Erlotinib Hydrochloride

FDA Drug Information • Also known as: Erlotinib, Erlotinib Hydrochloride

Brand Names: Erlotinib, Erlotinib Hydrochloride
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION Erlotinib, a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride. Erlotinib tablets contains erlotinib as the hydrochloride salt that has the following structural formula: Erlotinib hydrochloride has the molecular formula C 22 H 24 ClN 3 O 4 and a molecular weight of 429.90. The molecule has pK a of 4.44 at 25°C. Erlotinib hydrochloride is slightly soluble in methanol, practically insoluble in acetonitrile and in acetone. Aqueous solubility of erlotinib hydrochloride is dependent on pH with increased solubility at a pH of less than 5 due to protonation of the secondary amine. Over the pH range of 1.4 to 9.6, maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2. Erlotinib tablets for oral administration are available in three dosage strengths containing erlotinib hydrochloride (27.3 mg, 109.3 mg and 163.9 mg) equivalent to 25 mg, 100 mg and 150 mg erlotinib and the following inactive ingredients: hypromellose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, sodium starch glycolate, and titanium dioxide. srt

What Is Erlotinib Hydrochloride Used For?

1 INDICATIONS AND USAGE Erlotinib tablet is a kinase inhibitor indicated for: The treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test receiving first-line, maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen. ( 1.1 ) First-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine. ( 1.2 ) Limitations of Use: Safety and efficacy of erlotinib tablets have not been established in patients with NSCLC whose tumors have other EGFR mutations. ( 1.1 ) Erlotinib tablet is not recommended for use in combination with platinum-based chemotherapy. ( 1.1 ) 1.1 Non-Small Cell Lung Cancer (NSCLC) Erlotinib tablets are indicated for: The treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test receiving first-line, maintenance, or second or greater line treatment after progression following at least one prior chemotherapy regimen [ see Clinical Studies (14.1 , 14.3 )]. Limitations of use: Safety and efficacy of erlotinib tablets have not been established in patients with NSCLC whose tumors have other EGFR mutations [ see Clinical Studies (14.1, 14.2 )]. Erlotinib tablet is not recommended for use in combination with platinum-based chemotherapy [ see Clinical Studies (14.4) ]. 1.2 Pancreatic Cancer Erlotinib tablet in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer [ see Clinical Studies (14.5) ].

