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OSIMERTINIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Osimertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR) that binds irreversibly to certain mutant forms of EGFR.

Specific Substances

    1) Osimertinib mesylate
    2) C28-H33-N7-O2.CH4O3S
    1.2.1) MOLECULAR FORMULA
    1) C28-H33-N7-O2.CH4O3S (Prod Info TAGRISSO(TM) oral tablets, 2015)

Available Forms Sources

    A) FORMS
    1) Osmertinib is available as an 80 mg beige oval and biconvex tablet marked with "AZ 80" or a 40 mg beige, round and biconvex tablet marked with "AZ 40" (Prod Info TAGRISSO(TM) oral tablets, 2015).
    B) USES
    1) Osimertinib, a kinase inhibitor, is used for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer whose disease has progressed during or following EGFR TKI therapy. It has been approved by the FDA under an accelerated approval program, based on tumor response rate and duration of response. Ongoing approval is contingent upon verification and description of clinical benefits in confirmatory trials (Prod Info TAGRISSO(TM) oral tablets, 2015).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USE: Osimertinib, a kinase inhibitor, is used for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer whose disease has progressed during or following EGFR TKI therapy. It has been approved by the FDA under an accelerated approval program, based on tumor response rate and duration of response. Ongoing approval is contingent upon verification and description of clinical benefits in confirmatory trials.
    B) PHARMACOLOGY: Osimertinib is an epidermal growth factor receptor (EGFR) kinase inhibitor and acts irreversibly at certain mutant forms of EGFR including T790M, L858R, and exon 19 deletion at a 9-fold lower concentration than on wild-type forms of the receptor. The active metabolite AZ7550 exhibited similar potency of inhibition to osimertinib. AZ5104 was more potent than osimertinib against exon 19 deletion and T790M mutants (by about 8-fold) and wild-type (about 15-fold) EGFR.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: The most common adverse reactions occurring in more than 20% of patients receiving osimertinib were as follows: diarrhea, rash, dry skin and nail toxicity. LESS FREQUENT: Other adverse events reported with therapy include: nausea, decreased appetite, constipation, stomatitis, pruritus, eye changes, cough, fatigue, back pain, headache, and venous thromboembolism. QTc prolongation and neutropenia were the most common adverse events that led to dose reduction or interruption of osimertinib therapy. During clinical trials, one patient developed a QTc of greater than 500 msec, and 11 patients had an increase from baseline QTc of greater than 60 msec. SERIOUS EFFECTS: Pneumonia and pulmonary embolus occurred in more than 2% of patients receiving therapy. Cardiomyopathy, including cardiac failure, pulmonary edema, and ejection fraction decrease, developed in 1.4% of osimertinib treated patient during clinical trials; the events were fatal in 2 patients.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: At the time of this review, there are no reports of overdose with osimertinib. Overdose effects are anticipated to be an exaggeration of adverse effects following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) There are no data on the use of osimertinib in pregnant women. However, it can cause fetal harm based on the data from animal studies and its mechanism of action. Do not administer osimertinib to a pregnant woman. If pregnancy occurs, apprise the patient of the potential for fetal harm.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, carcinogenicity studies have not been performed with osimertinib.

