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  • CLASSES

    Other Antineoplastic Agents

    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. Pregnancies should be reported to Genentech at 1-888-835-2555.

    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
    Approved 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 metastatic basal cell carcinoma or locally advanced basal cell carcinoma that has recurred following surgery or in patients who are not candidates for surgery or radiation.
    Oral dosage
    Adults

    150 mg PO once daily until disease progression or unacceptable toxicity. At a median vismodegib treatment duration of approximately 10 months, 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 in a multinational, open-label, 2-cohort trial (ERIVANCE trial). Patients with locally advanced disease had unresectable BCC that recurred following radiotherapy (RT), unless RT was contraindicated or not appropriate. In a 24-month update of the ERIVANCE trial, the median duration of response (DOR) was 16.1 months. Additionally, patients with metastatic BCC and locally advanced BCC had median progression-free survival (PFS) times of 9.3 months and 12.9 months, respectively, and median overall survival (OS) times of 33.4 months and not estimable, respectively. The 2-year OS rate was 62.3% in patients with metastatic BCC and 85.4% in patients with locally advanced BCC. The efficacy and toxicity of vismodegib were evaluated in patients with metastatic or locally advanced BCC ineligible for surgery or radiation in an expanded access study (n = 119) and a multinational, nonrandomized, phase II trial (n = 499; the STEVIE trial). In a preplanned interim analysis of the STEVIE trial in BCC patients followed for 12 months or longer, the investigator-assessed (using RECIST criteria) ORR was 37.9% in 29 evaluable patients with metastatic BCC (median follow-up, 12.9 months) and 66.7% in 453 evaluable patients with locally advanced BCC (median follow-up, 12.7 months) following a median vismodegib treatment duration of 36.4 weeks. In BCC patients who had a response (n = 313), the median time to response was 2.7 months and the median DOR was 22.7 months. In the intent-to-treat population (n = 496), the median PFS time was 20.2 months (metastatic BCC, 13.1 months; locally advanced BCC, 24.5 months).

    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

    A vismodegib dose adjustment is not necessary in patients with baseline hepatic impairment. Vismodegib was evaluated in patients with mild (normal total bilirubin level and AST level > the upper limit of normal (ULN) OR a total bilirubin level of 1 to 1.5 times the ULN), moderate (total bilirubin level > 1.5 to 3 times the ULN), and severe (total bilirubin level > 3 to 10 times the ULN) hepatic impairment in a clinical study; hepatic impairment had minimal impact on the systemic exposure of vismodegib.

    Renal Impairment

    A vismodegib dose adjustment is not necessary in patients with baseline renal impairment. Vismodegib was evaluated in patients with mild (creatinine clearance (CrCl), 50 to 79 mL/min) and moderate (CrCl, 30 to 49 mL/min) renal impairment in a population pharmacokinetic analysis; renal impairment had no clinically significant impact on the systemic exposure of vismodegib.

    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.

    Children, growth inhibition, infants, neonates

    The safety and efficacy of vismodegib have not been established in adolescents, children, infants, and neonates. Growth inhibition due to premature fusion of the epiphyses may occur in pediatric patients. 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. In toxicity studies in rats receiving oral vismodegib, closure of the epiphyseal growth plate (at doses >= 50 mg/kg/dose given for 26 weeks) and incisor teeth abnormalities (at doses >= 15 mg/kg/dose) were observed.

    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. Pregnancies should be reported to Genentech at 1-888-835-2555.

    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

    According to the manufacturer, breast-feeding should be discontinued during therapy and for 24 months after the final dose due to the potential for serious adverse reactions in nursing infants from vismodegib. It is unknown if vismodegib is excreted into human milk.

    ADVERSE REACTIONS

    Severe

    weight loss / Delayed / 7.2-7.2
    fatigue / Early / 5.1-5.1
    anorexia / Delayed / 2.2-2.2
    azotemia / Delayed / 2.0-2.0
    diarrhea / Early / 0.7-0.7
    nausea / Early / 0.7-0.7
    arthralgia / Delayed / 0.7-0.7

    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
    secondary malignancy / Delayed / Incidence not known

    Mild

    alopecia / Delayed / 63.8-63.8
    dysgeusia / Early / 55.1-55.1
    vomiting / Early / 13.8-13.8
    amenorrhea / Delayed / Incidence not known

    DRUG INTERACTIONS

    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.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with vismodegib. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the Breast Cancer Resistance Protein (BCRP); vismodegib is an inhibitor of BCRP.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with vismodegib. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the Breast Cancer Resistance Protein (BCRP); vismodegib is an inhibitor of BCRP.
    Topotecan: (Major) Avoid the concomitant use of vismodegib, a weak, in vitro inhibitor of Breast Cancer Resistance Protein (BCRP), with oral topotecan, a BCRP substrate; the effect of vismodegib on intravenous topotecan is unknown. If coadministration of vismodegib and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant). When oral topotecan was administered concomitantly with escalating doses of a dual inhibitor of Breast Cancer Resistance Protein (BCRP) and P-gp, exposure to both total topotecan and topotecan lactone increased by approximately 2.5-fold compared with control.
    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

    According to the manufacturer, breast-feeding should be discontinued during therapy and for 24 months after the final dose due to the potential for serious adverse reactions in nursing infants from vismodegib. It is unknown if vismodegib is excreted into human milk.

    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 in a pharmacokinetic study (n = 3). 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: no clinically relevant CYP450 or P-gp interactions
    In vitro, vismodegib is a substrate of CYP2C9, CYP3A4, and P-glycoprotein (P-gp); inhibits CYP2C8, CYP2C9, and CYP2C19; and does not induce CYP1A2, CYP2B6, or CYP3A. The manufacturer states that clinically relevant pharmacokinetic interactions are not expected if vismodegib is co-administered with substrates, inducers, or inhibitors of cytochrome P450 isoenzymes or P-gp inhibitors.

    Oral Route

    The absolute bioavailability is 31.8% 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. Systemic exposure is not affected by food.