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  • CLASSES

    Small Molecule Antineoplastic Hedgehog Pathway Inhibitors

    BOXED WARNING

    Intrauterine fetal death, pregnancy

    Vismodegib use should be avoided during pregnancy. Vismodegib may cause fetal harm such as intrauterine fetal death or severe birth defects if used during pregnancy, based on its mechanism of action and animal reproduction studies. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating treatment with the drug. Although there are no human data on the use of vismodegib in pregnant women, it was embryotoxic, fetotoxic, and teratogenic in animals at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. Teratogenic effects including malformations (e.g., craniofacial anomalies, open perineum, absent or fused digits) and fetal retardation and other variations (e.g., dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws) occurred when pregnant rats received a dose resulting in approximately 0.2 times the exposure that was observed in humans who received the recommended dose. Advise patients to immediately notify their healthcare provider if they become pregnant or think they might be pregnant, or if a female partner of a male patient taking vismodegib becomes pregnant. Advise pregnant women of the potential risks to the fetus. There is a pregnancy exposure registry and pregnancies should be reported to Genentech at 1-888-835-2555.[59728]

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk during vismodegib treatment. Pregnancy testing should be performed in women of reproductive potential within 7 days prior to initiating therapy. Vismodegib is present in semen and male patients should not donate semen during vismodegib therapy or for 3 months after the last dose. Discuss contraception requirements to prevent pregnancy with male and female patients. Women of reproductive potential should use effective contraception during therapy and for 24 months after the final vismodegib dose. Due to the risk of male-mediated teratogenicity, male patients should use condoms, even after a vasectomy, to avoid potential drug exposure in pregnant partners and female partners of reproductive potential during therapy and for 3 months after the final vismodegib dose. The risk of infertility with vismodegib has not been studied in humans, although amenorrhea has been reported in premenopausal women who received vismodegib in clinical trials. In female rats, a decrease in the number of corpora lutea occurred following 26 weeks of oral vismodegib at doses (100 mg/kg/day) resulting in about 0.8 times the AUC observed in patients at the recommended human dose.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral hedgehog pathway inhibitor
    Used for metastatic or locally advanced basal cell carcinoma
    Black box warning for severe birth defects; pregnancy status must be verified prior to drug initiation

    COMMON BRAND NAMES

    Erivedge

    HOW SUPPLIED

    Erivedge Oral Cap: 150mg

    DOSAGE & INDICATIONS

    For the treatment of basal cell carcinoma (BCC).
    For the treatment of metastatic BCC or locally advanced BCC that has recurred following surgery or in patients who are not candidates for surgery or radiation.
    Oral dosage
    Adults

    150 mg orally once daily until disease progression. In patients who experience intolerable adverse reactions, withhold vismodegib for up to 8 weeks until the toxicity improves or resolves. Treatment durations shorter than 8 weeks prior to interruptions have not been studied.[59728] The objective response rate (ORR), assessed by independent review, was 30% in 33 evaluable patients with metastatic basal cell carcinoma (BCC) and 43% in 63 evaluable patients with locally advanced BCC who received vismodegib in a multinational, single-arm, 2-cohort, phase 2 trial (the ERIVANCE BCC trial).[52673] At a median follow-up of 39.1 months, the median progression-free survival (PFS) times were 9.3 months and 12.9 months in patients with metastatic BCC and locally advanced BCC, respectively; the 2-year overall survival rates were 62.3% and 85.5%, respectively.[63894] The best overall response rate was 36.9% in 84 evaluable patients with metastatic BCC and 68.5% in 1,077 evaluable patients with locally advanced BCC who received vismodegib in a multinational, nonrandomized, phase 2 trial (the STEVIE trial). At a median follow-up of 17.9 months, the median PFS times were 13.1 months and 23.2 months in patients with metastatic BCC and locally advanced BCC, respectively.[63893]

    MAXIMUM DOSAGE

    Adults

    150 mg/day PO.

    Geriatric

    150 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Vismodegib dosage adjustments are not necessary in patients with hepatic impairment.

    Renal Impairment

    Vismodegib dosage adjustments are not necessary in patients with renal impairment.[59728]

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer vismodegib with or without food.
    Swallow capsule whole; do not open or crush capsules.
    If the patient misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.

    STORAGE

    Erivedge:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Blood donation

    Blood donation or blood product donation is not recommended during vismodegib therapy and for at least 24 months after the last dose.