Laboratory Monitoring

    A) Monitor fluid and electrolyte status in patients with significant diarrhea.
    B) Monitor electrolytes including sodium and magnesium levels following a significant exposure or as indicated.
    C) Obtain a baseline ECG and repeat as indicated after a significant overdose or in patients with a history of congenital long QTc syndrome, congestive heart failure, or in patients that are taking medications known to prolong the QTc interval.
    D) Obtain an echocardiogram or multigated acquisition (MUGA) scan as indicated in patients with evidence of cardiomyopathy.
    E) Monitor CBC with differential and platelet count as necessary until patient recovery. At the time of this review, laboratory evidence of myelosuppression has occurred with therapy with no reports of clinical effects.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea. Treat persistent diarrhea with antidiarrheals. Electrolyte monitoring should include serum sodium and magnesium levels. Obtain a baseline ECG in patients following a significant exposure; prolonged QTc interval has been observed infrequently. Continuous cardiac monitoring may be indicated in patients with an underlying history or predisposition for QTc prolongation.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor respiratory and cardiac function following a significant exposure in patients at potential risk to develop cardiomyopathy (ie, cardiac failure, pulmonary edema, a decrease in ejection fraction) or interstitial lung disease/pneumonitis (ie, dyspnea, cough, fever).
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain their airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain their airway.
    D) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary following a minor exposure. Monitor respiratory function (ie, dyspnea, cough) following a significant exposure or in patients at potential risk to develop respiratory insufficiency. Initial treatment may include continuous pulse oximetry and oxygen therapy.
    E) ANTIDOTE
    1) None.
    F) STOMATITIS
    1) Evaluate patients for signs and symptoms of stomatitis. Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection.
    G) ENHANCED ELIMINATION
    1) Enhanced elimination is unlikely to be beneficial due to an increased volume of distribution (986 L) and theoretically high plasma protein binding based on its physiochemical properties.
    H) PATIENT DISPOSITION
    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 (including serum sodium and magnesium) and fluid balance. Obtain a baseline CBC with differential and platelet count; daily monitoring may be indicated. Outpatient laboratory monitoring should be considered until patient recovery. Patients that develop evidence of QTc interval prolongation, cardiomyopathy, or interstitial lung disease may require further diagnostic evaluation and clinical intervention. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for profuse diarrhea, severe dehydration, and significant laboratory abnormalities (ie, myelosuppression, electrolytes). Patients should be admitted to a monitored bed if they develop interstitial lung disease, severe cardiomyopathy and/or persistent, significant QTc interval prolongation.
    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.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established. At the time of this review, there have been no reports of overdose with osimertinib.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose is 80 mg once daily until disease progression or unacceptable toxicity. PEDIATRIC: The safety and efficacy of osimertinib have not been established in pediatric patients.

Clinical Effects

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, thrombocytopenia was reported in 54% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, anemia was reported in 44% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    C) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, neutropenia was reported in 33% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    D) LYMPHOCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, lymphopenia was reported in 63% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, pruritus was reported in 14% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, rash was reported in 41% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    C) DRY SKIN
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, dry skin was reported in 31% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    D) NAIL CHANGES
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, nail changes (including nail bed inflammation, tenderness, and discoloration; nail dystrophy, infection, and ridging, onychoclasis, onycholysis, onychomadesis, and paronychia) were reported in 25% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, back pain was reported in 13% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).

Reproductive

    3.20.1) SUMMARY
    A) There are no data on the use of osimertinib in pregnant women. However, it can cause fetal harm based on the data from animal studies and its mechanism of action. Do not administer osimertinib to a pregnant woman. If pregnancy occurs, apprise the patient of the potential for fetal harm.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In animal studies an increase in the rate of fetal malformations and variations were reported with administration of osimertinib at doses at least 0.1 times the recommended AUC from implantation through closure of the hard palate (Prod Info TAGRISSO(TM) oral tablets, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) There are no data on the use of osimertinib in pregnant women. However, it can cause fetal harm based on the data from animal studies and its mechanism of action. Do not administer osimertinib to a pregnant woman. If pregnancy occurs, apprise the patient of the potential for fetal harm (Prod Info TAGRISSO(TM) oral tablets, 2015).
    B) CONTRACEPTIVE USE
    1) Women of reproductive potential should be advised to use effective contraception during treatment with osimertinib and for 6 weeks after the final dose and men should use effective contraception during therapy and 4 months after the final dose of osimertinib (Prod Info TAGRISSO(TM) oral tablets, 2015).
    C) ANIMAL STUDIES
    1) During animal studies, administration of osimertinib prior to embryonic implantation through organogenesis and at doses approximately 1.5 times the clinical exposure resulted in postimplantation loss and early embryonic death. Osimertinib use during organogenesis through lactation day 6 caused an increase in total litter loss and postnatal death with 30 mg/kg/day doses while doses of 20 mg/kg/day resulted in increased postnatal death and reduced mean pup weight (Prod Info TAGRISSO(TM) oral tablets, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether osimertinib is excreted into human breast milk or if there is a potential for adverse effects in the nursing infant. Osimertinib administration during gestation and early lactation resulted in reduced growth rates and neonatal death during animal studies (Prod Info TAGRISSO(TM) oral tablets, 2015).
    2) Due to the potential risk to the infant, women should be advised not to breastfeed during therapy and for at least 2 weeks after the final dose (Prod Info TAGRISSO(TM) oral tablets, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In animal studies, osimertinib may impair fertility in males and females of reproductive potential; it is not known if these events are reversible (Prod Info TAGRISSO(TM) oral tablets, 2015).

