Erlotinib Hydrochloride
25mg/100mg/150mg Tablets

What is in this leaflet

This leaflet answers some common questions about ERLOTINIB tablets.

It does not contain all the available information.
It does not take the place of talking to your doctor or pharmacist.
All medicines have risks and benefits. Your doctor has weighed the risks of you taking ERLOTINIB against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.
Keep this leaflet with the medicine.
You may need to read it again.

What ERLOTINIB is used for

ERLOTINIB contains the active ingredient erlotinib hydrochloride.

ERLOTINIB is used for the treatment of advanced or metastatic (spreading) non-small cell lung cancer (NSCLC). It can be given as initial therapy if your cancer has specific mutations in a protein called epidermal growth factor receptor (EGFR). It can also be given soon after initial chemotherapy or it can be given later on when the initial chemotherapy has not worked.

ERLOTINIB is also used in combination with gemcitabine for the treatment of pancreatic cancer.
ERLOTINIB belongs to a group of medicines called anti-neoplastic (or anti-cancer) medicines, which are used to treat cancer.
ERLOTINIB prevents the activity of EGFR protein. This protein is known to be involved in the growth and spread of cancer cells.

Your doctor may have prescribed ERLOTINIB for another purpose.
Ask your doctor if you have any questions about why ERLOTINIB has been prescribed for you.

ERLOTINIB is not addictive.

This medicine is available only with a doctor’s prescription.

Before you take ERLOTINIB

When you must not take it
Do not take ERLOTINIB if:

• you have had an allergic reaction to ERLOTINIB or any ingredients listed at the end of this leaflet
  Some symptoms of an allergic reaction may include:
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching, hives on the skin
  the package is torn or shows signs of tampering
• the expiry date printed on the pack has passed. If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure if you should be taking ERLOTINIB, talk to your doctor.

Use in children
Do not give ERLOTINIB to children under 18 years of age.
Safety and effectiveness in patients less than 18 years of age have not been established.

Before you start to take ERLOTINIB
Your doctor must know about all the following before you start to take ERLOTINIB.
Tell your doctor if:

• you are pregnant or plan to become pregnant ERLOTINIB may be harmful to an unborn baby when taken by a pregnant woman.
  
  If you are a woman who could become pregnant use adequate contraception (birth control) during treatment, and continue using contraception for at least 2 weeks after taking the last tablet.
  
  If you become pregnant while you are being treated with ERLOTINIB, tell your doctor immediately. ERLOTINIB is not generally recommended for use in pregnant women unless the benefits of treatment to the mother outweigh the risk to the unborn baby. Your doctor will discuss the risks and benefits of ERLOTINIB treatment with you.
• you are breast-feeding or plan to breast-feed It is not known whether ERLOTINIB passes into breast milk. It is not recommended that you breast-feed while taking ERLOTINIB.
• you have liver problems
  It is not known whether ERLOTINIB has a different effect if your liver is not functioning normally.
• you have kidney problems
• you have a history of stomach ulcers or inflammation of the bowel wall
• you are a smoker
  Your doctor may advise you to quit smoking as smoking can reduce the effectiveness of ERLOTINIB.
• you are allergic to any other medicines, foods, dyes or preservatives
• you cannot tolerate lactose

If you have not told your doctor about any of the above, tell them before you start taking ERLOTINIB.

Taking other medicines

Tell your doctor if you are taking any other medicines including any that you have bought without a prescription from a pharmacy, supermarket or healthfood shop.

Some medicines may interfere with ERLOTINIB. These medicines include:

• ketoconazole, a medicine used to treat fungal infections
• rifampicin, a medicine used to treat infections
• ciprofloxacin, a medicine used to treat bacterial infections
• omeprazole, a medicine used to treat stomach reflux and stomach ulcers
• ranitidine, a medicine used to treat stomach reflux, and stomach ulcers
• antacids, a group of medicines used to treat stomach upset and indigestion
• corticosteroids, a group of medicines used to treat inflammation
• non-steroidal anti-inflammatory medicines (NSAIDs), a group of medicines commonly used as pain killers
• statins, a groups of medicines used to lower cholesterol levels
• other medicines used to treat cancer

These medicines may be affected by ERLOTINIB, or may affect how well it works. You may need to use different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

There are some medicines which may be taken with ERLOTINIB but may require close supervision by your doctor. These medicines include:

• warfarin, a medicine used to thin the blood. If you take warfarin your doctor will need to regularly monitor you with blood tests.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking ERLOTINIB.
Ask your doctor or pharmacist if you are not sure about this list of medicines.

