Afatinib (Tablets) Instructions for Use

ATC Code

L01EB03 (Afatinib)

Active Substance

Afatinib (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors

Pharmacological Action

Antitumor agent, a selective protein tyrosine kinase inhibitor. Afatinib is a potent and irreversible blocker of protein tyrosine kinase of the ErbB receptor family (epidermal growth factor receptors). Afatinib covalently binds and irreversibly blocks signaling from all homo- and heterodimers formed by the ErbB family (EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4).

In preclinical studies on tumor models created by dysregulation of the ErbB system, afatinib, used as a single agent, effectively blocks ErbB receptors and leads to inhibition of tumor growth or tumor regression. Models of non-small cell lung cancer caused by EGFR mutations (L858R or Del 19) are particularly sensitive to afatinib treatment. Afatinib retains significant antitumor activity in vitro on non-small cell lung cancer cell lines and in vivo on tumor models (models using xenografts or transgenic models) that are induced by mutant EGFR isoforms (e.g., T790M) with known resistance to reversible EGFR inhibitors such as erlotinib and gefitinib.

Pharmacokinetics

After oral administration, the C_max of afatinib was reached in approximately 2-5 hours. In the dose range from 20 mg to 50 mg, the mean C_max and AUC_0-∞ values increased proportionally. Administration of the drug with food led to a significant decrease in afatinib exposure in the blood by approximately 50% (C_max) and 39% (AUC_0-∞) compared to administration on an empty stomach. It was found that if food was consumed within 3 hours before taking the drug Giotrif^® or 1 hour after taking the drug, the AUC values at steady state during the dosing period decreased by an average of 26%.

The binding of afatinib to human plasma proteins in vitro is about 95%. The C_ss of afatinib in plasma is reached within 8 days after repeated administration of afatinib.

Metabolic reactions catalyzed by enzymes play a minor role in the metabolism of afatinib in vivo. The main circulating metabolites of afatinib are covalent protein adducts.

The terminal T_1/2 is 37 hours. Excreted in feces – 85.4% and in urine – 4.3%. Unchanged Afatinib accounted for 88%.

Indications

As monotherapy for patients previously untreated with tyrosine kinase inhibitors, for the treatment of locally advanced or metastatic non-small cell lung cancer with a mutation(s) in the epidermal growth factor receptor EGFR.

ICD codes

Dosage Regimen

Administer orally once daily. Take tablets on an empty stomach at least 1 hour before or 3 hours after a meal.

The recommended starting dose is 40 mg. The maximum daily dose is 50 mg.

Continue treatment until disease progression or unacceptable toxicity occurs.

For management of adverse reactions, employ dose interruption and/or dose reduction. For severe or persistent drug-related adverse reactions, interrupt therapy for up to 14 days until the event resolves to Grade 1 or baseline.

If re-initiation is warranted, resume treatment at a reduced dose: reduce the 40 mg dose to 30 mg; reduce the 50 mg dose to 40 mg; reduce the 30 mg dose to 20 mg.

Permanently discontinue afatinib if dose reduction below 20 mg is required, or if therapy cannot be resumed within 14 days, or in cases of severe renal impairment, confirmed interstitial lung disease, severe hepatic impairment, ulcerative keratitis, or life-threatening bullous, blistering or exfoliative skin conditions.

For patients with severe renal impairment (CrCl 15-29 mL/min), reduce the starting dose to 30 mg.

Monitor patients closely, especially during the first 6 weeks of therapy, for diarrhea, skin reactions, and hepatic function.

Adverse Reactions

Nervous system disorders: common – taste disturbance.

Eye disorders: common – conjunctivitis, dry eye; uncommon – keratitis.

Respiratory, thoracic and mediastinal disorders: very common – epistaxis; common – rhinorrhea; uncommon – interstitial lung disease; dyspnea, cough, pneumonitis, distress syndrome.

Gastrointestinal disorders: very common – diarrhea, stomatitis; common – cheilitis, dyspepsia: nausea, vomiting, constipation.

Hepatobiliary disorders: common – increased ALT activity, increased AST activity; increased total bilirubin concentration, cytolytic hepatitis, hepatic failure; possible – increased ALP activity.

Skin and subcutaneous tissue disorders: very common – rash, acneiform dermatitis, pruritus, dry skin; common – palmar-plantar erythrodysesthesia syndrome; nail changes.

Cardiac disorders: cardiac failure.