Summary Of Exposure

    A) USE: Osimertinib, a kinase inhibitor, is used for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer whose disease has progressed during or following EGFR TKI therapy. It has been approved by the FDA under an accelerated approval program, based on tumor response rate and duration of response. Ongoing approval is contingent upon verification and description of clinical benefits in confirmatory trials.
    B) PHARMACOLOGY: Osimertinib is an epidermal growth factor receptor (EGFR) kinase inhibitor and acts irreversibly at certain mutant forms of EGFR including T790M, L858R, and exon 19 deletion at a 9-fold lower concentration than on wild-type forms of the receptor. The active metabolite AZ7550 exhibited similar potency of inhibition to osimertinib. AZ5104 was more potent than osimertinib against exon 19 deletion and T790M mutants (by about 8-fold) and wild-type (about 15-fold) EGFR.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: The most common adverse reactions occurring in more than 20% of patients receiving osimertinib were as follows: diarrhea, rash, dry skin and nail toxicity. LESS FREQUENT: Other adverse events reported with therapy include: nausea, decreased appetite, constipation, stomatitis, pruritus, eye changes, cough, fatigue, back pain, headache, and venous thromboembolism. QTc prolongation and neutropenia were the most common adverse events that led to dose reduction or interruption of osimertinib therapy. During clinical trials, one patient developed a QTc of greater than 500 msec, and 11 patients had an increase from baseline QTc of greater than 60 msec. SERIOUS EFFECTS: Pneumonia and pulmonary embolus occurred in more than 2% of patients receiving therapy. Cardiomyopathy, including cardiac failure, pulmonary edema, and ejection fraction decrease, developed in 1.4% of osimertinib treated patient during clinical trials; the events were fatal in 2 patients.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: At the time of this review, there are no reports of overdose with osimertinib. Overdose effects are anticipated to be an exaggeration of adverse effects following therapeutic doses.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) EYE DISORDERS
    a) During clinical trials in two single-arm studies, eye disorders (including blepharitis, cataract, dry eye, eye irritation, eye pain, keratitis, lacrimation increased, vision blurred, and vitreous floaters) were reported in 18% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOMYOPATHY
    1) WITH THERAPEUTIC USE
    a) Cardiomyopathy, including cardiac failure, pulmonary edema, and a decreased ejection fraction, developed in 1.4% (n=11) of osimertinib treated patients (n=813) during clinical trials; the events were fatal in 2 patients. In addition, a left ventricular ejection fraction decline of greater than 10% and a decrease to less than 50% occurred in 2.4% (9/375) of patients (Prod Info TAGRISSO(TM) oral tablets, 2015).
    B) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) During clinical trials, one patient developed a QTc of greater than 500 msec and 11 patients had an increase from baseline QTc of greater than 60 msec in osimertinib-treated patients (n=411) (Prod Info TAGRISSO(TM) oral tablets, 2015).
    b) QTc prolongation led to dosage reduction or interruption in 2.2% of patients treated with osimertinib (Prod Info TAGRISSO(TM) oral tablets, 2015).
    C) THROMBOEMBOLISM OF VEIN
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, venous thromboembolism (including deep vein thrombosis, jugular venous thrombosis and pulmonary embolism) was reported in 7% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily. Grade 3 or 4 toxicity developed in 2.4% of patients (Prod Info TAGRISSO(TM) oral tablets, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) INTERSTITIAL LUNG DISEASE
    1) WITH THERAPEUTIC USE
    a) Interstitial lung disease (eg, dyspnea, cough and fever) and/or pneumonitis developed in 3.3% (n=27) of osimertinib treated patients (n=813) during clinical trials; the events were fatal in 4 (0.5%) patients (Prod Info TAGRISSO(TM) oral tablets, 2015).
    b) During therapeutic use, interstitial lung disease/pneumonitis and cerebrovascular accidents were the 2 most frequent adverse events that led to the discontinuation of treatment (Prod Info TAGRISSO(TM) oral tablets, 2015).
    B) COUGH
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, cough was reported in 14% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    C) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, pneumonia was reported in 4% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily. Grade 3 or 4 toxicity developed in 2.2% of patients (Prod Info TAGRISSO(TM) oral tablets, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, headache was reported in 10% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    B) CEREBROVASCULAR ACCIDENT
    1) WITH THERAPEUTIC USE
    a) Cerebrovascular accident developed in 2.7% of patients treated with osimertinib (Prod Info TAGRISSO(TM) oral tablets, 2015).
    b) During therapeutic use, interstitial lung disease/pneumonitis and cerebrovascular accidents were the 2 most frequent adverse events that led to the discontinuation of treatment (Prod Info TAGRISSO(TM) oral tablets, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, diarrhea was reported in 42% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, nausea was reported in 17% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, constipation was reported in 15% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    D) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, stomatitis was reported in 12% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).
    E) DECREASE IN APPETITE
    1) WITH THERAPEUTIC USE
    a) During clinical trials in two single-arm studies, a decrease in appetite was reported in 16% (all grades) of 411 patients with EGFR T790 mutation-positive non-small cell lung cancer receiving osimertinib at a dose of 80 mg daily (Prod Info TAGRISSO(TM) oral tablets, 2015).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, carcinogenicity studies have not been performed with osimertinib.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, carcinogenicity studies have not been performed with osimertinib (Prod Info TAGRISSO(TM) oral tablets, 2015).

