Afatinib (afatinib dimaleate)

Dosage of afatinib dimaleate is expressed in terms of afatinib.

If adverse effects occur during afatinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.

Permanently discontinue afatinib in patients who develop life-threatening bullous, blistering, or exfoliative skin lesions; interstitial lung disease; severe drug-induced hepatic impairment; GI perforation; persistent ulcerative keratitis; or symptomatic left ventricular dysfunction. The drug also should be permanently discontinued in patients who experience severe or intolerable adverse reactions to an afatinib dosage of 20 mg daily.

Administer orally once daily. Administer on an empty stomach, at least 1 hour before or 2 hours after a meal.

If a dose of afatinib is missed, the prescribed dose should be taken as soon as possible unless the next dose is within 12 hours; an additional dose should not be administered to replace the missed dose.

Store at 25oC (excursions permitted between 15-30oC). Store in original container and protect from excessive humidity and light.

In vitro studies in human hepatocytes indicate that afatinib does not inhibit or induce cytochrome P-450 (CYP) isoenzyme 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4. CYP-mediated mechanisms play a minor role in the drug's overall metabolism.

In vitro data indicate that afatinib is a substrate and inhibitor of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Selected P-Glycoprotein (P-Gp) Substrates/Venetoclax

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Venetoclax is an inhibitor of the P-glycoprotein (P-gp) system and may increase the absorption of P-gp substrates.(1)

CLINICAL EFFECTS: Concurrent use of venetoclax with P-gp substrates may result in elevated levels and toxicities of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of venetoclax states that the concurrent use of P-gp substrates should be avoided. If concurrent therapy cannot be avoided, the P-gp substrate should be taken at least 6 hours before venetoclax.(1) If concurrent therapy with afatinib is unavoidable and not tolerated, the US manufacturer of afatinib states that the afatinib dose should be reduced by 10 mg. Resume the previous dose of afatinib if venetoclax is discontinued.(2) The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant when coadministered with P-gp inhibitors. The initial dose of ubrogepant should not exceed 50 mg. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(8)

DISCUSSION: In vitro data suggests venetoclax is a P-gp inhibitor at therapeutic doses in the gut.(1) Administration of a single venetoclax 100 mg dose with digoxin increased the maximum concentration (Cmax) and area-under-the-curve of digoxin by 35% and 9%, respectively.(1) Selected P-gp substrates linked to this monograph include: afatinib, aliskiren, betrixaban, bilastine, cyclosporine, dabigatran, digoxin, edoxaban, everolimus, loperamide, sirolimus, talazoparib, topotecan, and ubrogepant.(1-9)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Afatinib/P-Glycoprotein (P-Gp) Inducers; Phenobarbital

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Afatinib is a substrate of the intestinal efflux transporter P-glycoprotein (P-gp). Apalutamide, carbamazepine, efavirenz, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort induce production of P-gp which may lead to decreased exposure to afatinib.(1,2) Phenobarbital may also induce the metabolism of afatinib.(1) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent or recent use of P-glycoprotein inducers (apalutamide, carbamazepine, efavirenz, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, or St. John's wort), phenobarbital, or primidone may result in decreased levels and effectiveness of afatinib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of afatinib recommends an increase of afatinib dose by 10 mg per day as tolerated in patients receiving chronic therapy with a P-gp inducer or phenobarbital.(1) Onset of induction is gradual and maximal induction may be delayed for many days or longer, depending upon the inducing agent and dose. If the P-gp inducer, phenobarbital, or primidone is stopped, the manufacturer of afatinib recommends resumption of previous afatinib dose 2 to 3 days after discontinuation of the inducing agent.(1)

DISCUSSION: In a drug interaction study, co-administration of rifampin 600 mg once daily for 7 days decreased afatinib exposure 34%.(1) P-gp inducers include apalutamide, carbamazepine, efavirenz, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort.(1,2) Based on 2 case reports(3,4) and in vitro studies,(5,6) the manufacturer of afatinib also includes phenobarbital as a P-gp inducer.(1)

Afatinib/P-Glycoprotein (P-Gp) Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) may increase the absorption of afatinib.(1)

CLINICAL EFFECTS: The concurrent administration of afatinib with an inhibitor of P-glycoprotein may result in elevated levels of afatinib and signs of toxicity. These signs may include but are not limited to worsening diarrhea, stomatitis, skin rash/exfoliation/bullae or paronychia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of afatinib states the afatinib dose should be reduced by 10 mg if the addition of a P-glycoprotein inhibitor is not tolerated.(1) If afatinib dose was reduced due to addition of a P-gp inhibitor, resume the previous dose after the P-gp inhibitor is discontinued.(1) The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to afatinib.(2) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(4)

