Pocket Oncology (Pocket Notebook Series), 1st Ed.

HORMONAL AGENTS

Angela G. Michael

Enzalutamide (Xtandi)

Dosing/dose adjustments: 160 mg oral daily (4–40 mg capsules). No renal or hepatic dose adjustments recommended. Concomitant strong CYP2C8 inhibitors: 80 mg oral daily. Adjust/withhold dose for grade ≥3 tox.

PK/PD: Rapid absorption, ∼97–98% protein bound, hepatic metabolism via CYP2C8 & CYP3A4, renal excretion (∼70%), T1/2 5.8 d

Adverse effects: Peripheral edema, fatigue, HA, hot flashes, diarrhea, back pain, arthralgia, dizziness, seizure (0.9%)

DDI: Strong CYP3A4 inducer, mod. CYP2C9 & 2C19 inducer, avoid use w/narrow therapeutic index agents metabolized via these enzymes, CYP3A4 inducers (↓ conc. of enzalutamide), strong CYP2C8 inhibitors (gemfibrozil, ↑ conc. of enzalutamide), CYP2C8 inducers (↓ conc. of enzalutamide), warfarin (↑ risk of bleeding)

Clinical pearls: Can be taken w/or w/o food. Potential ↑ in CV disease risk w/androgen deprivation Rx.

Bicalutamide (Casodex)

Dosing/dose adjustments: 50 mg oral daily in combination w/LHRH analog) OR 150 mg oral daily as monotherapy. No renal dose adjustment recommended. Use caution in mod-sev. hepatic impairment; ALT > 2× ULN: D/C

PK/PD: 96% protein bound, extensive hepatic metabolism, mod. renal excretion (∼36%), T1/2 ∼6 d (↑ to 10 d in sev. liver disease)

Adverse effects: Peripheral edema, pain, hot flashes, breast pain, gynecomastia (38–39%), constipation/diarrhea, pelvic pain, weakness, bone pain, dizziness, dyspnea, ↓ glu tolerance

DDI: CYP3A4 inhibitor, CYP3A4 substrates (↑ conc. of substrate), warfarin (↑ bleeding risk)

Clinical pearls: Can be taken w/ or w/o food. Potential ↑ in CV disease risk w/androgen deprivation Rx.

Flutamide (Eulexin)

Dosing/dose adjustments: 250 mg oral 3× daily. No renal dose adjustment recommended. Use contraindicated in sev. hepatic impairment, ALT > 2× ULN: Avoid use.

PK/PD: ∼94% protein binding, extensive hepatic metabolism, renal excretion, T1/2 5–6 h

Adverse effects: Hepatotoxicity (BBW), gynecomastia, hot flashes, breast tenderness, impotence, ↓ libido, tumor flare, ↑ AST (transient), ↑ LDH (transient), N/V, diarrhea

DDI: Abiraterone, mod.-strong CYP1A2 inhibitors, mod.-strong CYP3A4 inhibitors. Dasatinib (↑ levels of flutamide), CYP1A2 inducers, CYP3A4 inducers (↓ levels of flutamide), warfarin (↑ risk of bleeding)

Clinical pearls: Can be taken w/ or w/o food. Potential ↑ in CV disease risk w/androgen deprivation Rx. Measure LFTs before starting Rx.

Nilutamide (Nilandron)

Dosing/dose adjustments: 300 mg oral daily × 1 mo, then 150 mg oral daily. No renal dose adjustments recommended. Sev. hepatic impairment: Contraindicated. ALT > 2× ULN or jaundice (on Rx): D/C.

PK/PD: Rapid absorption, extensive hepatic metabolism, renal excretion (62%), T1/2 38–59 h, 59–126 h (metabolites)

Adverse effects: Interstitial pneumonitis (BBW), HA, hot flashes, insomnia, breast tenderness, impotence, ↓ libido, tumor flare, ↑ AST/ALT, N/V, constipation, impaired dark adaptation (up to 57%)

DDI: CYP2C19 inhibitors/inducers (↑/↓ conc. of nilutamide), ethanol (intolerance)

Clinical pearls: Can be taken w/ or w/o food

Anastrozole (Arimidex)

Dosing/dose adjustments: 1 mg oral daily. No renal dose adjustment recommended. Use caution in sev. hepatic impairment.

