1) ACUTE EFFECTS: COMMON: The most common adverse effects occurring in greater than or equal to 10% of patients treated with 200 mg of sonidegib include: headache, abdominal pain, nausea, vomiting, diarrhea, dysgeusia, decreased appetite, decreased weight, muscle spasm, myalgia, musculoskeletal pain, fatigue, pruritus, alopecia, anemia, and lymphopenia. In a clinical study, common adverse events appeared to be dose-dependent; common adverse events were greater in patients treated with 800 mg compared to 200 mg of sonidegib daily. Laboratory abnormalities can include: hyperglycemia, increased liver enzymes, increases in amylase and lipase, and increased serum creatine kinase and creatinine.

1) OVERDOSE: Limited data. There have been no reports of overdose. It is anticipated that overdose effects may be similar to adverse reactions observed with therapeutic use.

1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Treat persistent diarrhea with antidiarrheals.

1) Treatment is symptomatic and supportive. Monitor serum creatine kinase and creatinine levels as indicated; rhabdomyolysis may develop in patients following a significant exposure.

1) PREHOSPITAL: Sonidegib is unlikely to cause significant toxicity following a minor exposure; prehospital gastrointestinal decontamination may not be necessary. Vomiting may develop following a significant exposure.
2) HOSPITAL: Severe toxicity is not expected after overdose of sonidegib. Gastrointestinal decontamination may not be necessary. Consider activated charcoal if coingestants with significant toxicity are involved.

1) Airway support is unlikely to be necessary following a mild to moderate exposure. Airway management may be necessary if other toxic agents have been ingested.

1) None.

1) Hemodialysis is unlikely to be beneficial following exposure because sonidegib is highly bound to human plasma proteins in vitro (greater than 97%) and has a large volume of distribution (9166 L).

1) HOME CRITERIA: A patient with an inadvertent minor exposure (1 to 2 tablets), that remains asymptomatic can be managed at home.
2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolytes and fluid balance. Monitor creatine kinase and liver enzymes as indicated. Patients that remain asymptomatic can be discharged.
3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and significant laboratory abnormalities (ie, creatine kinase, electrolytes).
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

1) Less than 10% of an oral dose is absorbed. Tmax: 2 to 4 hours following the administration of a single dose (100 to 3000 mg) in cancer patients. It is highly protein bound (greater than 97%) to human plasma proteins. The estimated steady-state volume of distribution is 9,166 L. Primarily metabolized by CYP3A. Of the absorbed dose, an estimated 30% was eliminated in the urine and an estimated 70% was eliminated in the feces. Elimination half-life estimated from population pharmacokinetics modeling is approximately 28 days.

1) Symptoms of overdose are likely to be similar to reported side effects of the medication. Patients taking sonidegib may be receiving other drugs that may produce synergistic effects.

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) In animal studies, severe malformations were observed at doses approximately 0.05 times the recommended human dose. The effects included vertebral malformations, distal limb malformations, digit malformations, severe craniofacial malformations, and other severe midline defects. Skeletal variations also developed when maternal exposure to sonidegib was below the limit of detection (Prod Info ODOMZO(R) oral capsules, 2015).

1) There are no adequate or well-controlled studies of sonidegib use in pregnant women. Women should be apprised that based on its mechanism of action and animal data there is potential risk to the fetus if sonidegib is administered during pregnancy (Prod Info ODOMZO(R) oral capsules, 2015).

1) Women of childbearing potential should use effective contraception during and for at least 20 months following discontinuation of therapy. Men should wear condoms during intercourse and refrain from donating semen during and for at least 8 months following discontinuation of therapy, even if a vasectomy has been performed (Prod Info ODOMZO(R) oral capsules, 2015).

1) In animal studies, abortion and complete fetus resorption were observed at doses approximately 0.05 times the recommended human dose (RHD). A decrease in the number of pregnant females, an increase in the number of early resorptions and a decrease in the number of viable fetuses were observed at doses approximately 0.12 times the RHD. In a 6-month repeat-dose toxicology study, atrophy of the uterus and ovaries occurred at doses approximately 2 times the RHD (Prod Info ODOMZO(R) oral capsules, 2015).

1) It is unknown if sonidegib is present in breast milk, its effect on milk production, or the effect on breastfed infants. Because of the potential risk to the nursing infant, women should discontinue breastfeeding during treatment (Prod Info ODOMZO(R) oral capsules, 2015).

1) In animal studies, lack of fertility was observed in female rats at doses approximately 1.3 times the recommended human dose. No impact on fertility was observed in male rats at doses up to 20 mg/kg/day, the highest dose tested (Prod Info ODOMZO(R) oral capsules, 2015).

1) At the time of this review, carcinogenicity studies with sonidegib have not been conducted (Prod Info ODOMZO(R) oral capsules, 2015).

A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and significant laboratory abnormalities (ie, creatine kinase, electrolytes).

A) A patient with an inadvertent minor exposure (1 to 2 tablets), that remains asymptomatic can be managed at home.

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolytes and fluid balance. Monitor creatine kinase and liver enzymes as indicated. Patients that remain asymptomatic can be discharged.

1) Severe toxicity is not expected following overdose of sonidegib. Gastrointestinal decontamination may not be necessary. Consider activated charcoal if coingestants with significant toxicity are involved.
2) CHARCOAL ADMINISTRATION
3) CHARCOAL DOSE

1) MANAGEMENT OF MILD TO MODERATE TOXICITY
2) MANAGEMENT OF SEVERE TOXICITY

1) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
2) Monitor serum creatine kinase and creatinine levels as indicated following exposure; monitor for adverse musculoskeletal reactions (ie, muscle pain, tenderness or weakness), renal function and urine output in patients with suspected or evidence of rhabdomyolysis.
3) Monitor liver enzymes after a significant overdose.

1) During clinical trials, elevated creatine kinase has been observed; rhabdomyolysis has only been reported in one patient. Monitor input and output, serum electrolytes, CK and renal function (Prod Info ODOMZO(R) oral capsules, 2015).
2) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
3) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
4) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
5) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
6) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).