How to take ERLOTINIB

Follow all directions given to you by your doctor or pharmacist.
They may differ from the information contained in this leaflet.

How much to take
Take ERLOTINIB exactly as your doctor has prescribed.
Your doctor will tell you how many ERLOTINIB tablets to take each day.
For non-small-cell lung cancer, the usual dose is one 150 mg ERLOTINIB tablet each day.
For pancreatic cancer, given in combination with gemcitabine, the usual dose is one 100 mg ERLOTINIB tablet each day.
Your doctor may adjust your dose if necessary.

How to take it
Swallow the tablets whole with a glass of water.
Do not chew the tablets.

When to take it
Take ERLOTINIB on an empty stomach.
Take ERLOTINIB at least one hour before food or two hours after food.
Food can interfere with the absorption and effectiveness of ERLOTINIB.

How long to take it
How long you will be treated with ERLOTINIB will depend on your cancer and how well you respond to the medicine.
Continue taking ERLOTINIB until your doctor tells you to stop.

If you forget to take it
Do not take an extra dose. Wait until the next dose and take your normal dose then.
Do not try to make up for the dose that you missed by taking more than one dose at a time.

This may increase the chance of getting a side effect.
If you are not sure what to do, ask your doctor or pharmacist.
If you have trouble remembering your dose, ask your pharmacist for some hints.

If you take too much (overdose)
Immediately telephone your doctor or National Poisons Information Centre (telephone 0800 POISON or 0800 764 766) for advice, or go to your nearest Accident and Emergency Centre, if you think you or anyone else may have taken too much ERLOTINIB. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.
If you take too many tablets, you may get diarrhoea or a rash.
Keep telephone numbers for these places handy.
If you are not sure what to do, contact your doctor or pharmacist.

While you are taking ERLOTINIB

Things you must do
Tell all doctors, dentists and pharmacists who are treating you that you are taking ERLOTINIB.
Tell your doctor if you become pregnant while taking ERLOTINIB.
If you are a smoker, try not to smoke while you are taking ERLOTINIB.
Smoking can interfere with how well ERLOTINIB will work and reduce the effectiveness of the medicine.

If you develop severe diarrhoea, tell your doctor immediately.
Your doctor may need to give you medicine to stop the diarrhoea, and may reduce your dose temporarily until the side effect settles.

If you develop severe abdominal pain associated with nausea and vomiting, or you develop blood in your stools, or if you are vomiting blood or material that looks like coffee grounds, tell your doctor immediately.

You may need urgent medical treatment.
If you suddenly develop a cough or worsening breathing difficulties with fever, tell your doctor immediately.

You may have interstitial lung disease, and may require urgent medical treatment.
If you develop eye-pain or blisters around the nose, mouth and eyes, tell your doctor immediately.

You may need urgent medical treatment.
Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.

Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.
Tell your doctor if you feel the tablets are not helping your condition.
Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Things you must not do
Do not stop taking ERLOTINIB or change the dose without first checking with your doctor.
Do not let yourself run out of medicine over the weekend or on holidays.
Do not give ERLOTINIB to anyone else even if they have the same condition as you
Do not use ERLOTINIB to treat other complaints unless your doctor says to.
Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Things to be careful of
Be careful driving or operating machinery until you know how ERLOTINIB affects you.
However, ERLOTINIB is not expected to affect your ability to drive or operate machinery.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ERLOTINIB.

ERLOTINIB can help people with non-small cell lung cancer but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.
Tell your doctor if you notice any of the following and they worry you:

• tiredness
• loss of appetite
• itching
• dry skin
• acne
• folliculitis (infection of hair follicles)
• eye irritation, discharge with itching of the eyes and crusty eyelids
• nose bleeds
• unusual hair loss or thinning
• nail bed infection or swelling around the nails

These are the milder side effects of ERLOTINIB, and are usually short-lived.
Tell your doctor as soon as possible if you notice any of the following and they worry you:

• rash
• diarrhoea
• cough
• nausea or vomiting
• dehydration. Some signs of dehydration include dry skin, dark coloured urine, thirst, weakness or fatigue and loss of appetite
• weight loss

These side effects are usually short-lived, but may be persistent or get worse. Your doctor may recommend other medicines or may change the dose of ERLOTINIB if you experience these side effects.

