Prasterone

For the treatment of moderate to severe dyspareunia associated with vulvovaginal atrophy:

• Standard Dose: One 6.5 mg vaginal insert administered once daily at bedtime.
• Duration: Treatment should continue as long as the clinical benefit outweighs the potential risks. Healthcare providers typically re-evaluate the need for therapy every 3 to 6 months.

Prasterone is not indicated for use in the pediatric population. It is specifically designed for postmenopausal women. There is no clinical data regarding the safety or efficacy of prasterone in children or adolescents, and its hormonal nature could potentially interfere with normal growth and development in younger individuals.

Renal Impairment

The effect of renal (kidney) impairment on the pharmacokinetics of prasterone has not been formally studied. However, because the dose is low and the primary action is local, dosage adjustments are generally not expected to be necessary for patients with mild to moderate renal impairment. Use with caution in severe renal disease.

Hepatic Impairment

Prasterone is metabolized in the liver. While systemic levels remain low with vaginal administration, patients with significant hepatic (liver) impairment should be monitored closely, as the body's ability to clear metabolites may be reduced.

Elderly Patients

No specific dosage adjustments are required for elderly patients. Clinical trials for prasterone included a significant number of women over the age of 65, and no overall differences in safety or effectiveness were observed compared to younger postmenopausal women.

Proper administration is crucial for the effectiveness of prasterone. Patients should follow these steps:

1. 1Preparation: Wash your hands thoroughly before handling the insert or applicator.
2. 2Loading: Remove one insert from its blister pack and place it into the open end of the provided applicator.
3. 3Insertion: While lying on your back with knees bent (or in any comfortable position), gently insert the applicator into the vagina as far as it will comfortably go.
4. 4Release: Press the plunger to release the insert into the vagina. Remove the applicator.
5. 5Timing: Administer the dose at bedtime to maximize local absorption and minimize leakage during the day.
6. 6Storage: Store the inserts at room temperature or in the refrigerator (2°C to 30°C or 36°F to 86°F). Do not freeze.

If you miss a dose of prasterone:

• Take the missed dose as soon as you remember, unless it is almost time for your next scheduled dose.
• If it is within a few hours of your next dose, skip the missed dose and return to your regular schedule.
• Do not use two inserts at once to make up for a missed dose.

Because prasterone is administered as a local vaginal insert with low systemic absorption, an acute overdose is unlikely to cause life-threatening symptoms. However, excessive use may lead to increased systemic levels of androgens and estrogens, potentially causing symptoms such as breast tenderness, mood swings, or acne. In the event of accidental ingestion or suspected overdose, contact a poison control center or seek emergency medical attention immediately.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or frequency of use without medical guidance, as this may affect the safety and efficacy of the treatment.

The most frequently reported side effect in clinical trials for prasterone vaginal inserts is:

• Vaginal Discharge: This occurred in approximately 14% of patients. The discharge is typically related to the melting of the insert's base (usually a hard fat) and is not necessarily a sign of infection. It is often described as a white or clear leakage that occurs shortly after administration or the following morning.

In clinical studies, the following side effects were reported by 1% to 10% of users:

• Abnormal Pap Smear: Some patients experienced changes in cervical cytology, primarily Low-grade Squamous Intraepithelial Lesions (LSIL). While these were not necessarily caused by the drug, regular gynecological monitoring is required.
• Application Site Reactions: Mild irritation, itching, or a burning sensation in the vaginal area immediately following insertion.
• Weight Changes: Small fluctuations in weight were noted in some clinical trial participants, though a direct causal link to the 6.5 mg dose is not definitively established.

Rare but possible side effects may include:

• Androgenic Effects: Because prasterone can be converted into testosterone, some women may experience mild acne, oily skin, or increased facial hair growth (hirsutism). These effects are more common with high-dose oral supplements than with the 6.5 mg vaginal insert.
• Breast Tenderness: Minimal systemic absorption of estrogen may lead to occasional breast sensitivity or swelling.
• Headache or Migraine: Hormonal shifts can sometimes trigger or worsen headaches in sensitive individuals.

