BIRLOTIB

Erlotinib a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7bis(2-methoxyethoxy)-4-quinazolinamine Hydrochloride.

Erlotinib contains erlotinib as the hydrochloride salt that has the following structural formula: Erlotinib hydrochloride has the molecular formula C 22 H 23 N 3 O 4 •HCl and a molecular weight of 429.90.

The molecule has a pKa of 5.4.

Erlotinib hydrochloride is slightly soluble in

Dimethyl sulfoxide, Dimethyl formamide and Methanol.

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 1.69 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: micro crystalline cellulose, lactose monohydrate, sodium starch glycolate, sodium lauryl sulfate, magnesium stearate, and finished tablets are coated with opadry white[Y-5-7068] contains following ingredients hypromellose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol Er-des.

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 First-line treatment of patients with locally advanced, unrespectable or metastatic pancreatic cancer, in combination with gemcitabine.

Safety and efficacy of erlotinib tablets have not been established in patients with NSCLC whose tumors have other EGFR mutations.

Erlotinib tablets are not recommended for use in combination with platinum-based chemotherapy. 1.1 Non-Small Cell Lung Cancer (NSCLC) Erlotinib Tablets was 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.

Limitations of use

Safety and efficacy of erlotinib have not been established in patients with NSCLC whose tumors have other EGFR mutations.

Erlotinib tablet is not recommended for use in combination with platinum-based chemotherapy. 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.

History of hepatopathies History of radiation therapy Chemotherapy, history Diverticulosis, history (de) Female likely to be pregnant Pregnancy Hepatitis Lacrimal hyposecretion, antecedent (d) Respiratory infection Hepatic impairment Severe renal impairment Keratopathy Keratopathy, history Pulmonary metastasis Obstruction of bile pathways Pneumopathy Subject at risk of dehydration Subject under 18 Japanese subject Subject with contact lenses Subject on chemotherapy Smoking Hepatotoxic treatment in progress Serum transaminases > 5 times the normal upper limit Gastroduodenal ulcer, history (d).

Epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells.

In some tumor cells signaling through this receptor plays a role in tumor cell survival and proliferation irrespective of EGFR mutation status.

Erlotinib reversibly inhibits the kinase activity of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor and thereby inhibiting further downstream signaling.

Erlotinib binding affinity for EGFR exon 19 deletion or exon 21 (L858R) mutations is higher than its affinity for the wild type receptor.

Erlotinib inhibition of other tyrosine kinase receptors has not been fully characterized. 12.3 Pharmacokinetics Absorption Erlotinib is about 60% absorbed after oral administration.

Peak plasma levels occur 4 hours after dosing.

Food increased the bioavailability of erlotinib to approximately 100%.

Erlotinib is 93% protein bound to plasma albumin and alpha-1 acid glycoprotein (AAG).

Erlotinib has an apparent volume of distribution of 232 liters.

Erlotinib is eliminated with a median half-life of 36.2 hours in patients receiving the single-agent erlotinib tablets 2 nd /3 rd line regimen.

Time to reach steady state plasma concentration would therefore be 7-8 days.

Metabolism Erlotinib is metabolized primarily by

CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1, in vitro.

Following a 100 mg oral dose, 91% of the dose was recovered: 83% in feces (1% of the dose as intact parent) and 8% in urine (0.3% of the dose as intact parent).

Neither age, body weight, nor gender had a clinically significant effect on the systemic exposure of nd rd erlotinib in NSCLC patients receiving single-agent erlotinib tablets for 2 nd /3 rd line treatment or for maintenance treatment, and in pancreatic cancer patients who received erlotinib plus gemcitabine.

The pharmacokinetics of erlotinib tablets in patients with compromised renal function is unknown.

In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver.

However, erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases.

In a single-dose pharmacokinetics trial in healthy volunteers, cigarette smoking (moderate CYP1A2 inducer) increased erlotinib clearance and decreased erlotinib AUC0-inf by 64% (95% CI, 46-76%) in current smokers compared with former/never smokers.

In a

NSCLC trial, current smokers achieved erlotinib steady-state trough plasma concentrations which were approximately 2-fold less than the former smokers or patients who had never smoked.

This effect was accompanied by a 24% increase in apparent erlotinib plasma clearance.

In another study which was conducted in NSCLC patients who were current smokers, pharmacokinetic analyses at steady-state indicated a dose-proportional increase in erlotinib exposure when the erlotinib tablets dose was increased from 150 mg to 300 mg. .