PK/PD: 40% protein bound, extensive hepatic metabolism (∼85%), onset of estradiol reduction 70% after 24 h, 80% after 2 wks, T1/2 50 h

Adverse effects: Vasodilation, HTN, fatigue, HA, hot flashes, mood disturbance, Ø BMD, ≠ cholesterol (≠ CV risk), arthralgia, weakness, fatigue, peripheral edema, ↑ LFTs, insomnia

DDI: Estrogen derivatives (↓ anastrozole effect), tamoxifen (↓ efficacy of anastrozole, conc. ↓ by 27%)

Clinical pearls: Can be taken w/ or w/o food, consider Ca & Vit D supplementation while on anastrozole

Letrozole (Femara)

Dosing/dose adjustments: 2.5 mg oral daily. No renal dose adjustment recommended. Sev. hepatic dysfunction (Child-Pugh class C) & cirrhosis: 2.5 mg oral every other day.

PK/PD: Rapid absorption, hepatic metabolism via CYP3A4/2D6, renal excretion (90%), T1/2 2 d

Adverse effects: Edema, HA, ≠ cholesterol, hot flashes, weakness, arthralgia, Ø BMD, diaphoresis, fatigue, dizziness

DDI: CYP2A6 substrates (↑ conc. of substrate), tamoxifen (↓ conc. of letrozole by 38%)

Clinical pearls: Can be taken w/ or w/o food, consider Ca & Vit D supplementation while on letrozole

Exemestane (Aromasin)

Dosing/dose adjustments: 25 mg oral daily. Use caution in pts w/mod.-to-sev. renal or hepatic dysfunction. Concomitant CYP3A4 inducer: 50 mg oral daily.

PK/PD: 40% ↑ absorption w/high fat meal, 90% protein bound, extensive tissue distribution, hepatic oxidation via CYP3A4, mod. renal excretion (∼40%), T1/2 24 h

Adverse effects: HTN, fatigue, insomnia, HA, depression, hyperhidrosis, hot flashes, nausea, arthralgia, ↑ Alk Phos, edema, dizziness, ↓ BMD

DDI: CYP3A4 inducers (↓ conc. of exemestane), no effect of CYP3A4 inhibitors

Clinical pearls: Administer after a high fat meal, consider Ca & Vit D supplementation while on exemestane

Abiraterone (Zytiga)

Dosing/dose adjustments: 1000 mg oral daily. No renal dose adjustment recommended. Hepatic (prior): Child-Pugh class B: 250 mg oral daily, Child-Pugh class C: Avoid; hepatic (during): AST/ALT >5× ULN or Tbili > 3× ULN: Withhold until AST/ALT <2.5× ULN & TBili <1.5× ULN, resume at 750 mg oral daily, if recurrent, ↓ to 500 mg oral daily.

PK/PD: ↑ absorption w/food (AUC ↑ 10-fold), >99% protein bound, extensive distribution, hydrolyzed to active metabolite, metabolism via CYP3A4/SULT2A1 to inactive metabolites, T1/2 14–16 h

Adverse effects: Mineralocorticoid excess (edema, HTN, ↓ K), fatigue, ↑ TG, hyperglycemia, ↑ LFTs, joint swelling, hot flashes, cough, insomnia

DDI: Strong inhibitor of CYP1A2, CYP2D6, CYP2C8, mod. inhibitor of CYP2C9, CYP2C19, CYP2C8. Strong CYP3A4 inhibitors/inducers (↑/↓ effect of abiraterone), CYP2D6 substrates w/narrow therapeutic index (ie, thioridazine, ↑ effect of substrate)

Clinical pearls: Available as 250 mg tablets. Take on empty stomach (at least 1 h before or 2 h after food), administered in combination w/prednisone 5 mg oral twice daily (suppression of ACTH drive). Monitor LFTs before starting, every 2 wks × 3 mos, then monthly while on Rx.

Fulvestrant (Faslodex)

Dosing/dose adjustments: 500 mg IM d 1, 15, 29, then 500 mg IM monthly. No renal dose adjustment recommended. Hepatic: Child-Pugh class B: ↓ initial & maintenance dose to 250 mg; Child-Pugh class C: Caution use.

PK/PD: Steady state achieved ∼1 mo, 99% protein bound, hepatic metabolism (CYP3A4 involved but contribution unknown), T1/2 ∼40 d

Adverse effects: Hot flashes, ↑ LFTs, joint disorders, injection site pain, bone pain, arthralgia, fatigue, HA, nausea, vasodilation, pharyngitis

DDI: No known significant drug interactions

Clinical pearls: IM administration ONLY

Goserelin (Zoladex)

Dosing/dose adjustments: Prostate CA (advanced): 3.6 mg SC every 28 d OR 10.8 mg every 12 wks; prostate CA (local w/antiandrogens + RT): 3.6 mg SC every 28 d × 4 doses or 3.6 mg once followed by 10.8 mg implant; breast CA: 3.6 mg SC every 28 d. No renal or hepatic dose adjustments recommended.