Musculoskeletal and connective tissue disorders: common – muscle spasms; back pain.

Renal and urinary disorders: common – renal impairment, renal failure.

Metabolism and nutrition disorders: very common – decreased appetite; common – dehydration, hypokalemia, weight loss.

Blood and lymphatic system disorders: possible – anemia, neutropenia.

Infections and infestations: very common – paronychia; common – cystitis.

General disorders and administration site conditions: common – pyrexia; fatigue.

Contraindications

Severe hepatic impairment, children and adolescents under 18 years of age, pregnancy, lactation (breastfeeding), hypersensitivity to afatinib.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Special Precautions

Afatinib should be used with caution in the following diseases and conditions: keratitis; ulcerative keratitis; severe dry eyes; interstitial lung disease; impaired left ventricular ejection fraction; concomitant heart disease.

To assess the patient’s EGFR mutation status, it is important to use a well-validated and reliable method to avoid false-negative or false-positive results.

Prophylactic treatment of diarrhea is essential, especially in the first 6 weeks of therapy at the first signs. Treatment consists of replenishing body water loss and simultaneous use of antidiarrheal agents (loperamide), the dose of which should be increased if necessary to the maximum recommended. Antidiarrheal agents should be available to patients so that treatment can be started at the first signs of diarrhea and continued until there is no loose stool for 12 hours. In patients with severe diarrhea, treatment interruption, dose reduction, or discontinuation of therapy may be required. In case of dehydration, intravenous administration of electrolytes and fluids may be necessary.

Patients who are forced to be in the sun are advised to wear protective clothing and/or use sunscreens. Timely intervention for dermatological reactions (e.g., emollients, antibiotics) may allow treatment to continue.

In patients with prolonged or severe skin reactions, temporary interruption of therapy, dose reduction, additional therapeutic intervention, and consultation with a specialist experienced in the treatment of such dermatological reactions may also be required. If a patient develops serious bullous rash, blisters, or exfoliative changes, treatment should be interrupted or discontinued.

In women, in patients with lower body weight, and with concomitant renal impairment, the risk of developing adverse reactions such as diarrhea, rash/acne, and stomatitis may be increased. In the presence of these risk factors, more careful monitoring of patients is recommended.

All patients with acute onset and/or unexplained worsening of pulmonary symptoms (dyspnea, cough, fever) should be thoroughly examined to rule out interstitial lung disease. Until this examination is completed, afatinib should be interrupted. If a diagnosis of interstitial lung disease is established, Afatinib should be discontinued and appropriate treatment initiated if necessary.

In patients with concomitant liver disease, periodic monitoring of liver function is recommended. In case of worsening liver function, treatment interruption may be required. In patients with severe hepatic impairment, treatment should be discontinued.

If new or worsening symptoms such as eye inflammation, lacrimation, photophobia, blurred vision, eye pain and/or eye redness occur, the patient should immediately consult an ophthalmologist. If a diagnosis of ulcerative keratitis is confirmed, afatinib treatment should be interrupted or discontinued. The benefit and risk of continuing treatment should be carefully weighed. The use of contact lenses is also a risk factor for keratitis and corneal ulcers.

In patients with risk factors for heart disease and conditions that may impair left ventricular ejection fraction, left ventricular ejection fraction should be assessed before starting and during treatment with afatinib. If signs/symptoms of cardiac damage develop during treatment, cardiac monitoring, including assessment of left ventricular ejection fraction, should be performed.

In cases where left ventricular ejection fraction values fall below the lower limit of normal established in the medical institution, consultation with a cardiologist and consideration of interruption or discontinuation of afatinib treatment is recommended.

Drug Interactions

Based on in vitro data, Afatinib has been established to be a substrate for P-glycoprotein. Changes in plasma concentrations of other P-glycoprotein substrates during afatinib administration are considered unlikely. Clinical data indicate that concomitant use of strong inhibitors or inducers of P-glycoprotein may alter afatinib exposure.

Afatinib can be safely combined with P-glycoprotein inhibitors (such as ritonavir) simultaneously with or after afatinib intake. However, if strong P-glycoprotein inhibitors (including, for example, ritonavir, cyclosporine, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) are used before afatinib intake, an increase in afatinib exposure is possible; caution is required with these combinations.

Strong inducers of P-glycoprotein (including, for example, carbamazepine, phenytoin, phenobarbital, or St. John’s wort (Hypericum perforatum)) may decrease the AUC of afatinib.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.