Dosage and Administration

2 DOSAGE AND ADMINISTRATION NSCLC: 150 mg orally, on an empty stomach, once daily. ( 2.2 ) Pancreatic cancer: 100 mg orally, on an empty stomach, once daily. ( 2.3 ) 2.1 Selection of Patients with Metastatic NSCLC Select patients for the treatment of metastatic NSCLC with erlotinib tablets based on the presence of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor or plasma specimens [ See Clinical Studies (14.1 , 14.2 )]. If these mutations are not detected in a plasma specimen, test tumor tissue if available. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dose – NSCLC The recommended daily dose of erlotinib tablets for NSCLC is 150 mg taken on an empty stomach, i.e., at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs. 2.3 Recommended Dose – Pancreatic Cancer The recommended daily dose of erlotinib tablets for pancreatic cancer is 100 mg taken once daily in combination with gemcitabine. Take erlotinib tablets on an empty stomach, i.e., at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs [ see Clinical Studies (14.5) ]. 2.4 Dose Modifications Adverse Reactions Pulmonary † Interstitial Lung Disease (ILD) Discontinue erlotinib tablets During diagnostic evaluation for possible ILD Withhold erlotinib tablets * Hepatic † Severe hepatic toxicity that does not improve significantly or resolve within three weeks Discontinue erlotinib tablets In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline Withhold erlotinib tablets * and consider discontinuation In patients without pre-existing hepatic impairment for total bilirubin levels greater than 3 times the upper limit of normal or transaminases greater than 5 times the upper limit of normal Withhold erlotinib tablets * and consider discontinuation Renal † For severe (CTCAE grade 3 to 4) renal toxicity Withhold erlotinib tablets * and consider discontinuation Gastrointestinal † Gastrointestinal perforation Discontinue erlotinib tablets For persistent severe diarrhea not responsive to medical management (e.g., loperamide) Withhold erlotinib tablets * Skin † Severe bullous, blistering or exfoliating skin conditions Discontinue erlotinib tablets For severe rash not responsive to medical management Withhold erlotinib tablets * Ocular † Corneal perforation or severe ulceration Discontinue erlotinib tablets For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks Withhold erlotinib tablets * For acute/worsening ocular disorders such as eye pain Withhold erlotinib tablets * and consider discontinuation Drug Interactions CYP3A4 inhibitors ‡ If severe reactions occur...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the labeling: Interstitial Lung Disease (ILD) [ see Warnings and Precautions (5.1) ] Renal Failure [ see Warnings and Precautions (5.2) ] Hepatotoxicity with or without Hepatic Impairment [ see Warnings and Precautions (5.3) ] Gastrointestinal Perforation [ see Warnings and Precautions (5.4) ] Bullous and Exfoliative Skin Disorders [ see Warnings and Precautions (5.5) ] Cerebrovascular Accident [ see Warnings and Precautions (5.6) ] Microangiopathic Hemolytic Anemia with Thrombocytopenia [ see Warnings and Precautions (5.7) ] Ocular Disorders [ see Warnings and Precautions (5.8) ] Hemorrhage in Patients Taking Warfarin [ see Warnings and Precautions (5.9) ] The most common adverse reactions (≥ 20%) with erlotinib from a pooled analysis in patients with NSCLC across all approved lines of therapy, with and without EGFR mutations, and in patients with pancreatic cancer were rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety evaluation of erlotinib is based on more than 1200 cancer patients who received erlotinib as monotherapy, more than 300 patients who received erlotinib 100 or 150 mg plus gemcitabine, and 1228 patients who received erlotinib concurrently with other chemotherapies. The most common adverse reactions with erlotinib are rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of erlotinib for the treatment of NSCLC and pancreatic cancer were 70% for rash and 42% for diarrhea. Non-Small Cell Lung Cancer First-Line Treatment of Patients with EGFR Mutations The most frequent (≥ 30%) adverse reactions in erlotinib-treated patients were diarrhea, asthenia, rash, cough, dyspnea, and decreased appetite. In erlotinib-treated patients the median time to onset of rash was 15 days and the median time to onset of diarrhea was 32 days. The most frequent Grade 3-4 adverse reactions in erlotinib-treated patients were rash and diarrhea. Dose interruptions or reductions due to adverse reactions occurred in 37% of erlotinib-treated patients, and 14.3% of erlotinib- treated patients discontinued therapy due to adverse reactions. In erlotinib-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%). Common adverse reactions in Study 1, occurring in at least 10% of patients who received erlotinib or chemotherapy and an increase in ≥ 5% in the erlotinib-treated group, are graded by National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (NCI-CTCAE v3.0) Grade in Table 1. The median duration of erlotinib treatment was 9.6 months in Study 1. Table 1: Adverse Reactions with an Incidence Rate ≥ 10% and an Increase of ≥ 5% in the Erlotinib-Treated Group (Study 1) Erlotinib N = 84 Chemotherapy † N = 83 Adverse Reaction All Grades % Grades 3-4 % All Grades % Grades 3-4 % Rash ‡ 85 14 5 0 Diarrhea 62 5 21 1 Cough 48 1 40 0 Dyspnea 45 8 30 4 Dry skin 21 1 2 0 Back pain 19 2 5 0 Chest pain 18 1 12 0 Conjunctivitis 18 0 0 0 Mucosal inflammation 18 1 6 0 Pruritus 16 0 1 0 Paronychia 14 0 0 0 Arthralgia 13 1 6 1 Musculoskeletal pain 11 1 1 0 † Platinum-based chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel). ‡Rash as a composite term includes rash, acne, folliculitis, erythema, acneiform dermatitis, dermatitis, palmar-plantar...

