 15 seconds to deliver full dose, when viewing window is fully blocked (completely orange), the full dose has been administered
-Do not inject into areas where skin is tender, bruised, red, scaly, raised, thick, or hard; avoid areas with scars, tattoos, or stretch marks

-IM administration:
-Administer 250 mg (1 mL) by slow IM injection (over 1 minute or longer) in the upper outer quadrant of the gluteus maximus; rotate injection site to alternate side weekly
-Applying pressure to the injection site may minimize bruising and swelling

General:
-The effectiveness of this drug is based on improvement in the proportion of women who delivered at less than 37 weeks of gestation.
-There are no controlled trials demonstrating a direct clinical benefit, such as improvement in neonatal mortality and morbidity.

Monitoring:
-Monitor blood pressure
-Monitor glycemic control in women with diabetes or pre-diabetes
-Monitor for fluid retention in women with conditions that might be influenced by this effect
-Monitor for clinical depression in women with a history of depression
-Monitor for jaundice

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

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

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

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

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

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

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

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

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

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

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

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

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

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: Progestins may diminish the therapeutic effect of Ulipristal. Ulipristal may diminish the therapeutic effect of Progestins. 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

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.
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 Considerations

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.

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 sex drive, increased sex drive, 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, passing a lot of urine, 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; chest pain; shortness of breath; fast heartbeat; or coughing up blood); vision changes; severe headache; severe dizziness; passing out; depression; shortness of breath; excessive weight gain; swelling of arms or legs; no menstrual periods; 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 yellow skin (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 health care 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.

Side effects:

Commonly reported side effects of hydroxyprogesterone include: urticaria and swelling at injection site.

Other side effects include: pruritus.

General

The most commonly reported adverse reaction is injection site pain.

Local

Injection site cellulitis was reported in 1 subject. In a study that compared IM injection to subcutaneous auto-injector, injection site pain was reported in 10% of subjects receiving drug via the auto-injector compared with 7% receiving an IM injection. In a second study, 34% reported injection site pain with the auto-injector and 8% with IM injection.^[Ref]

Very common (10% or more): Injection site pain (up to 34.8%), injection site swelling (up to 17.1%)

Common (1% to 10%): Injection site pruritus, injection site nodules

Frequency not reported: Injection site cellulitis

Postmarketing reports: Local injection site reactions of erythema, urticaria, rash, irritation, hypersensitivity, warmth^[Ref]

Endocrine

Common (1% to 10%): Pregnancy complications

Postmarketing reports: Cervical incompetence, premature rupture of membranes

Certain pregnancy-related fetal and maternal complications or events were numerically increased in patients receiving this drug compared with placebo including miscarriage at less than 20 weeks (5/209 vs 0/107), stillbirth (6/302 vs 2/153), admission for preterm labor (16% vs 13.8%), preeclampsia or gestation hypertension (8.8% vs 4.6%), gestational diabetes (5.6% vs 4.6%), and oligohydramnios (3.6% vs 1.3%).

Genitourinary

Frequency not reported: Admission for preterm labor, preeclampsia or gestational hypertension, gestational diabetes, oligohydramnios

Postmarketing reports: Urinary tract infection, cervical incompetence, premature rupture of membranes, cervical dilation, shortened cervix^[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, diarrhea

Postmarketing reports: Vomiting

Dermatologic

Very common (10% or more): Urticaria (12.3%)

Common (1% to 10%): Pruritus

Postmarketing reports: Rash

Nervous system

Postmarketing reports: Headache, dizziness

Respiratory
Frequency not reported: Pulmonary embolus

Postmarketing reports: Dyspnea, chest discomfort
Pulmonary embolus was reported in 1 patient.