Tell your doctor immediately if you notice any of the following:

• shortness of breath or,difficulty breathing
• infection, fever, chills
• pain, redness, swelling or sores in the mouth
• stomach pain
• numbness or weakness of the arms and legs
• depression

These may be serious side effects. Your doctor may recommend a change the dose of ERLOTINIB if you experience any of these side effects.

Tell your doctor immediately or go to your nearest Accident and Emergency Centre if you notice any of the following:

• severe or persistent diarrhoea, nausea, loss of appetite or vomiting
• bleeding from the stomach or intestines Signs and symptoms may include severe stomach pain, vomiting blood or material that looks like coffee grounds, bleeding from your rectum, black sticky bowel motions, bloody diarrhoea.
• sudden onset of new or progressively worsening breathing difficulties, associated with cough or fever These symptoms may indicate interstitial lung disease
• nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes and dark coloured urine
• blisters on the skin especially in the nose, mouth and eyes
• red or purple rash that spreads
• eye pain and/or inflammation

These may be very serious side effects. You may need urgent medical attention. This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don’t understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking ERLOTINIB

Storage
Keep your tablets in their container until it is time to take them.
If you take the tablets out of their container they may not keep well.

Keep ERLOTINIB in a cool dry place where the temperature stays below 30°C.
Do not store it, or any other medicine, in a bathroom or near a sink.
Do not leave it in the car or on window sills.
Heat and dampness can destroy some medicines.

Keep ERLOTINIB where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal
If your doctor tells you to stop taking ERLOTINIB, or the medication has passed its expiry date, ask your pharmacist what to do with any tablets that are left over. Do not throw out your medicine into the general household rubbish or flush it down the toilet.

Product description

Availability
ERLOTINIB is available in three strengths, 25 mg, 100 mg and 150 mg.
Each tablet strength comes in packs of 30 tablets.

What ERLOTINIB looks like

• ERLOTINIB 25 mg tablets are white to yellowish, round tablets marked with “T 25” engraved on one side.
• ERLOTINIB 100 mg tablets are white to yellowish, round tablets marked with “T 100” engraved on one side.
• ERLOTINIB 150 mg tablets are white to yellowish, round tablets marked with “T 150” engraved on one side.

Ingredients
Active ingredient: erlotinib hydrochloride

Inactive ingredients: Lactose monohydrate, microcrystalline cellulose, sodium starch glycollate, sodium lauryl sulphate, magnesium stearate

The tablets have a film-coating which contains:
hydroxypropyl cellulose, titanium dioxide, polyethylene glycol, hydroxypropyl methylcellulose

ERLOTINIB tablets are gluten free.

Erlotinib Hydrochloride
25mg/100mg/150mg Tablets

INDICATIONS AND USAGE

Non-Small Cell Lung Cancer (NSCLC)

Erlotinibis indicated for:

• The first-line 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
• The maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy
• The treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen

Limitations of use:

• Erlotinibis not recommended for use in combination with platinum-based chemotherapy
• Safety and efficacy of Erlotinibhave not been evaluated as first-line treatment in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution

Pancreatic Cancer
Erlotinibin combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

DOSAGE AND ADMINISTRATION

Patient Selection
Select patients for the first-line treatment of metastatic NSCLC with Erlotinibbased on the presence of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor specimens. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC

Recommended Dose - NSCLC
The recommended daily dose of Erlotinibfor 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.

Recommended Dose - Pancreatic Cancer
The recommended daily dose of Erlotinibfor pancreatic cancer is 100 mg taken once daily in combination with gemcitabine. Take Erlotinibon 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.