Drug Interactions

7 DRUG INTERACTIONS CYP3A4 Inhibitors Co-administration of erlotinib with a strong CYP3A4 inhibitor or a combined CYP3A4 and CYP1A2 inhibitor increased erlotinib exposure. Erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2. Increased erlotinib exposure may increase the risk of exposure-related toxicity [ see Clinical Pharmacology (12.3) ]. Avoid co-administering erlotinib with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or a combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin). Reduce the erlotinib dosage when co-administering with a strong CYP3A4 inhibitor or a combined CYP3A4 and CYP1A2 inhibitor if co-administration is unavoidable [ see Dosage and Administration (2.4) ]. CYP3A4 Inducers Pre-treatment with a CYP3A4 inducer prior to erlotinib decreased erlotinib exposure [ see Clinical Pharmacology (12.3) ] . Increase the erlotinib dosage if co-administration with CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital and St. John's wort) is unavoidable [ see Dosage and Administration (2.4) ]. CYP1A2 Inducers and Cigarette Smoking Cigarette smoking decreased erlotinib exposure. Avoid smoking tobacco (CYP1A2 inducer) and avoid concomitant use of erlotinib with moderate CYP1A2 inducers (e.g., teriflunomide, rifampin, or phenytoin). Increase the erlotinib dosage in patients that smoke tobacco or when co-administration with moderate CYP1A2 inducers is unavoidable [ see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ]. Drugs the Increase Gastric pH Co-administration of erlotinib with proton pump inhibitors (e.g., omeprazole) and H-2 receptor antagonists (e.g., ranitidine) decreased erlotinib exposure [ see Clinical Pharmacology (12.3) ]. For proton pump inhibitors, avoid concomitant use if possible. For H-2 receptor antagonists and antacids, modify the dosing schedule [ see Dosage and Administration (2.4) ]. Increasing the dose of erlotinib when co-administered with gastric PH elevating agents is not likely to compensate for the loss of exposure. Anticoagulants Interaction with coumarin-derived anticoagulants, including warfarin, leading to increased International Normalized Ratio (INR) and bleeding adverse reactions, which in some cases were fatal, have been reported in patients receiving erlotinib. Regularly monitor prothrombin time or INR in patients taking coumarin-derived anticoagulants. Dose modifications of erlotinib are not recommended [ see Warnings and Precautions (5.9) and Adverse Reactions (6.1) ]. CYP3A4 inhibitors or a combined CYP3A4 and CYP1A2 inhibitor increase erlotinib plasma concentrations. Avoid concomitant use. If not possible, reduce erlotinib dose. ( 2.4 , 7 ) CYP3A4 inducers decrease erlotinib plasma concentrations. Avoid...

Contraindications

4 CONTRAINDICATIONS None. None. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on animal data and its mechanism of action, erlotinib can cause fetal harm when administered to a pregnant woman. Limited available data on use of erlotinib in pregnant women are not sufficient to inform a risk of major birth defects or miscarriage. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at exposures approximately 3 times the exposure at the recommended human daily dose of 150 mg. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Erlotinib has been shown to cause maternal toxicity resulting in embryo-fetal lethality and abortion in rabbits when given during the period of organogenesis at doses that result in plasma drug concentrations approximately 3 times those achieved at the recommended dose in humans (AUCs at 150 mg daily dose). During the same period, there was no increase in the incidence of embryo-fetal lethality or abortion in rabbits or rats at doses resulting in exposures approximately equal to those in humans at the recommended daily dose. In an independent fertility study female rats treated with 30 mg/m 2 /day or 60 mg/m 2 /day (0.3 or 0.7 times the recommended daily dose, on a mg/m 2 basis) of erlotinib had an increase in early resorptions that resulted in a decrease in the number of live fetuses. No teratogenic effects were observed in rabbits or rats dosed with erlotinib during organogenesis at doses up to 600 mg/m 2 /day in the rabbit (3 times the plasma drug concentration seen in humans at 150 mg/day) and up to 60 mg/m 2 /day in the rat (0.7 times the recommended dose of 150 mg/day on a mg/m 2 basis).

Overdosage

10 OVERDOSAGE Withhold erlotinib in patients with an overdose or suspected overdose and institute symptomatic treatment.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 25 mg Tablets: White colored, round shaped, biconvex, film coated tablets, debossed with “E 25” on one side and plain on other side; supplied in: Bottles of 30: NDC 72205-080-30 100 mg Tablets: White colored, round shaped, biconvex, film coated, tablets, debossed with “E 100” on one side and plain on other side; supplied in: Bottles of 30: NDC 72205-081-30 150 mg Tablets: White colored, round shaped, biconvex, film coated tablets, debossed with “E 150” on one side and plain on other side; supplied in: Bottles of 30: NDC 72205-082-30 Store at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). See USP Controlled Room Temperature.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.