ERLOTINIB HYDROCHLORIDE (Page 3 of 7)

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of erlotinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis, in combination with statin therapy

Eye Disorders: ocular inflammation including uveitis

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 modification of erlotinib is not recommended [see Warnings and Precautions (5.9) and Adverse Reactions (6.1)].

8 USE IN SPECIFIC POPULATIONS

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 to 4% and 15 to 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/m2 /day or 60 mg/m2 /day (0.3 or 0.7 times the recommended daily dose, on a mg/m2 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/m2 /day in the rabbit (3 times the plasma drug concentration seen in humans at 150 mg/day) and up to 60 mg/m2 /day in the rat (0.7 times the recommended dose of 150 mg/day on a mg/m2 basis).

8.2 Lactation

Risk Summary

There are no data on the presence of erlotinib in human milk, or the effects of erlotinib on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from erlotinib, including interstitial lung disease, hepatotoxicity, bullous and exfoliative skin disorders, microangiopathic hemolytic anemia with thrombocytopenia, ocular disorders, and diarrhea. Advise a lactating woman not to breastfeed during treatment with erlotinib and for 2 weeks after the final dose.

8.3 Females and Males of Reproductive Potential

Contraception

Females

Erlotinib can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during treatment with erlotinib and for one month after the last dose of erlotinib.

8.4 Pediatric Use

The safety and effectiveness of erlotinib in pediatric patients have not been established.

In an open-label, multicenter trial, 25 pediatric patients (median age 14 years, range 3 to 20 years) with recurrent or refractory ependymoma were randomized (1:1) to erlotinib or etoposide. Thirteen patients received erlotinib at a dose of 85 mg/m2 /day orally until disease progression, death, patient request, investigator decision to discontinue study drug, or intolerable toxicity. Four patients randomized to etoposide also received erlotinib following disease progression. The trial was terminated prematurely for lack of efficacy; there were no objective responses observed in these 17 erlotinib-treated patients.

No new adverse events were identified in the pediatric population.

Based on the population pharmacokinetics analysis conducted in 105 pediatric patients (2 to 21 years old) with cancer, the geometric mean estimates of CL/F/BSA (apparent clearance normalized to body surface area) were comparable across the three age groups: 2 to 6 years (n = 29), 7 to 16 years (n = 59), and 17 to 21 years (n = 17).

8.5 Geriatric Use

Of the 1297 subjects in clinical studies of erlotinib for the treatment of NSCLC and pancreatic cancer 40% were 65 and older while 10% were 75 and older. No overall differences in safety or efficacy were observed between subjects 65 years and older and those younger than 65.

8.6 Hepatic Impairment

Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with erlotinib treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment [see Warnings and Precautions (5.3), Adverse Reactions (6.1, 6.2), and Dosage and Administration]. Monitor patients with hepatic impairment (total bilirubin greater than upper limit of normal (ULN) or Child-Pugh A, B and C) during therapy with erlotinib. Treatment with erlotinib should be used with increased monitoring in patients with total bilirubin greater than 3 x ULN [see Warnings and Precautions (5.3), Adverse Reactions (6.1, 6.2), and Dosage and Administration (2.4)].

10 OVERDOSAGE

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

11 DESCRIPTION

Erlotinib, a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. Erlotinib tablet contains erlotinib as the hydrochloride salt that has the following structural formula:Structure

Erlotinib hydrochloride has the molecular formula C22 H23 N3 O4 .HCl and a molecular weight of 429.9. The molecule has a pKa of 5.42 at 25°C. It is freely soluble in formic acid, very slightly soluble in N,N-Dimethyl formamide and practically insoluble in water.

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: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate and sodium lauryl sulfate. The film-coat inactive ingredients are hypromellose, hydroxypropyl cellulose, titanium dioxide and polyethylene glycol 400.

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