1) COMMON (20% or greater): Diarrhea, rash/dermatitis, stomatitis, paronychia, dry skin, decreased appetite, and pruritus. OTHER EFFECTS: Vomiting, hypokalemia, cheilitis, cystitis, renal impairment, conjunctivitis, elevated liver enzymes, epistaxis, rhinorrhea, fever, ventricular dysfunction (eg, diastolic dysfunction, left ventricular dysfunction, ventricular dilation). RARE: Hepatotoxicity with fatalities.

1) Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase (less than 1.5 times upper limit of normal) have been reported with overdose.

1) Treatment is symptomatic and supportive.

1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Severe nausea and vomiting may respond to a combination of agents from different drug classes.

1) PREHOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.

1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias or severe respiratory distress.

1) None.

1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).

1) 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. In patients with an afatinib overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.

1) Hemodialysis is unlikely to be effective due to high protein binding (approximately 95%) of afatinib.

1) HOME CRITERIA: Asymptomatic adults with inadvertent ingestions of 1 or 2 extra doses can be monitored at home.
2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions, or inadvertent ingestion of more than 1 or 2 extra dose should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.
3) ADMISSION CRITERIA: Patients demonstrating severe fluid and electrolyte imbalance should be admitted.
4) CONSULT CRITERIA: Consult with an oncologist, medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.

1) When managing a suspected afatinib overdose, the possibility of multi-drug involvement should be considered.

1) Tmax, Oral: 2 to 5 hours. Bioavailability: The geometric mean afatinib bioavailability of a afatinib 20 mg tablet was 92% that of an oral solution. Protein binding: approximately 95% bound to human plasma proteins. Metabolism: The major circulating metabolites of afatinib are covalent adducts to proteins; enzymatic metabolism is negligible. Excretion: Primarily eliminated via biliary/fecal excretion. Following oral administration of radiolabeled afatinib solution, 4% of the administered dose was recovered in urine and 85% of the administered dose was recovered in feces. Of the entire amount recovered, 88% of the dose was unchanged parent compound. Elimination half-life: 37 hours.

1) Includes other agents that may cause hepatotoxicity, severe diarrhea, or hypokalemia.

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, reduced fetal weights, an increased incidence of runts, and visceral and dermal variations were observed at approximately 0.7 times the recommended human dose. Skeletal alterations, including incomplete or delayed ossification, and reduced fetal weights were observed at approximately twice the recommended human dose during embryofetal development (Prod Info GILOTRIF(R) oral tablets, 2016).

1) Based on its mechanism of action, afatinib is expected to cause fetal harm when administered during pregnancy. Therefore, women should be cautioned against becoming pregnant while receiving afatinib. Women of childbearing potential should be advised to use highly effective contraception during afatinib therapy and for at least 2 weeks after the last dose. If a patient becomes pregnant under these circumstances, she should be advised of the potential consequences to the fetus (Prod Info GILOTRIF(R) oral tablets, 2016).

1) In animal studies, administration during organogenesis of approximately 0.2 times the recommended human dose of 40 mg/day resulted in postimplantation loss and, in animals showing maternal toxicity, late-term spontaneous abortion (Prod Info GILOTRIF(R) oral tablets, 2016).

1) It is unknown whether afatinib is excreted in human milk or affects milk production or the breastfed infant. However, afatinib is excreted in the milk of lactating rats at 80- to 150-fold the maternal plasma levels at 1 and 6 hours after administration, respectively (Prod Info GILOTRIF(R) oral tablets, 2016).

1) In animal studies, a mild decrease in the number of corpora lutea, a mild increase in postimplantation loss rate due to early resorptions, and decreased ovarian weights were observed upon the administration of approximately 0.63 times the exposure by AUC in patients at the recommended human dose of 40 mg daily. An increase in the incidence of low or no sperm counts was observed after the administration of a dose approximately equal to the recommended human dose. Increased apoptosis in the testes and atrophy in the seminal vesicles and the prostate supported these decreases in sperm count (Prod Info GILOTRIF(R) oral tablets, 2016).

1) FEVER: Pyrexia occurred in 12% (all grades) of adult patients (n=229) with epidermal growth factor receptor mutation-positive, metastatic, nonsquamous, non-small cell lung cancer who received oral afatinib 40 mg daily for a median of 11 months compared with 6% of patients (n=111) who received IV pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) every 3 weeks for a maximum of 6 cycles in a randomized, open-label trial (Prod Info GILOTRIF(TM) oral tablets, 2013).

1) CONJUNCTIVITIS: Conjunctivitis occurred in 11% (all grades) of adult patients (n=229) with epidermal growth factor receptor mutation-positive, metastatic, nonsquamous, non-small cell lung cancer who received oral afatinib 40 mg daily for a median of 11 months compared with 3% of patients (n=111) who received IV pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) every 3 weeks for a maximum of 6 cycles in a randomized, open-label trial (Prod Info GILOTRIF(TM) oral tablets, 2013).

1) EPISTAXIS
2) RHINORRHEA

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH POISONING/EXPOSURE

1) WITH POISONING/EXPOSURE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH POISONING/EXPOSURE

1) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) At the time of this review, carcinogenicity studies have not been conducted (Prod Info GILOTRIF(TM) oral tablets, 2013).

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

A) Patients demonstrating severe fluid and electrolyte imbalance should be admitted.

A) Asymptomatic adults with inadvertent ingestions of 1 or 2 extra doses can be monitored at home.

A) Consult with an oncologist, medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.

A) All patients with deliberate self-harm ingestions, or inadvertent ingestion of more than 1 or 2 extra dose should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.

1) CHARCOAL ADMINISTRATION
2) CHARCOAL DOSE

1) CHARCOAL ADMINISTRATION
2) CHARCOAL DOSE

1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Severe nausea and vomiting may respond to a combination of agents from different drug classes.

1) Monitor vital signs.
2) Serum afatinib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
4) Institute continuous cardiac monitoring and obtain serial ECGs.
5) Monitor liver enzymes and renal function after significant overdose.

1) 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).
2) Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In these patients, palifermin is administered before and after chemotherapy. DOSES: 60 mcg/kg/day IV bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy for a total of 6 doses. Palifermin should not be given within 24 hours before, during infusion, or within 24 hours after administration of myelotoxic chemotherapy, as this has been shown to increase the severity and duration of mucositis. (Hensley et al, 2009; Prod Info KEPIVANCE(TM) IV injection, 2005). In patients with an afatinib overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
3) Total parenteral nutrition may provide nutritional requirements during the healing phase of drug-induced oral ulceration, mucositis, and esophagitis.