    Serious rash

    Serious rash/severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with vismodegib use. Permanently discontinue therapy in patients who develop SCARs.

    Children, growth inhibition, infants, neonates, precocious puberty

    The safety and efficacy of vismodegib have not been established in adolescents, children, infants, or neonates. Growth inhibition due to premature fusion of the epiphyses and precocious puberty may occur in pediatric patients; therefore, vismodegib is not indicated for use in this patient population.[59728] Patients who have not reached skeletal maturity and their parents should be informed of the risk of premature epiphyseal closure and growth inhibition prior to starting vismodegib therapy. Premature epiphyseal fusion was reported in 3 pediatric patients who received vismodegib following radiation and chemotherapy for the treatment of medulloblastoma (off label use). Epiphyseal growth plate fusion continued to progress in 2 of the 3 patients after vismodegib was discontinued. Patient were approximately 2, 5, and 7 years of age; the duration of vismodegib therapy was 4 months in the 2 year old patient and 12 months in the other 2 patients.[60901] In toxicity studies in rats receiving oral vismodegib, closure of the epiphyseal growth plate (at doses 50 mg/kg/dose or higher given for 26 weeks) and incisor teeth abnormalities (at doses 15 mg/kg/dose or higher) were observed.[59728]

    Intrauterine fetal death, pregnancy

    Vismodegib use should be avoided during pregnancy. Vismodegib may cause fetal harm such as intrauterine fetal death or severe birth defects if used during pregnancy, based on its mechanism of action and animal reproduction studies. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating treatment with the drug. Although there are no human data on the use of vismodegib in pregnant women, it was embryotoxic, fetotoxic, and teratogenic in animals at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. Teratogenic effects including malformations (e.g., craniofacial anomalies, open perineum, absent or fused digits) and fetal retardation and other variations (e.g., dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws) occurred when pregnant rats received a dose resulting in approximately 0.2 times the exposure that was observed in humans who received the recommended dose. Advise patients to immediately notify their healthcare provider if they become pregnant or think they might be pregnant, or if a female partner of a male patient taking vismodegib becomes pregnant. Advise pregnant women of the potential risks to the fetus. There is a pregnancy exposure registry and pregnancies should be reported to Genentech at 1-888-835-2555.[59728]

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk during vismodegib treatment. Pregnancy testing should be performed in women of reproductive potential within 7 days prior to initiating therapy. Vismodegib is present in semen and male patients should not donate semen during vismodegib therapy or for 3 months after the last dose. Discuss contraception requirements to prevent pregnancy with male and female patients. Women of reproductive potential should use effective contraception during therapy and for 24 months after the final vismodegib dose. Due to the risk of male-mediated teratogenicity, male patients should use condoms, even after a vasectomy, to avoid potential drug exposure in pregnant partners and female partners of reproductive potential during therapy and for 3 months after the final vismodegib dose. The risk of infertility with vismodegib has not been studied in humans, although amenorrhea has been reported in premenopausal women who received vismodegib in clinical trials. In female rats, a decrease in the number of corpora lutea occurred following 26 weeks of oral vismodegib at doses (100 mg/kg/day) resulting in about 0.8 times the AUC observed in patients at the recommended human dose.

    Breast-feeding

    It is not known if vismodegib is secreted in human milk or if it has effects on the breast-fed infant or milk production. Because there is a potential for adverse reactions in nursing infants from vismodegib, women should discontinue breast-feeding during vismodegib therapy and for at 24 months after the last dose.[59728]

    ADVERSE REACTIONS

    Severe

    new primary malignancy / Delayed / 0-30.0
    weight loss / Delayed / 7.0-7.0
    fatigue / Early / 5.7-5.7
    muscle cramps / Delayed / 3.6-3.6
    anorexia / Delayed / 2.2-2.2
    azotemia / Delayed / 2.0-2.0
    nausea / Early / 0.7-0.7
    diarrhea / Early / 0.7-0.7
    arthralgia / Delayed / 0.7-0.7
    teratogenesis / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 21.0-21.0
    hyponatremia / Delayed / 4.0-4.0
    hypokalemia / Delayed / 1.0-1.0
    growth inhibition / Delayed / 0-1.0

    Mild

    alopecia / Delayed / 63.8-63.8
    dysgeusia / Early / 55.0-55.0
    amenorrhea / Delayed / 30.0-30.0
    vomiting / Early / 14.0-14.0

