Aquagest

Approved Indications

• Hormone Replacement Therapy (HRT) in Postmenopausal Women
  • Used in combination with estrogen to prevent endometrial hyperplasia in women with an intact uterus.
• Secondary Amenorrhea
  • Indicated for inducing withdrawal bleeding in women with secondary amenorrhea due to hormonal imbalance (excluding anatomical causes).
• Assisted Reproductive Technology (ART)
  • Luteal phase support in infertile women undergoing ART procedures, such as in vitro fertilization (IVF).
• Luteal Phase Support in Natural or Stimulated Cycles
  • Used to supplement insufficient endogenous progesterone production during the luteal phase.
• Prevention of Endometrial Hyperplasia
  • In women receiving continuous estrogen therapy as part of HRT.

Clinically Accepted Off-Label Uses

• Prevention of Preterm Birth
  • Vaginal progesterone is used in pregnant women with a short cervix (<25 mm) or history of spontaneous preterm birth.
• Premenstrual Syndrome (PMS) / Premenstrual Dysphoric Disorder (PMDD)
  • Sometimes used cyclically to relieve mood, irritability, and somatic symptoms.
• Dysfunctional Uterine Bleeding and Menstrual Irregularities
  • Used to stabilize endometrial lining and normalize menstrual cycles.

Route of Administration: Oral, Vaginal, Intramuscular (IM)

Adults (Females)

• HRT (with estrogen):
  • Oral: 200 mg once daily at bedtime for 12 days per 28-day cycle (usually days 15–26)
  • Alternatively, 100 mg orally once daily continuously if taken with daily estrogen.
• Secondary Amenorrhea:
  • Oral: 400 mg once daily at bedtime for 10 days
  • Withdrawal bleeding typically occurs within 7 days of the last dose.
• Luteal Phase Support in ART:
  • Vaginal: 100–200 mg once or twice daily beginning on oocyte retrieval or embryo transfer day.
  • IM: 50–100 mg once daily, continued until 10–12 weeks of gestation if pregnancy occurs.
• Prevention of Preterm Birth (Off-label):
  • Vaginal: 100–200 mg daily starting at 16–24 weeks of gestation, continued until 36 weeks or delivery.

Elderly:

• Not routinely indicated except for postmenopausal women on HRT.
• Use the lowest effective dose; assess cardiovascular and cancer risk before initiation.

Pediatric:

• Not indicated for use in pediatric or adolescent populations.

Hepatic/Renal Impairment:

• Hepatic: Contraindicated in severe hepatic dysfunction due to hepatic metabolism.
• Renal: Use cautiously; no specific dose adjustment guidelines, but monitor for fluid retention.

Micronised progesterone is a natural, bioidentical hormone that binds to progesterone receptors in the uterus, breast, brain, and other tissues. It transforms estrogen-primed proliferative endometrium into a secretory state, preparing it for implantation and supporting early pregnancy. In HRT, it protects the endometrium from hyperplasia associated with unopposed estrogen. It suppresses gonadotropin-releasing hormone (GnRH) from the hypothalamus, reducing LH and FSH release. The micronisation process enhances its gastrointestinal absorption and systemic availability when taken orally.

• Absorption:
  • Oral: Rapid absorption; micronisation improves bioavailability, though still subject to first-pass hepatic metabolism.
  • Vaginal: Provides high local uterine concentration with reduced systemic exposure.
  • IM: Slow release into circulation with sustained levels.
• Distribution:
  • Extensively distributed; crosses the blood-brain barrier and placenta.
  • >90% bound to serum albumin and corticosteroid-binding globulin.
• Metabolism:
  • Primarily hepatic via CYP3A4 enzymes into inactive metabolites, mainly pregnanediol.
• Excretion:
  • Excreted in urine as glucuronide and sulfate conjugates of metabolites.
• Bioavailability:
  • Oral: ~10–15%
  • Vaginal and IM: Higher bioavailability with bypass of hepatic first-pass metabolism.
• Half-Life:
  • Oral: 13–18 hours
  • Vaginal: Variable; depends on formulation and dosage
  • IM: Sustained levels for 24+ hours depending on dose

