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VISMODEGIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Vismodegib is a hedgehog pathway inhibitor. It binds to and inhibits Smoothened, a transmembrane protein that is involved in Hedgehog signal transduction.

Specific Substances

    1) Vismodegibum
    2) GDC-0449
    3) RG-3616
    4) CAS 879085-55-9
    5) C19H14Cl2N2O3S
    1.2.1) MOLECULAR FORMULA
    1) C19H14Cl2N2O3S (Prod Info ERIVEDGE(TM) oral capsules, 2012)

Available Forms Sources

    A) FORMS
    1) Vismodegib is available in 150 mg capsules (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    B) USES
    1) Vismodegib is indicated for the treatment of patients with metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Vismodegib is indicated for the treatment of patients with metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.
    B) PHARMACOLOGY: Vismodegib is a Hedgehog pathway inhibitor. It binds to and inhibits Smoothened, a transmembrane protein that is involved in Hedgehog signal transduction.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects include: muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, constipation, joint pain, vomiting, decreased appetite, and ageusia.
    2) LESS FREQUENT: Other adverse effects occurring less frequently include hyponatremia, azotemia, hypokalemia, and amenorrhea.
    3) In postmarketing surveillance, there have been infrequent reports of hepatotoxicity including elevated liver enzymes, hepatitis, or hepatocellular damage.
    E) WITH POISONING/EXPOSURE
    1) Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) There are no adequate and well-controlled studies of vismodegib use in pregnant women; however, vismodegib can cause fetal harm based on the mechanism of action and animal data. Evidence shows pre- and postimplantation loss among rats exposed to oral doses.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of vismodegib.

Laboratory Monitoring

    A) Monitor serum electrolytes and renal function after overdose.
    B) Toxic levels of vismodegib have not been established; routine drug plasma levels are not likely to be available.
    C) Due to the risk of embryo-fetal death or severe birth defects, a pregnancy test is recommended in women of childbearing age who have been exposed to vismodegib.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Management is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with vomiting and/or diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Management is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea or vomiting. Significant alterations in sodium may lead to seizures; correct hyponatremia and treat seizures (eg, benzodiazepines).
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not routinely required following a minor exposure.
    2) HOSPITAL: Consider activated charcoal for a large overdose if the ingestion is recent and the patient is not vomiting and the airway can be maintained.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression or seizure activity.
    E) ANTIDOTE
    1) None.
    F) HYPONATREMIA
    1) Evaluate for hyponatremia and associated symptoms. Patients with mild symptoms can be managed with water restriction. Patients with moderate to severe symptoms should receive 0.9% sodium chloride (rarely 3% NaCl in patients with very severe symptoms). The goal is slow correction; the serum sodium should not increase more than 2 mEq/L/hour in any 4-hour period or more than 15 mEq/L per day. Rapid correction may cause central pontine myelinolysis. Monitor serum electrolytes, fluid intake and output, and urine volume and electrolytes.
    G) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the high degree of protein binding (99% or greater). Plasmapheresis might be effective based on the small volume of distribution and high protein binding, but has not been used in overdose.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A minor (a single dose) inadvertent dose in a patient currently being treated with vismodegib can likely be managed at home. An asymptomatic child with an inadvertent exposure (a single dose) can likely be monitored at home, if a responsible adult is present.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients demonstrating persistent electrolyte imbalance should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) Patients with a history of decreased gastrointestinal motility due to other causes. Consider the possibility of multidrug involvement when managing a suspected vismodegib overdose.
    J) PHARMACOKINETICS
    1) Following the administration of an oral dose, absolute bioavailability is 31.8%. Approximately, 99% protein bound. The volume of distribution ranges from 16.4 to 26.6 L. Greater than 98% of the total circulating drug-related components are parent drug. The metabolic pathways of vismodegib include oxidation, glucuronidation, and pyridine ring cleavage. The two primary oxidative metabolites recovered in the feces are produced in vitro by recombinant CYP2C9 and CYP3A4/5. Vismodegib and its metabolites are primarily eliminated by the hepatic route with 4.4% recovered in the urine and 82% recovered in the feces. The estimated elimination half-life is 4 days with continuous once-daily dosing and 12 days after a single dose.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes overdose of other agents that may cause adverse gastrointestinal effects, hyponatremia or muscle spasms.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established .Doses up to 540 mg once daily were tolerated in clinical trials, and were not associated with increased exposure compared to a dose of 150 mg once daily.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose is 150 mg orally once daily until disease progression or unacceptable toxicity occurs. PEDIATRIC: Safety and efficacy of vismodegib have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Vismodegib is indicated for the treatment of patients with metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.
    B) PHARMACOLOGY: Vismodegib is a Hedgehog pathway inhibitor. It binds to and inhibits Smoothened, a transmembrane protein that is involved in Hedgehog signal transduction.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects include: muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, constipation, joint pain, vomiting, decreased appetite, and ageusia.
    2) LESS FREQUENT: Other adverse effects occurring less frequently include hyponatremia, azotemia, hypokalemia, and amenorrhea.
    3) In postmarketing surveillance, there have been infrequent reports of hepatotoxicity including elevated liver enzymes, hepatitis, or hepatocellular damage.
    E) WITH POISONING/EXPOSURE
    1) Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea (all grades) occurred in 42 (30.4%) patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months) (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting (all grades) occurred in 19 (13.8%) patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months) (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea (all grades) occurred in 49 (29%) patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months) (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation (all grades) occurred in 29 (21%) patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months) (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    E) DECREASE IN APPETITE
    1) WITH THERAPEUTIC USE
    a) Decreased appetite (all grades) occurred in 35 (25.4%) of patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months). Grade 3 decreased appetite occurred in 3 (2.2%) patients (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    F) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) Dysgeusia (all grades) occurred in 76 (55.1%) patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months) (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    G) LOSS OF TASTE
    1) WITH THERAPEUTIC USE
    a) Ageusia (all grades) occurred in 15 (10.9%) patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months) (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance, a case of marked reversible hepatitis occurred in an individual 3 weeks after the initiation of vismodegib therapy. Following a review of the FDA Adverse Events Reporting System, 15 cases of hepatotoxicity associated with vismodegib were reported. Adverse reactions included elevated liver enzymes, or bilirubin, hepatitis, or hepatocellular damage (Ventarola & Silverstein, 2014).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) AZOTEMIA
    1) WITH THERAPEUTIC USE
    a) Grade 3 azotemia occurred in 3 (2%) patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months) (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    B) AMENORRHEA
    1) WITH THERAPEUTIC USE
    a) Amenorrhea occurred in 3 of 10 premenopausal women who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months) (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia (all grades) occurred in 88 (63.8%) patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months) (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) SKELETAL MUSCLE SPASM
    1) WITH THERAPEUTIC USE
    a) Muscle spasms (all grades) occurred in 99 (71.7%) patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months). Grade 3 muscle spasms occurred in 5 (3.6%) patients (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgias (all grades) occurred in 22 (15.9%) patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months). Grade 3 arthralgias occurred in 1 patient (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) WEIGHT LOSS FINDING
    1) WITH THERAPEUTIC USE
    a) Weight loss (all grades) occurred in 62 (44.9%) patients who received 150 mg/day or more of oral vismodegib for advanced basal cell carcinoma in 4 open-label, uncontrolled, dose-ranging or fixed single dose clinical trials (n=138) for a median duration of 305 days (range, 0.7 to 36 months). Grade 3 weight loss occurred in 10 (7.2%) patients (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Reproductive