    DRUG INTERACTIONS

    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Grapefruit juice: (Moderate) Concomitant use of vismodegib and grapefruit juice may result in increased exposure of vismodegib and an increased risk of vismodegib adverse events. Vismodegib is a substrate of P-glycoprotein (PGP) and grapefruit is a PGP inhibitor. Use these agents together with caution and monitor patients for toxicity.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Warfarin: (Moderate) Elevated INR values up to 9.5 occurred when vismodegib was added to a medication regimen that included warfarin in a 78-year old man with recurrent basal-cell carcinoma and recurrent deep vein thrombosis. Therefore, use these drugs together with caution; consider increased INR monitoring. Using the Drug Interaction Probability Scale (DIPS), a score of 7 indicated a probable warfarin-vismodegib interaction. CYP isoenzyme inhibition (i.e., CYP2C9) and/or warfarin displacement from protein binding (as both drugs are highly protein bound) are possible reasons for this drug-drug interaction per the authors of this case report. The patient had been stable on warfarin therapy for 9 months prior to starting vismodegib; the medical chart listed no other medication changes and the patient reported no change alcohol consumption, smoking, or diet and denied symptoms of diarrhea or vomiting. His INR increased from 2.3 to 4.6 about 3 weeks after starting vismodegib 150 mg PO once daily. After skipping one dose and resuming warfarin therapy at the previous dose (total dose of 55 mg/week) for 3 weeks, the patient's INR was 9.5. Warfarin therapy was held for 5 days and then resumed at a 31.8% decrease in weekly dose (to a total dose of 37.5 mg/week). Within one week, warfarin therapy was again held and resumed at a lower dose (total of a 36% decrease in weekly dose from the original dose), his INR level was 2.9 one week later. Within 2 weeks of the last warfarin dosage change, the patient was admitted to the hospital with altered mental status and loss of consciousness unrelated to warfarin therapy; the INR level was 4.7 on admission and warfarin and vismodegib were discontinued. The patient died in the hospital for reasons not caused by an elevated INR.

    PREGNANCY AND LACTATION

    Pregnancy

    It is not known if vismodegib is secreted in human milk or if it has effects on the breast-fed infant or milk production. Because there is a potential for adverse reactions in nursing infants from vismodegib, women should discontinue breast-feeding during vismodegib therapy and for at 24 months after the last dose.[59728]

    MECHANISM OF ACTION

    Vismodegib is a hedgehog (Hh) signaling pathway inhibitor. It works by binding to and inhibiting the transmembrane protein smoothened (SMO) that is necessary for Hh signal transduction. The Hh signaling pathway regulates normal cell development, replication, and differentiation and hair growth. Dysregulation of the Hh signaling pathway is associated with basal cell carcinoma (BCC) development; mutations in transmembrane protein receptors that result in SMO activation are common in BCC.

    PHARMACOKINETICS

    Vismodegib is administered orally. It has low aqueous solubility and is highly permeable. It has a volume of distribution ranging from 16.4 to 26.6 liters. Plasma protein binding, both to serum albumin and alpha-1 acid glycoprotein (AAG), is greater than 99%; binding to AAG is saturable. Vismodegib is present in semen. The average concentration of vismodegib in semen was 6.5% of the average steady-state plasma concentration on day 8. Vismodegib is metabolized by oxidation, glucuronidation, and pyridine ring cleavage. Oxidative metabolites recovered in the feces are produced in vitro by CYP2C9 and CYP3A4/5 isoenzymes. More than 98% of the total circulating drug-related components are the parent drug. The primary route of elimination for vismodegib and its metabolites is hepatic with 82% and 4.4% of the administered dose recovered in the feces and urine, respectively. The estimated elimination half-life is 4 days following prolonged once daily dosing or 12 days after a single dose.
    Affected cytochrome P450 isoenzymes and drug transporters: none
    In vitro, vismodegib is a substrate of CYP2C9 and CYP3A4. It inhibits the breast cancer resistance protein (BCRP) transporter and does not induce CYP1A2, CYP2B6, or CYP3A in vitro.[59728]

    Oral Route

    The absolute bioavailability is 32% following a single vismodegib dose. Absorption is saturable; no proportional increase in systemic exposure was observed following a single 270 mg or 540 mg dose of vismodegib. The average steady-state plasma concentration was about 23 micromolar following vismodegib 150 mg/day dosing. Cmax and AUC(0 to 24 hr) values are not affected by food.[59728]