> Warning: Stop taking Prasterone and call your doctor immediately if you experience any of these serious symptoms:

• Hypersensitivity Reactions: Signs of a severe allergic reaction, including hives, difficulty breathing, or swelling of the face, lips, tongue, or throat.
• Unusual Vaginal Bleeding: Any undiagnosed vaginal bleeding must be evaluated immediately by a healthcare provider to rule out endometrial hyperplasia or malignancy.
• Signs of a Blood Clot: Although the risk is considered very low with local prasterone, seek help for sudden leg pain, swelling, warmth, shortness of breath, or chest pain.
• Severe Pelvic Pain: Pain that is distinct from the dyspareunia being treated.

Long-term safety data for prasterone (up to 52 weeks in clinical trials) suggests that the risk of endometrial thickening (overgrowth of the uterine lining) is very low. However, because prasterone is converted into estrogens and androgens, the long-term effects on breast tissue and the cardiovascular system are still being monitored. Unlike systemic HRT, prasterone does not appear to significantly alter systemic lipid profiles or coagulation factors over a one-year period.

There are currently no FDA black box warnings for prasterone (Intrarosa). However, the labeling does include precautions regarding its use in women with a history of breast cancer, as the metabolic products (estrogens and androgens) could theoretically stimulate the growth of hormone-sensitive tumors.

Report any unusual or persistent symptoms to your healthcare provider. You may also report side effects to the FDA at 1-800-FDA-1088.

Prasterone is a hormonal precursor. While its primary action is intended to be local within the vaginal tissue, it is not entirely free from systemic considerations. Patients should be aware that prasterone is metabolized into active sex hormones, which can influence various physiological systems. It is not a lubricant; it is a medication that changes the structure and function of the vaginal lining.

No FDA black box warnings for Prasterone. Unlike some systemic estrogen therapies, prasterone has not been required to carry boxed warnings regarding cardiovascular risks or endometrial cancer, largely due to its localized intracrine mechanism and the low doses used.

• History of Breast Cancer: Prasterone has not been studied in women with a history of breast cancer. Because it is converted into estrogens and androgens, there is a theoretical risk that it could stimulate the recurrence of hormone-sensitive malignancies. Discuss the risks and benefits thoroughly with your oncologist.
• Undiagnosed Vaginal Bleeding: Before starting prasterone, any abnormal or unexplained vaginal bleeding must be investigated by a healthcare professional to exclude serious conditions such as uterine cancer.
• Hormone-Sensitive Conditions: Use with caution if you have a history of endometriosis, uterine fibroids, or other conditions that may be exacerbated by estrogen or androgen exposure.
• Liver Disease: While systemic exposure is low, patients with active liver disease should be monitored, as the liver is responsible for the conjugation and clearance of steroid metabolites.

Patients using prasterone should undergo regular medical follow-ups, typically including:

• Pelvic Examinations: To monitor the response of the vaginal tissue and check for any abnormalities.
• Breast Exams and Mammography: Routine screening as recommended for your age group to monitor for any changes in breast tissue.
• Pap Smears: To monitor cervical health, as abnormal results were noted in a small percentage of clinical trial participants.

Prasterone is not known to cause drowsiness, dizziness, or cognitive impairment. It is considered safe to drive or operate heavy machinery while using this medication.

There are no known direct interactions between alcohol and prasterone vaginal inserts. However, excessive alcohol consumption can affect overall hormonal balance and bone health in postmenopausal women.

If you stop using prasterone, the symptoms of vulvovaginal atrophy (such as dryness and painful intercourse) are likely to return over time as the vaginal tissue reverts to its postmenopausal state. There is no known withdrawal syndrome associated with stopping prasterone, and tapering the dose is generally not required.