Dose Modifications
Discontinue Erlotinibfor:

• Interstitial Lung Disease (ILD)
• Severe hepatic toxicity that does not improve significantly or resolve within three weeks
• Gastrointestinal perforation
• Severe bullous, blistering or exfoliating skin conditions
• Corneal perforation or severe ulceration

Withhold Erlotinib:

• During diagnostic evaluation for possible ILD.
• For severe (CTCAE grade 3 to 4) renal toxicity, and consider discontinuation of Erlotinib
• 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, and consider discontinuation of Erlotinib
• In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline and consider discontinuation of Erlotinib
• For persistent severe diarrhea not responsive to medical management (e.g., loperamide).
• For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks
• For acute/worsening ocular disorders such as eye pain, and consider discontinuation of Erlotinib

Reduce Erlotinibby 50 mg decrements:

• 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). Avoid concomitant use if possible
• When restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤ 1.

Increase Erlotinibby 50 mg increments as tolerated for:

• Concomitant use with CYP3A4 inducers, such as rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, or St. John’s Wort. Increase doses by 50 mg increments at 2 week intervals to a maximum of 450 mg. Avoid concomitant use, if possible.
• Concurrent cigarette smoking. Increase by 50 mg increments at 2 week intervals to a maximum of 300 mg. Immediately reduce the dose of Erlotinibto the recommended dose (150 mg or 100 mg daily) upon cessation of smoking

Drugs Affecting Gastric pH

• Avoid concomitant use of Erlotinibwith proton pump inhibitors if possible. Separation of doses may not eliminate the interaction since proton pump inhibitors affect the pH of the upper GI tract for an extended period.
• If treatment with an H2-receptor antagonist such as ranitidine is required, Erlotinibmust be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist.
• Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the Erlotinibdose should be separated by several hours, if an antacid is necessary.

DOSAGE FORMS AND STRENGTHS

25 mg tablets
White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in orange with a “T” and “25” on one side and plain on the other side.

100 mg tablets
White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in gray with “T” and “100” on one side and plain on the other side.

150 mg tablets
White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in maroon with “T” and “150” on one side and plain on the other side.

CONTRAINDICATIONS

None

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease (ILD)
Cases of serious ILD, including fatal cases, can occur with Erlotinibtreatment. The overall incidence of ILD in approximately 32,000 Erlotinib-treated patients in uncontrolled studies and studies with concurrent chemotherapy was approximately 1.1%. In patients with ILD, the onset of symptoms was between 5 days to more than 9 months (median 39 days) after initiating Erlotinibtherapy.

Withhold Erlotinibfor acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, permanently discontinue Erlotinib.

Renal Failure
Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can occur with Erlotinibtreatment. Renal failure may arise from exacerbation of underlying baseline hepatic impairment or severe dehydration. The pooled incidence of severe renal impairment in the 3 monotherapy lung cancer studies was 0.5% in the Erlotinibarms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the Erlotinibplus gemcitabine arm and 0.4% in the control arm. Withhold Erlotinibin patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during Erlotinibtreatment.

Hepatotoxicity with or without Hepatic Impairment 
Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with Erlotinibtreatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. In clinical studies where patients with moderate to severe hepatic impairment were excluded, the pooled incidence of hepatic failure in the 3 monotherapy lung cancer studies was 0.4% in the Erlotinibarms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the Erlotinibplus gemcitabine arm and 0.4% in the control arm. In a pharmacokinetic study in 15 patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 of these 15 patients died within 30 days of the last Erlotinibdose. One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the remaining 8 patients died from progressive disease. Six out of the 10 patients who died had baseline total bilirubin > 3 x ULN.

Perform periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with Erlotinib. Increased frequency of monitoring of liver function is required for patients with pre-existing hepatic impairment or biliary obstruction. Withhold Erlotinibin 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 Erlotinibin patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline. Discontinue Erlotinibin patients whose abnormal liver tests meeting the above criteria do not improve significantly or resolve within three weeks

Gastrointestinal Perforation
Gastrointestinal perforation, including fatal cases, can occur with Erlotinibtreatment. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease may be at increased risk of perforation. The pooled incidence of gastrointestinal perforation in the 3 monotherapy lung cancer studies was 0.2% in the Erlotinibarms and 0.1% in the control arms. The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the Erlotinibplus gemcitabine arm and 0% in the control arm. Permanently discontinue Erlotinibin patients who develop gastrointestinal perforation.