Genotoxicity

    A) At the time of this review, the manufacturer reported that osimertinib did not cause genetic damage in in vitro and in vivo assays (Prod Info TAGRISSO(TM) oral tablets, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor fluid and electrolyte status in patients with significant diarrhea.
    B) Monitor electrolytes including sodium and magnesium levels following a significant exposure or as indicated.
    C) Obtain a baseline ECG and repeat as indicated after a significant overdose or in patients with a history of congenital long QTc syndrome, congestive heart failure, or in patients that are taking medications known to prolong the QTc interval.
    D) Obtain an echocardiogram or multigated acquisition (MUGA) scan as indicated in patients with evidence of cardiomyopathy.
    E) Monitor CBC with differential and platelet count as necessary until patient recovery. At the time of this review, laboratory evidence of myelosuppression has occurred with therapy with no reports of clinical effects.

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 should be admitted for profuse diarrhea, severe dehydration, and significant laboratory abnormalities (ie, myelosuppression, electrolytes). Patients should be admitted to a monitored bed if they develop interstitial lung disease, severe cardiomyopathy and/or persistent, significant QTc interval prolongation.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent minor exposure (1 to 2 tablets), that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolytes (including serum sodium and magnesium) and fluid balance. Obtain a baseline CBC with differential and platelet count; daily monitoring may be indicated. Outpatient laboratory monitoring should be considered until patient recovery. Patients that develop evidence of QTc interval prolongation, cardiomyopathy, or interstitial lung disease may require further diagnostic evaluation and clinical intervention. Patients that remain asymptomatic can be discharged