> Important: Discuss all your medical conditions, especially any history of cancer or blood clots, with your healthcare provider before starting Prasterone.

While there are no absolute contraindications listed for specific drug-drug interactions in the FDA label, the following should be avoided due to conflicting mechanisms:

• Other Vaginal Estrogen Products: Using prasterone alongside vaginal estrogen creams, rings, or tablets is not recommended, as it may lead to excessive local hormone exposure and has not been studied for safety.

• Aromatase Inhibitors (e.g., Anastrozole, Letrozole): These medications are used to treat breast cancer by blocking the conversion of precursors into estrogen. Prasterone provides a precursor (DHEA) that could theoretically interfere with the efficacy of aromatase inhibitors. Patients on these medications should consult their oncologist before using prasterone.
• Tamoxifen: Similar to aromatase inhibitors, the hormonal metabolites of prasterone could potentially interfere with the anti-estrogenic effects of tamoxifen in breast cancer treatment.

• Systemic Hormone Replacement Therapy (HRT): If you are already taking oral or transdermal estrogen or progestin, the addition of prasterone may increase your total hormone burden. Your doctor may need to adjust your systemic HRT dose.
• Exogenous Androgens: Using prasterone with other androgenic steroids (e.g., testosterone gels) may lead to additive androgenic side effects like acne or hair growth.

There are no known interactions between prasterone vaginal inserts and specific foods. Because the drug is administered vaginally and acts locally, its absorption is not affected by the presence of food in the digestive tract.

• DHEA Supplements: Do not take over-the-counter DHEA supplements while using prescription prasterone. This can lead to unpredictable systemic hormone levels and increased risk of side effects.
• St. John's Wort: This herb can induce liver enzymes (CYP3A4) that metabolize steroids. While the effect on local vaginal prasterone is likely minimal, it could theoretically reduce systemic levels of its metabolites.
• Soy and Red Clover: These contain phytoestrogens which may have additive effects on the vaginal lining.

Prasterone use may affect certain laboratory results:

• Total DHEA-S, Testosterone, and Estradiol: You may see slight increases in these levels on blood tests, although they typically remain within the normal postmenopausal range.
• Thyroid Function Tests: Estrogens can increase thyroid-binding globulin, though this effect is usually associated with oral estrogens rather than local prasterone.

For each major interaction, the primary concern is the potential for prasterone to provide the "fuel" (precursors) for hormone production that other medications are trying to suppress. Management usually involves avoiding the combination or performing more frequent monitoring of the underlying condition.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, especially any hormonal therapies.

Prasterone must NEVER be used in the following circumstances:

• Undiagnosed Abnormal Genital Bleeding: Any vaginal bleeding of unknown cause must be fully evaluated before starting therapy. This is because bleeding can be a precursor or symptom of endometrial cancer, which is sensitive to the hormones produced by prasterone metabolism.
• Known Hypersensitivity: If you have had a severe allergic reaction to prasterone or any of the inactive ingredients (such as the hard fat base) in the insert, you must not use this medication.

Conditions requiring a careful risk-benefit analysis by a healthcare provider include:

• History of Breast Cancer: While not an absolute contraindication in the same way as undiagnosed bleeding, the use of prasterone in women with a history of breast cancer is generally avoided because the metabolites (estrogens and androgens) could potentially stimulate tumor cells.
• Active Thromboembolic Disorders: Patients with a current or recent history of blood clots (DVT, pulmonary embolism) should use prasterone with extreme caution, although the systemic risk is significantly lower than with oral estrogens.
• Endometriosis: The conversion of prasterone to estrogen could theoretically worsen endometriosis symptoms.

There is little evidence of cross-sensitivity between prasterone and other non-steroidal medications. However, individuals sensitive to other steroid hormones (like testosterone or estrogen) should be monitored for similar adverse reactions. Additionally, those with allergies to coconut oil or palm kernel oil derivatives should check the inactive ingredients, as the hard fat base may be derived from these sources.