Bullous and Exfoliative Skin Disorders
Bullous, blistering and exfoliative skin conditions, including cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal, can occur with Erlotinibtreatment. The pooled incidence of bullous and exfoliative skin disorders in the 3 monotherapy lung cancer studies was 1.2% in the Erlotinibarms and 0% in the control arms. The incidence of bullous and exfoliative skin disorders in the pancreatic cancer study was 0.4% in the Erlotinibplus gemcitabine arm and 0% in the control arm. Discontinue Erlotinibtreatment if the patient develops severe bullous, blistering or exfoliating conditions.

Myocardial Infarction/Ischemia
In the pancreatic carcinoma trial, six patients (incidence of 2.1%) in the Erlotinib/gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.1%), and one died due to myocardial infarction. The pooled incidence of myocardial infarction/ischemia in the 3 monotherapy lung cancer studies was 0.2% in the Erlotinibarms and 0.4% in the control arms.

Cerebrovascular Accident
In the pancreatic carcinoma trial, seven patients in the Erlotinib/gemcitabine group developed cerebrovascular accidents (incidence: 2.5%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents. The pooled incidence of cerebrovascular accident in the 3 monotherapy lung cancer studies was 0.6% in the Erlotinibarms and 0.9% in the control arms.

Microangiopathic Hemolytic Anemia with Thrombocytopenia
>The pooled incidence of microangiopathic hemolytic anemia with thrombocytopenia in the 3 monotherapy lung cancer studies was 0% in the Erlotinibarms and 0.1% in the control arms. The incidence of microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic cancer study was 1.4% in the Erlotinibplus gemcitabine arm and 0% in the control arm.

Ocular Disorders
Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with Erlotinibtreatment and can lead to corneal perforation or ulceration. The pooled incidence of ocular disorders in the 3 monotherapy lung cancer studies was 17.8% in the Erlotinibarms and 4% in the control arms. The incidence of ocular disorders in the pancreatic cancer study was 12.8% in the Erlotinibplus gemcitabine arm and 11.4% in the control arm. Interrupt or discontinue Erlotinibtherapy if patients present with acute or worsening ocular disorders such as eye pain.

Hemorrhage in Patients Taking Warfarin
Severe and fatal hemorrhage associated with International Normalized Ratio (INR) elevations can occur when Erlotiniband warfarin are administered concurrently. Regularly monitor prothrombin time and INR during Erlotinibtreatment in patients taking warfarin or other coumarin-derivative anticoagulants.

Embryo-Fetal Toxicity
Based on its mechanism of action, Erlotinibcan cause fetal harm when administered to a pregnant woman. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at doses approximately 3 times the recommended human daily dose of 150 mg. If Erlotinibis used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 2 weeks after the last dose of Erlotinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Erlotinib.

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)
• Renal Failure
• Hepatotoxicity with or without Hepatic Impairment
• Gastrointestinal Perforation
• Bullous and Exfoliative Skin Disorders
• Myocardial Infarction/Ischemia
• Cerebrovascular Accident
• Microangiopathic Hemolytic Anemia with Thrombocytopenia
• Ocular Disorders
• Hemorrhage in Patients Taking Warfarin

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 Erlotinibis based on more than 1200 cancer patients who received Erlotinibas monotherapy, more than 300 patients who received Erlotinib100 or 150 mg plus gemcitabine, and 1228 patients who received Erlotinib concurrently with other chemotherapies. The most common adverse reactions with Erlotinibare rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of Erlotinibfor 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%).

Selected, common adverse reactions in Study 4, occurring in at least 10% of patients who received Erlotinibor chemotherapy and an increase in ≥ 5% in the Erlotinibtreated group, are summarized by NCI-CTC (version 3.0) Grade in Table 1. The median duration of Erlotinibtreatment was 9.6 months in Study 4.

Hepatic Toxicity: One Erlotinib-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 4.

Maintenance Treatment
Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent Erlotinibat 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial (Study 3) are summarized by NCI-CTC (version 3.0) Grade in Table 2.

The most common adverse reactions in patients receiving single-agent Erlotinib150 mg were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 2%, respectively, in Erlotinib-treated patients. Rash and diarrhea resulted in study discontinuation in 1% and 0.5% of Erlotinib-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of patients, respectively. In Erlotinib-treated patients the median time to onset of rash was 10 days, and the median time to onset of diarrhea was 15 days.

Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% of Erlotinib-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin elevations were observed in 5% of Erlotinib-treated patients and in < 1% in the placebo group.

