Phexxi
Phexxi
Generic Name
Phexxi
Mechanism
- Selective ER modulation: Phexxi’s esterified estrone is hydrolyzed to estrone, which binds estrogen receptor‑α (ER‑α) with high affinity.
- Tissue‑specific antagonism: In breast tissue, the drug induces receptor down‑regulation and promotes corepressor recruitment, thereby blocking proliferation of ER‑positive tumor cells.
- Modest agonist activity in bone and endometrium keeps bone mineral density stable while maintaining low endometrial thickness (70 % at steady state).
Pharmacokinetics
| Parameter | Value (steady‑state) |
| Absorption | Oral bioavailability ~70 %; peak plasma (Cmax) at ~6 h. |
| Distribution | High plasma protein binding (~94 %). |
| Metabolism | Primarily hepatic via CYP3A4/2D6 to estrone and subsequent sulfation. |
| Elimination | Renal excretion ~20 %; half‑life ≈ 12 h (steady‑state). |
| Drug‑drug interactions | CYP3A4 inducers (e.g., rifampin) reduce exposure; CYP3A4 inhibitors (e.g., ketoconazole) increase exposure by ~1.5‑fold. |
Indications
- Primary: 5‑year adjuvant therapy to prevent recurrence of early‑stage, estrogen‑receptor‑positive breast cancer in post‑menopausal women, following adjuvant endocrine therapy or tamoxifen.
- Exploratory/Off‑label: Pre‑clinical studies suggest potential benefit in chemoprevention of high‑risk pre‑menopausal women, but not yet approved.
Contraindications
Contraindications
• Known hypersensitivity to estrone, estriol, or excipients.
• Current or history of estrogen‑sensitive malignancy (e.g., metastatic breast cancer, endometrial carcinoma).
Warnings
• Venous thromboembolism (VTE) – risk increased; baseline assessment of VTE risk factors recommended.
• Hypertension – monitor BP; consider if significant uncontrolled hypertension.
• Endometrial hyperplasia – monitor via transvaginal ultrasound and cytology for patients >5 years of therapy.
• Cardiovascular disease – caution in patients with active coronary artery disease or stroke history.
Dosing
- Standard dose: 20 mg (oral) once daily (with water and food).
- Initiation: Start first dose immediately after completion of prior endocrine therapy (e.g., aromatase inhibitors).
- Titration: No dose adjustment needed unless drug interactions or adverse events occur.
- Discontinuation: Taper over one cycle if severe adverse effect develops (optional).
Adverse Effects
| Adverse Effect | Frequency | Notes |
| Hot flashes | 40–50 % | Moderate to severe in ~10 % |
| Mood changes, anxiety | 10–15 % | Monitor mood; consider counseling |
| Vasomotor symptoms | 25 % | Reduce with supportive therapies |
| Headache | 8–12 % | Usually mild |
| Weight gain | 6–10 % | Monitor BMI annually |
| Endometrial thickening | 1–2 % >2 mm | Screening recommended |
| Venous thromboembolism | <1 % | Symptoms: leg swelling, dyspnea |
Serious
• VTE (DVT/PE) – immediate evaluation if suspected.
• Cardiovascular events – monitor cardiac status in high‑risk patients.
• Severe endometrial hyperplasia – requires biopsy and potential hysterectomy.
Monitoring
- Baseline: CBC, CMP, lipid panel, fasting glucose, BP, BMI.
- Endocrine: Serum estrone, estradiol, LH, FSH every 6 months.
- VTE risk: D-dimer if symptomatic; routine surveillance not required.
- Endometrial: Transvaginal ultrasound ± cytology at baseline, 1 year, and every 2 years thereafter.
- Bone density: DXA at baseline and annually.
- Cardiovascular: ECG and lipid profile annually in patients ≥55 yrs.
- Patient-reported outcomes: Hot flash diaries, quality‑of‑life questionnaires.
Clinical Pearls
- Once‑daily convenience: The hexestanyl ester ensures high plasma exposure and low variability, eliminating the dose‑skipping risk seen with tamoxifen BID.
- VTE risk stratification: Use the Khorana score; consider anticoagulation prophylaxis in patients with ≥3 points who remain symptomatic.
- Neuropsychiatric side‑effects: Early identification of mood changes reduces drug discontinuation; simple counseling tools can be integrated into clinic visits.
- Endometrial surveillance: Even though endometrial thickening is rare, annual ultrasound provides early detection of any pathology, ensuring patient safety.
- Drug interactions: Counsel patients on OTC CYP3A4 inducers (e.g., St. John's wort) that can lower Phexxi exposure; adjust or monitor serum levels if applicable.
- Patient education: Emphasize adherence; a single pill once daily is a significant improvement over tamoxifen's daily BID regimen.
Key Takeaway: Phexxi offers a targeted, convenient chemopreventive option for post‑menopausal women with ER‑positive early‐stage breast cancer, balancing efficacy with a safety profile that is manageable through structured monitoring and patient education.