> Important: Your healthcare provider will evaluate your complete medical history, including any history of cancer or liver disease, before prescribing Prasterone.

Prasterone is not indicated for use in pregnant women. According to FDA standards, it is essentially contraindicated in pregnancy (formerly Category X). There is no clinical need for prasterone during pregnancy, and exposure to exogenous androgens and estrogens can interfere with the normal hormonal environment necessary for fetal development. If pregnancy occurs while using prasterone, the medication should be discontinued immediately.

Prasterone is not indicated for use in nursing mothers. It is not known whether prasterone or its metabolites are excreted in human milk. However, because of the potential for serious adverse reactions in a nursing infant from exposure to sex hormones, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established. Prasterone is specifically intended for use in postmenopausal women. The use of steroid precursors in children could lead to premature epiphyseal closure (stopping bone growth) and precocious puberty.

In clinical trials of prasterone, a significant percentage of participants were aged 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger postmenopausal subjects. Prasterone is a mainstay of treatment for VVA in the geriatric population, as the prevalence of dyspareunia increases with the time elapsed since menopause.

Specific studies in patients with renal impairment have not been conducted. However, since the 6.5 mg dose is administered locally and systemic absorption is minimal, renal impairment is not expected to significantly alter the clinical effect or safety profile. No dose adjustment is currently recommended for mild to moderate renal dysfunction.

No studies have been performed in patients with hepatic impairment. Because the liver is the primary site for the metabolism of steroid hormones, patients with severe hepatic impairment should be monitored closely. In such patients, the clearance of any systemically absorbed prasterone or its metabolites might be reduced, potentially leading to higher systemic levels.

> Important: Special populations, particularly those with a history of hormone-sensitive cancers, require individualized medical assessment and frequent monitoring.

Prasterone (DHEA) acts as a pro-hormone. Its molecular mechanism is based on the concept of intracrinology. After vaginal administration, prasterone enters the vaginal cells (epithelial cells, fibroblasts, and smooth muscle cells). Inside these cells, it is converted by intracellular enzymes (such as 3β-HSD, 17β-HSD, and aromatase) into active androgens and estrogens.

• Estrogenic Action: The resulting estradiol binds to estrogen receptors (α and β), promoting the growth of the vaginal epithelium and increasing collagen production.
• Androgenic Action: The resulting testosterone binds to androgen receptors, which are believed to improve the structural integrity of the vaginal muscularis and contribute to improved sexual function.

The primary pharmacodynamic effect of prasterone is the improvement of the vaginal maturation index (increasing the percentage of superficial cells and decreasing parabasal cells) and the lowering of vaginal pH. These changes usually begin within the first 2 weeks of treatment, with maximal effects observed by 12 weeks. Unlike systemic estrogens, prasterone at the 6.5 mg dose does not typically cause significant proliferation of the endometrium.

| Parameter | Value |

|---|---|

| Bioavailability | Low systemic bioavailability (primarily local action) |

| Protein Binding | ~95% (primarily to Albumin and SHBG) |

| Half-life | ~15-20 hours (for DHEA-S metabolite) |

| Tmax | 1.0 to 4.0 hours (post-vaginal administration) |

| Metabolism | Intracellular conversion; Hepatic sulfation/glucuronidation |

| Excretion | Primarily Renal (as metabolites) |

• Molecular Formula: C19H28O2
• Molecular Weight: 288.43 g/mol
• Solubility: Practically insoluble in water; soluble in alcohol and organic solvents.
• Structure: A 17-ketosteroid consisting of an androstane skeleton with a double bond at C5-C6 and a hydroxyl group at the 3β position.

Prasterone is classified as a steroid precursor and a vaginal hormone replacement therapy. It is unique among VVA treatments because it provides both estrogenic and androgenic precursors, whereas most other treatments are exclusively estrogenic.