    3.20.1) SUMMARY
    A) There are no adequate and well-controlled studies of vismodegib use in pregnant women; however, vismodegib can cause fetal harm based on the mechanism of action and animal data. Evidence shows pre- and postimplantation loss among rats exposed to oral doses.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of vismodegib use in pregnant women; however, vismodegib can cause fetal harm based on the mechanism of action and animal data (Prod Info ERIVEDGE(R) oral capsules, 2015).
    B) ANIMAL STUDIES
    1) EMBRYO/FETAL RISK
    a) During animal studies, vismodegib was embryotoxic, fetotoxic, and teratogenic at exposures less than the recommended human exposure of 150 mg/day. At doses approximately 0.2 times the human exposure, malformations, retardations, or variations were observed (Prod Info ERIVEDGE(R) oral capsules, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Do not administer this drug to a pregnant woman (Prod Info ERIVEDGE(R) oral capsules, 2015)
    B) PREGNANCY REGISTRY
    1) Advise women if pregnancy occurs to report pregnancies to Genentech by calling 1-888-835-2555 (Prod Info ERIVEDGE(R) oral capsules, 2015)
    C) PREGNANCY TESTING
    1) Verify pregnancy status 7 days prior to treatment initiation (Prod Info ERIVEDGE(R) oral capsules, 2015)
    D) CONTRACEPTION
    1) Females of reproductive potential must use adequate contraception during treatment and for at least 9 months after discontinuation (Genentech Inc, 2016). Male patients must use condoms, even after vasectomy, during treatment and for at least 3 months after discontinuation. Males should not donate semen while receiving treatment and for at least 3 months following the last dose (Prod Info ERIVEDGE(R) oral capsules, 2015).
    E) ANIMAL STUDIES
    1) EMBRYO/FETAL RISK
    a) During animal studies, increases in pre- and postimplantation loss were reported with vismodegib at doses greater than or equal to 2 times the human exposure (Prod Info ERIVEDGE(R) oral capsules, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) RISK SUMMARY
    1) It is unknown if vismodegib is present in human milk or the effects of the drug on the breastfed infant. However, breastfeeding is not recommended. Advise nursing women not to breastfeed during treatment and for 9 months after the last dose (Genentech Inc, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In animal studies, male and female reproductive function and fertility were impaired (Prod Info ERIVEDGE(R) oral capsules, 2015)

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of vismodegib.
    3.21.4) ANIMAL STUDIES
    A) NEOPLASM
    1) RATS: Benign cutaneous neoplasms (pilomatricoma) were observed in rats exposed to oral vismodegib at a dose of 100 mg/kg/day (0.8 times the recommended human dose) for 26 weeks (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Genotoxicity