DISCUSSION: A drug interaction study evaluated the effects of ritonavir 200 mg twice daily on afatinib exposure. Administration of ritonavir 1 hour before afatinib administration increased systemic exposure by 48%. Afatinib exposure was not changed when ritonavir was administered simultaneously with or 6 hours after afatinib dose.(1) P-glycoprotein inhibitors linked to this monograph are: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, cyclosporine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diosmin, dronedarone, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, isavuconazonium, itraconazole, ivacaftor, josamycin, ketoconazole, lapatinib, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, posaconazole, propafenone, quinidine, ranolazine, ritonavir, saquinavir, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, telaprevir, tepotinib, tucatinib, valbenazine, vemurafenib, vepdegestrant, verapamil, vimseltinib and voclosporin.(1-3)

The manufacturer states there are no known contraindications to the use of afatinib.

• Lactation

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Diverticulitis of gastrointestinal tract
• Drug-induced hepatitis
• Gastrointestinal ulcer
• Interstitial lung disease
• Left ventricular failure
• Pregnancy
• Severe diarrhea

• Keratitis

The most common adverse reactions (>=20%) in patients receiving afatinib include diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, and pruritus.

More Frequent

• Abnormal hepatic function tests

Less Frequent

• Anemia
• Cellulitis
• Dehydration
• Gastrointestinal perforation
• Increased alanine transaminase
• Interstitial lung disease
• Left ventricular failure
• Leukopenia
• Myocardial dysfunction
• Palmar-plantar erythrodysesthesia
• Severe diarrhea

Rare or Very Rare

• Acute respiratory failure
• Bacterial sepsis
• Bullous dermatitis
• Dyspnea
• Exfoliative dermatitis
• Hepatic failure
• Hypersensitivity pneumonitis
• Hypokalemia
• Interstitial pneumonitis
• Keratitis
• Pancreatitis
• Pneumonia
• Stevens-johnson syndrome
• Toxic epidermal necrolysis

More Frequent

• Acneiform eruption
• Anorexia
• Diarrhea
• Dry skin
• Erythema
• Nausea
• Paronychia
• Pruritus of skin
• Skin rash
• Stomatitis
• Vomiting

Less Frequent

• Abdominal distension
• Acute abdominal pain
• Alopecia
• Arthralgia
• Back pain
• Blepharitis
• Cheilitis
• Conjunctivitis
• Constipation
• Cough
• Cystitis
• Dizziness
• Dysesthesia
• Dysphagia
• Epistaxis
• Fever
• Gastritis
• Gastroesophageal reflux disease
• Glossitis
• Headache disorder
• Hirsutism
• Muscle spasm
• Musculoskeletal pain
• Myalgia
• Nail disorders
• Pharyngitis
• Phototoxicity
• Proteinuria
• Rectal pain
• Rhinorrhea
• Skin fissure
• Skin pigmentation enhancement
• Upper respiratory infection
• Weight loss

Rare or Very Rare

• Fatigue

No enhanced messaging available.

Safety and efficacy of afatinib have not been established in pediatric patients.

Afatinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.

Afatinib is distributed into milk in rats; it is not known whether the drug is distributed into milk in humans or if the drug has any effect on milk production or the nursing infant. Because of the potential for serious adverse reactions to afatinib in nursing infants, women should be advised to discontinue nursing while receiving the drug and for 2 weeks after the drug is discontinued.

The manufacturer makes no specific dosage recommendations for geriatric patients.

The LUX-Lung 3 study evaluating afatinib in patients with previously untreated metastatic NSCLC did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults. In subgroup analyses of 3 clinical studies, including LUX-Lung 3, evaluating afatinib as first-line therapy in patients with EGFR mutation-positive NSCLC, efficacy of afatinib in patients 65 years of age and older was consistent with that observed in the overall study population.

In the LUX-Lung 8 study evaluating afatinib in patients with previously treated metastatic squamous NSCLC, 53% of patients were 65 years of age or older and 11% were 75 years of age or older. In an exploratory subgroup analysis, afatinib reduced the risk of death by 5% in patients 65 years of age and older and 32% in those younger than 65 years of age. No overall differences in safety were observed between geriatric patients and younger adults.