Co-administration of gemcitabine had no effect on erlotinib plasma clearance.

CYP3A4 Inhibitors Co-administration with a strong CYP3A4 inhibitor, ketoconazole, increased erlotinib AUC by 67%.Co-administration with a combined CYP3A4 and CYP1A2 inhibitor, ciprofloxacin, increased erlotinib exposure [AUC] by 39%, and increased erlotinib maximum concentration [C max ] by 17%. .

CYP3A4 Inducers Pre-treatment with the CYP3A4 inducer rifampicin, for 7-11 days prior to erlotinib tablets, decreased erlotinib AUC by 58% to 80% .

CYP1A2 Inducers or Smoking Tobacco See Specific Populations Section.

Drugs that Increase Gastric pH

Erlotinib solubility is pH dependent and decreases as pH increases.

When a proton pump inhibitor (omeprazole) was co-administered with erlotinib tablets the erlotinib exposure [AUC] was decreased by 46% and the erlotinib maximum concentration [C max ] was decreased by 61%.

When erlotinib tablets was administered 2 hours following a 300 mg dose of an H-2 receptor antagonist (ranitidine), the erlotinib AUC was reduced by 33% and the erlotinib C max was reduced by 54%.

When erlotinib tablets was administered with ranitidine 150 mg twice daily (at least 10 h after the previous ranitidine evening dose and 2 h before the ranitidine morning dose), the erlotinib AUC was decreased by 15% and the erlotinib C max was decreased by 17% .

Mechanism of action

Erlotinib is an inhibitor of tyrosine kinase of the human epidermal growth factor type 1 receptor (Epidermal Growth Factor Receptor: EGFR, also known as HER1).

Erlotinib is a potent inhibitor of intracellular phosphorylation of EGFR.

EGFR is expressed on the surface of normal and cancerous cells.

In non-clinical models, inhibition of EGFR phosphotyrosin results in a cessation of proliferation and/or cell death.

EGFR mutations can lead to a constitutive activation of anti-apopteral signaling pathways and proliferation.

The potent efficacy of erlotinib in blocking EGFR-mediated signaling in these tumours with positive EGFR mutations is attributed to narrow binding of erlotinib at the ATP binding site in the field of EGFR mutated kinase.

These cell-dead cell-dead mutations are observed.

• Proteinuria (Uncommon)
• ASAT (increase)
• Neutropenia Hypokalaemia Hyperbilirubinaemia
• ALT (increase)
• Alopecia (Common)
• Dry skin (Common)
• Skin crack (Common)
• Follicleitis (Common)
• Skin reaction (Uncommon)
• Acne (Common)
• Pruritus (Very common)
• Rash (Very common)
• Perionyxis (Common)
• Onychoclasia (Uncommon)
• Acneiform eruption (Common)
• Onycholysis (Uncommon)
• Toxic epidermal necrolysis (Very rare)
• Stevens-Johnson Syndrome (Very rare)
• Palmoplantary Erythrodysaesthesia (Rare)
• Skin hyperpigmentation Skin Erythema Cellulite Populo-pustulose Rosacea Frisher (Very common)
• Asthenia (Very common)
• Fever (Very common)
• Hirsutism (Uncommon)
• Liver function exploration (abnormality) (Very common)
• Hepatic impairment (Rare)
• Hepatitis (Rare)
• Acute hepatitis Infectious Cellulitis
• Infection (Very common)
• Septicaemia Anorexia (Very common)
• Weight (decrease) (Very common)
• Dehydration Eyes (amendment) (Uncommon)
• Keratoconjunctivitis dry (Very common)
• Eyebrows (change) (Uncommon)
• Keratoconjunctivitis (Very common)
• Keratite (Common)
• Conjunctivitis (Common)
• Corneal perforation (Very rare)
• Uveitis (Very rare)
• Corneal ulcer (Very rare)
• Eyelash growth Lashes are sore Trichiasis
• Epistaxis (Common)
• Stomatitis (Very common)
• Depression (Very common)
• Gastrointestinal perforation (Uncommon)
• Gastrointestinal haemorrhage (Common)
• Flatulence (Very common)
• Nausea (Very common)
• Dyspepsia (Very common)
• Diarrhoea (Very common)
• Abdominal pain (Very common)
• Vomiting (Very common)
• Cystic pneumatosis of the intestine (Rare)
• Headache (Very common)
• Neuropathy (Very common)
• Cough (Very common)
• Dyspnoea (Very common)
• Diffuse pore-pitching (Uncommon)
• Interstitial pneumopathy (Uncommon)
• Pneumopathy Pneumonia Renal impairment (Common)
• Nephropathy (Uncommon).