• Pregnancy:
  • FDA Category B (Micronised Progesterone)
  • Safe and commonly used for luteal support and prevention of preterm birth.
  • No known teratogenicity; widely used in fertility protocols and early pregnancy.
• Lactation:
  • Excreted in small amounts in breast milk.
  • Generally considered safe; monitor infant for signs of sedation or poor feeding.
  • Avoid prolonged use during lactation unless clinically indicated.

• Primary Class: Progestin Hormone
• Subclass: Natural (Bioidentical) Progestogen
• Formulation Note: Micronised for enhanced oral absorption

• Known hypersensitivity to progesterone or formulation components
• Undiagnosed vaginal bleeding
• Active or history of thromboembolic disorders (e.g., DVT, PE)
• Active or history of hormone-sensitive cancers (e.g., breast, uterine)
• Severe hepatic impairment or liver disease
• Missed abortion or incomplete miscarriage
• Cerebrovascular disease or stroke

• Cardiovascular Risk: Caution in women with risk factors for thromboembolism or stroke.
• Depression or Mood Disorders: May exacerbate underlying depression—monitor mental status.
• Fluid Retention: Use cautiously in patients with cardiac, renal, or epileptic disorders.
• Visual Disturbances: Discontinue if sudden loss of vision, papilledema, or proptosis occurs.
• Breast Cancer: Long-term use with estrogen may increase breast cancer risk; perform regular breast exams.
• Monitoring Parameters:
  • Blood pressure
  • Liver function
  • Breast and pelvic examination for long-term users

Common Side Effects:

• Neurologic: Drowsiness, dizziness, headache, fatigue
• Gastrointestinal: Nausea, bloating, abdominal cramps
• Breast: Breast tenderness or fullness
• General: Mood swings, fluid retention, weight gain

Less Common or Serious Side Effects:

• Depression or worsening of mood disorders
• Breakthrough bleeding or irregular menses
• Allergic skin reactions
• Visual changes, migraine exacerbation
• Thromboembolic events (rare but serious)

Timing & Dose Dependency:

• Sedation and dizziness are dose-related, especially with oral forms
• Vaginal formulations typically cause fewer systemic effects

• CYP3A4 Inducers (e.g., rifampin, carbamazepine, phenytoin):
  • May reduce progesterone effectiveness by increasing hepatic metabolism.
• CYP3A4 Inhibitors (e.g., ketoconazole, erythromycin):
  • May increase progesterone plasma concentration, potentially enhancing side effects.
• Estrogens:
  • Combined use requires caution due to increased risk of endometrial and breast cancer.
• Anticoagulants:
  • Progesterone may alter coagulation; monitor INR in patients on warfarin or similar agents.
• Alcohol:
  • May enhance sedative effects of oral progesterone; avoid concurrent use.

• NICE 2024 Guidelines:
  • Micronised progesterone preferred in HRT due to a lower risk of breast cancer and thromboembolic events compared to synthetic progestins.
• WHO Reproductive Health Updates:
  • Vaginal progesterone remains a recommended option for prevention of recurrent preterm birth in high-risk pregnancies.
• IVF Protocols (2023–2024):
  • Continued preference for micronised progesterone (oral or vaginal) for luteal support due to better tolerability and improved pregnancy outcomes.

• Temperature: Store below 25°C (77°F)
• Humidity: Keep away from moisture; store in a dry place
• Light Protection: Store in original packaging to protect from light
• Handling Precautions:
  • Oral capsules should be taken with water at bedtime
  • Vaginal preparations should be administered using the applicator provided
  • Keep out of reach of children
• Refrigeration: Not required unless specified by the manufacturer
• Shelf Life: Typically 24–36 months if unopened; refer to packaging