PK/PD: Estradiol & testosterone suppression w/in 2–4 wks, rapid absorption, slow release × 8 d, then continuous release × 28 d, renal excretion (90% unchanged), T1/2 4 h (males, ↑ to 12 h in renal impairment), 2 h (females)

Adverse effects: Peripheral edema, HA (up to 75% in females), emotional lability/depression (↑ females), acne/seborrhea, hot flashes, ↓ libido, Ø BMD, tumor flare, hyperglycemia, vaginal dryness

DDI: No known significant drug interactions

Clinical pearls: Tumor flare can be alleviated w/concomitant antiandrogen Rx, consider Ca & Vit D supplementation while on goserelin. Potential ↑ in CV disease risk w/androgen deprivation Rx.

Leuprolide (Lupron, Lupron Depot, Eligard)

Dosing/dose adjustments: Prostate CA: Lupron (IM), Eligard (SC): 7.5 mg every month, 22.5 mg every 12 wks, 30 mg every 16 wks, 45 mg every 24 wks; breast CA: 3.75 mg every 28 d OR 11.25 mg every 3 mo, continue up to 24 mo. No renal or hepatic dose adjustments recommended.

PK/PD: Testosterone suppression w/in 2–4 wks, ∼45% protein bound

Adverse effects: Injection site pain, edema, HA, fatigue, depression, hot flashes, ↓ libido, vaginitis, ↓ BMD, ↑ glu

DDI: Antidiabetic agents (potential ↑ glu & insulin resistance)

Clinical pearls: Tumor flare can be alleviated w/concomitant antiandrogen Rx, consider Ca & Vit D supplementation while on goserelin. Potential ↑ in CV disease risk w/androgen deprivation Rx.

Degarelix (Firmagon)

Dosing/dose adjustments: Loading dose: 240 mg (2–120 mg injections) SC × 1; maintenance dose: 80 mg SC every 28 d. Use w/caution in CrCl < 50 mL/min & in sev. hepatic impairment.

PK/PD: Biphasic release, rapid onset of action (w/in 3 d), ∼90% protein bound, hepatobiliary metabolism via hydrolysis, mod. renal excretion (∼30%), T1/2 ∼53 d

Adverse effects: Hot flashes, injection site rxns, ↑ LFTs, Ab formation, wt gain, arthralgia

DDI: QTc-prolonging agents (↑ QTc prolongation)

Clinical pearls: Consider Ca & Vit D supplementation while on degarelix

Raloxifene (Evista)

Dosing/dose adjustments: breast CA risk reduction: 60 mg oral daily × 5 y. Use caution w/mod.-sev. renal impairment. Use caution in hepatic impairment (↑ conc. in hepatic impairment).

PK/PD: Rapid absorption, bioavailability ∼2%, onset 8 wks, >95% protein bound (albumin & alpha-glycoprotein), hepatic metabolism, extensive first-pass metabolism, T1/2 28–33 h

Adverse effects: ≠ VTE risk (BBW), ≠ risk of stroke (BBW), peripheral edema, hot flashes, arthralgia, leg cramps, flu-like syndrome

DDI: Levothyroxine (↓ effects of levothyroxine), bile acid sequestrants (↓ absorption of raloxifene)

Clinical pearls: Can be taken w/ or w/o food

Tamoxifen (Nolvadex, Soltamox)

Dosing/dose adjustments: 20 mg oral daily. No renal or hepatic dose adjustments recommended.

PK/PD: Well absorbed, distributes well into uterine, endometrial & breast tissue, 99% protein bound, hepatic metabolism via CYP2D6 & CYP3A4/5, min. renal excretion (∼10%), T1/2 (tamoxifen) 5–7 d, (metabolite) ∼14 d

Adverse effects: ↑ uterine/endometrial CA (BBW), ≠ VTE risk (BBW), flushing, vasodilation, skin changes, hot flashes, fluid retention, amenorrhea, nausea, wt loss, vaginal D/C, weakness, arthralgia

DDI: CYP2D6 inhibitors (↓ conc. of tamoxifen, risk ↑ breast CA recurrence), SSRI (↓ tamoxifen efficacy, esp. fluoxetine, paroxetine, sertraline) (J Clin Psychiatry 2009;70:1688), QTc-prolonging agents (↑ QTc prolongation), P-gp substrates (↓ conc. of substrates), CYP3A4 inhibitors/inducers (↑/↓ conc. of tamoxifen), CYP2C9 inhibitors/inducers (↑/↓ conc. of tamoxifen), grapefruit juice (↓ metabolism of tamoxifen)

Clinical pearls: CYP2D6 poor metabolizers (↓ endoxifen conc. & efficacy), can be taken w/ or w/o food

Info. based on publicly available drug inserts from Abbott, Astellas, AstraZeneca, Eli Lilly, Janssen, Novartis, Schering, & Sanofi-Aventis.