Monitoring

    A) Monitor fluid and electrolyte status in patients with significant diarrhea.
    B) Monitor electrolytes including sodium and magnesium levels following a significant exposure or as indicated.
    C) Obtain a baseline ECG and repeat as indicated after a significant overdose or in patients with a history of congenital long QTc syndrome, congestive heart failure, or in patients that are taking medications known to prolong the QTc interval.
    D) Obtain an echocardiogram or multigated acquisition (MUGA) scan as indicated in patients with evidence of cardiomyopathy.
    E) Monitor CBC with differential and platelet count as necessary until patient recovery. At the time of this review, laboratory evidence of myelosuppression has occurred with therapy with no reports of clinical effects.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Consider activated charcoal if the overdose is recent, the patient is not vomiting and is able to maintain their airway.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea. Treat persistent diarrhea with antidiarrheals. Electrolyte monitoring should include serum sodium and magnesium levels. Obtain a baseline ECG in patients following a significant exposure; prolonged QTc interval has been observed infrequently. Continuous cardiac monitoring may be indicated in patients with an underlying history or predisposition for QTc prolongation.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Monitor respiratory and cardiac function following a significant exposure in patients at potential risk to develop cardiomyopathy (ie, cardiac failure, pulmonary edema, a decrease in ejection fraction) or interstitial lung disease/pneumonitis (ie, dyspnea, cough, fever).
    B) MONITORING OF PATIENT
    1) Monitor fluid and electrolyte status in patients with significant diarrhea.
    2) Monitor electrolytes including sodium and magnesium levels following a significant exposure or as indicated.
    3) Obtain a baseline ECG and repeat as indicated after a significant overdose or in patients with a history of congenital long QTc syndrome, congestive heart failure, or in patients that are taking medications known to prolong the QTc interval.
    4) Obtain an echocardiogram or multigated acquisition (MUGA) scan as indicated in patients with evidence of cardiomyopathy.
    5) Monitor CBC with differential and platelet count as necessary until patient recovery. At the time of this review, laboratory evidence of myelosuppression has occurred with therapy with no reports of clinical effects.
    C) STOMATITIS
    1) Evaluate patients for signs and symptoms of stomatitis. Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics (eg, morphine, hydrocodone, oxycodone, fentanyl). Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Patients who are receiving myelosuppressive therapy may receive prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection (Bensinger et al, 2008).

Enhanced Elimination

    A) SUMMARY
    1) Enhanced elimination is unlikely to be beneficial due to an increased volume of distribution (986 L) and theoretically high plasma protein binding based on its physiochemical properties (Prod Info TAGRISSO(TM) oral tablets, 2015).

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established. At the time of this review, there have been no reports of overdose with osimertinib.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose is 80 mg once daily until disease progression or unacceptable toxicity. PEDIATRIC: The safety and efficacy of osimertinib have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is 80 mg orally once daily until disease progression or unacceptable toxicity (Prod Info TAGRISSO(TM) oral tablets, 2015).
    B) The drug should not be initiated until there is confirmation of a T790M EGFR mutation in tumor specimens (Prod Info TAGRISSO(TM) oral tablets, 2015).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness of osimertinib in the pediatric population have not been established (Prod Info TAGRISSO(TM) oral tablets, 2015).

Minimum Lethal Exposure

    A) At the time of this review, a minimum lethal dose has not been established. There have been no reports of overdose with osimertinib.

Maximum Tolerated Exposure

    A) A maximum tolerated dose has not been established with osimertinib (Prod Info TAGRISSO(TM) oral tablets, 2015).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) The median Tmax of osimertinib was 6 hours with a range of 3 to 24 hours (Prod Info TAGRISSO(TM) oral tablets, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Osimertinib is an epidermal growth factor receptor (EGFR) kinase inhibitor and acts irreversibly at certain mutant forms of EGFR including T790M, L858R, and exon 19 deletion at a 9-fold lower concentration than on wild-type forms of the receptor. The active metabolite AZ7550 exhibited similar potency of inhibition to osimertinib. AZ5104 was more potent than osimertinib against exon 19 deletion and T790M mutants (by about 8-fold) and wild-type (about 15-fold) EGFR. In-vitro inhibition of HER2, HER3, HER4, ACK1, and BLK also occurred at clinically-relevant concentrations (Prod Info TAGRISSO(TM) oral tablets, 2015).

Physicochemical

Molecular Weight

    A) 596 g/mol (Prod Info TAGRISSO(TM) oral tablets, 2015)

References

General Bibliography

    1) Bensinger W, Schubert M, Ang KK, et al: NCCN Task Force Report. prevention and management of mucositis in cancer care. J Natl Compr Canc Netw 2008; 6 Suppl 1:S1-21.
    2) Product Information: TAGRISSO(TM) oral tablets, osimertinib oral tablets. AstraZeneca Pharmaceuticals LP (per FDA), Wilmington, DE, 2015.