    A) There was no evidence of mutagenicity in the following test: in vitro bacterial reverse mutation (Ames) assay. There was no evidence of clastogenicity in the following tests: in vitro human chromosomal aberration assay in human peripheral blood lymphocytes and in vivo rat bone marrow micronucleus assay (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes and renal function after overdose.
    B) Toxic levels of vismodegib have not been established; routine drug plasma levels are not likely to be available.
    C) Due to the risk of embryo-fetal death or severe birth defects, a pregnancy test is recommended in women of childbearing age who have been exposed to vismodegib.
    4.1.2) SERUM/BLOOD
    A) SUMMARY
    1) Monitor serum electrolytes and renal function after overdose.
    2) Toxic levels of vismodegib have not been established; routine drug plasma levels are not likely to be available.
    B) PREGNANCY
    1) Due to the risk of embryo-fetal death or severe birth defects, a pregnancy test is recommended in women of childbearing age who have been exposed to vismodegib. Encourage women who may have been exposed during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients demonstrating persistent electrolyte imbalance should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A minor (a single dose) inadvertent dose in a patient currently being treated with vismodegib can likely be managed at home. An asymptomatic child with an inadvertent exposure (a single dose) can likely be monitored at home, if a responsible adult is present.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Monitor serum electrolytes and renal function after overdose.
    B) Toxic levels of vismodegib have not been established; routine drug plasma levels are not likely to be available.
    C) Due to the risk of embryo-fetal death or severe birth defects, a pregnancy test is recommended in women of childbearing age who have been exposed to vismodegib.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not routinely required following a minor exposure.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes and renal function.
    2) Monitor vital signs.
    3) Toxic levels of vismodegib have not been established; routine drug plasma levels are not likely to be available.
    4) Due to the risk of embryo-fetal death or severe birth defects, a pregnancy test is recommended in women of childbearing age who have been exposed to vismodegib.
    C) HYPONATREMIA
    1) Evaluate for hyponatremia and associated symptoms. Patients with mild symptoms can be managed with water restriction. Patients with moderate to severe symptoms should receive 0.9% sodium chloride (rarely 3% NaCl in patients with very severe symptoms). The goal is slow correction; the serum sodium should not increase more than 2 mEq/L/hour in any 4-hour period or more than 15 mEq/L per day. Rapid correction may cause central pontine myelinolysis. Monitor serum electrolytes, fluid intake and output, and urine volume and electrolytes.

Enhanced Elimination

    A) LACK OF EFFECT
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the high degree of protein binding (99% or greater). Plasmapheresis might be effective based on the small volume of distribution and high protein binding, but has not been used in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established .Doses up to 540 mg once daily were tolerated in clinical trials, and were not associated with increased exposure compared to a dose of 150 mg once daily.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose is 150 mg orally once daily until disease progression or unacceptable toxicity occurs. PEDIATRIC: Safety and efficacy of vismodegib have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose of vismodegib is 150 mg orally once daily until disease progression or unacceptable toxicity occurs (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    7.2.2) PEDIATRIC
    A) Safety and efficacy of vismodegib have not been established in pediatric patients (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Minimum Lethal Exposure

    A) There have been no reports of vismodegib toxicity at the time of this review (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Maximum Tolerated Exposure

    A) A specific toxic dose has not been established and there have been no reports of vismodegib overdose at the time of this review. Patients in clinical trials tolerated doses up to 540 mg orally once daily, and this dose was not associated with increased exposure compared to a dose of 150 mg/day (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Vismodegib is a hedgehog pathway inhibitor. It binds to and inhibits Smoothened, a transmembrane protein that is involved in Hedgehog signal transduction (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Physicochemical

Physical Characteristics

    A) Vismodegib is a white to tan powder with solubility that is pH-dependent, with 0.1 mcg/mL at pH 7 and 0.99 mg/mL at pH 1 (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Molecular Weight

    A) 421.3 g/mol (Prod Info ERIVEDGE(TM) oral capsules, 2012)

References

General Bibliography

    1) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    2) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    3) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    4) Genentech Inc: Dear Healthcare Professional letter for ERIVEDGE(R) (vismodegib). Genentech Inc. South San Francisco, CA. 2016. Available from URL: http://www.gene.com/download/pdf/Erivedge_HCP_Letter_February2016.pdf. As accessed 2016-03-15.
    5) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    6) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    7) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    8) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    9) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    10) Product Information: ERIVEDGE(R) oral capsules, vismodegib oral capsules. Genentech USA, Inc. (per manufacturer), South San Francisco, CA, 2015.
    11) Product Information: ERIVEDGE(TM) oral capsules, vismodegib oral capsules. Genentech USA, Inc. (per FDA), South San Francisco, CA, 2012.
    12) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    13) Ventarola DJ & Silverstein DI: Vismodegib-associated hepatotoxicity: a potential side effect detected in postmarketing surveillance. J Am Acad Dermatol 2014; 71(2):397-398.