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

150mg orally, on an empty stomach, once daily Pancreatic cancer: 100 mg orally, on an empty stomach, once daily. 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.

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: . 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 tablet 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. 2.4 Dose Modifications Adverse Reactions Pulmonary † Interstitial Lung Disease (ILD) Discontinue Erlotinib tablet During diagnostic evaluation for possible ILD Withhold Erlotinib tablet 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 tablet 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 tablet and consider discontinuation Renal † For severe (CTCAE grade to 4) renal toxicity Withhold Erlotinib tablet and consider discontinuation Gastrointestinal † Gastrointestinal perforation Discontinue Erlotinib tablet For persistent severe diarrhea not responsive to medical management (e.g., loperamide) Withhold Erlotinib tablet Skin † Severe bullous, blistering or exfoliating skin conditions Discontinue Erlotinib tablet For severe rash not responsive to medical management Withhold Erlotinib tablet Ocular † Corneal perforation or severe ulceration Discontinue Erlotinib tablet For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks Withhold Erlotinib tablet For acute/worsening ocular disorders such as eye pain Withhold Erlotinib tablet and consider discontinuation Drug Interactions CYP3A4 inhibitors ‡ If severe reactions occur with concomitant use of strong.

\ CYP3A4 inhibitors [such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice] or when using concomitantly with an inhibitor of both CYP3A4 and CYP1A2 (e.g., ciprofloxacin Reduce erlotinib by 50 mg decrements; avoid concomitant use if possible CYP3A4 inducers ‡ Concomitant use with CYP3A4 inducers, such as rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, or St. John's Wort Increase erlotinib by 50 mg increments at 2-week intervals to a maximum of 450 mg as tolerated. Avoid concomitant use if possible Concurrent Cigarette Smoking ‡§ Concurrent cigarette smoking Increase erlotinib by 50 mg increments at 2-week intervals to a maximum of 300 mg. Immediately reduce the dose of erlotinib tablet to the recommended dose (150 mg or 100 mg daily) upon cessation of smoking Proton Pump inhibitors Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period Avoid concomitant use if possible H2-receptor antagonists If treatment with an H2-receptor antagonist such as ranitidine is required, separate dosing.

Erlotinib tablet must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2 receptor antagonist Antacids The effect of antacids on erlotinib pharmacokinetics has not been evaluated The antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary † For additional information see Warnings and Precautions. * Reduce erlotinib by 50 mg decrements when restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤ 1. ‡ For additional information see Drug Interactions. § For additional information see Clinical Pharmacology.

mg Tablets: White to off white round, biconvex film-coated tablets, debossed with “S13” on one side and plain on other side.

Supplied in

Bottles of 30: NDC 72485-217-30 100 mg Tablets: White to off white round, biconvex film-coated tablets, debossed with “S12” on one side and plain on other side.

Bottles of 30: NDC 72485-218-30 150 mg Tablets: White to off white round, biconvex film-coated tablets, debossed with “S11” on one side and plain on other side.

Bottles of 30: NDC 72485-219-30 Store at 25°C (77°F); excursions permitted to 15°C -30°C (59°F -86°F). .

Based on animal data and its mechanism of action, erlotinib tablets can cause fetal harm when administered to a pregnant woman.

Limited available data on use of erlotinib tablets 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.

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).

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

In an open-label, multicenter trial, 25 pediatric patients (median age 14 years, range 3-20 years) with recurrent or refractory ependymoma were randomized (1:1) to erlotinib tablets or etoposide.

Thirteen patients received erlotinib tablets at a dose of 85 mg/m 2 /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 tablets following disease progression.

The trial was terminated prematurely for lack of efficacy; there were no objective responses observed in these 17 erlotinib tablets -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: 2-6 years (n = 29), 7-16 years (n = 59), and 17-21 years (n = 17).

Of the 1297 subjects in clinical studies of erlotinib tablets for the treatment of NSCLC and pancreatic cancer 40% were and older while 10% were and older.

No overall differences in safety or efficacy were observed between subjects 65 years and older and those younger than 65.