Second/Third Line Treatment
Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single-agent Erlotinibat 150 mg and at least 5% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC (version 2.0) Grade in Table 3.

The most common adverse reactions in this patient population were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 6%, respectively, in Erlotinib-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of Erlotinib-treated patients. Six percent and 1% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days.

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent Erlotinib150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 (> 2.5 – 5.0 x ULN) ALT elevations occurred in 4% and < 1% of Erlotiniband placebo treated patients, respectively. Grade 3 (> 5.0 – 20.0 x ULN) elevations were not observed in Erlotinib-treated patients. Erlotinibdosing should be interrupted or discontinued if changes in liver function are severe.

Pancreatic Cancer - ErlotinibAdministered Concurrently with Gemcitabine

This was a randomized, double blind placebo-controlled study of Erlotinib(150 mg or 100 mg daily) or placebo plus gemcitabine (1000 mg/m2 IV) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 2). The safety population comprised 282 patients in the erlotinib group (259 in the 100 mg cohort and 23 in the 150 mg cohort) and 280 patients in the placebo group (256 in the 100 mg cohort and 24 in the 150 mg cohort).

Adverse reactions that occurred in at least 10% of patients treated with Erlotinib100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer (Study 2) are summarized by NCI-CTC (version 2.0) Grade in Table 4.

The most common adverse reactions in pancreatic cancer patients receiving Erlotinib100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the Erlotinibplus gemcitabine arm, Grade 3-4 rash and diarrhea were each reported in 5% of patients. The median time to onset of rash and diarrhea was 10 days and 15 days, respectively. Rash and diarrhea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving Erlotinibplus gemcitabine. Severe adverse reactions (≥ Grade 3 NCI-CTC) in the Erlotinibplus gemcitabine group with incidences < 5% included syncope, arrhythmias, ileus, pancreatitis, hemolytic anemia including microangiopathic hemolytic anemia with thrombocytopenia, myocardial infarction/ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency.

The 150 mg cohort was associated with a higher rate of certain class-specific adverse reactions including rash and required more frequent dose reduction or interruption.

Ten patients (4%) in the Erlotinib/gemcitabine group and three patients (1%) in the placebo/gemcitabine group developed deep venous thrombosis. The overall incidence of grade 3 or 4 thrombotic events, including deep venous thrombosis was 11% for Erlotinibplus gemcitabine and 9% for placebo plus gemcitabine.

The incidences of liver test abnormalities (≥ Grade 2) in Study 2 are provided in Table 5.

NSCLC and Pancreatic Indications: Selected Low Frequency Adverse Reactions

Gastrointestinal Disorders
Cases of gastrointestinal bleeding (including fatalities) have been reported, some associated with concomitant warfarin or NSAID administration. These adverse reactions were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis.

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

Eye Disorders: ocular inflammation including uveitis

DRUG INTERACTIONS

CYP3A4 Inhibitors
Erlotinib is metabolized predominantly by CYP3A4. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increased erlotinib AUC by 67%. When Erlotinibwas co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum concentration [Cmax] increased by 39% and 17%, respectively. Dose modifications are recommended.

CYP3A4 Inducers
Pre-treatment with the CYP3A4 inducer rifampicin for 7-11 days prior to Erlotinibdecreased erlotinib AUC by 58% to 80%. Dose modifications are recommended.

Drugs Affecting Gastric pH
Co-administration of Erlotinibwith omeprazole decreased erlotinib AUC by 46% and co-administration of Erlotinibwith ranitidine 300 mg decreased erlotinib AUC by 33%. When Erlotinibwas 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), erlotinib AUC decreased by 15%. Increasing the dose of Erlotinibwhen co-administered with such agents is not likely to compensate for the loss of exposure. Scheduling modifications are recommended.

Cigarette Smoking
Cigarette smoking results in reductions in erlotinib AUC. Dose modifications are recommended.

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 Erlotinibare not recommended.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D
Risk Summary
Based on its mechanism of action, Erlotinibcan cause fetal harm when administered to a pregnant woman. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at doses approximately 3 times the recommended human daily dose of 150 mg. If Erlotinibis used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

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).

Nursing Mothers
It is not known whether erlotinib is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Erlotinib, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use
The safety and effectiveness of Erlotinibin pediatric patients have not been established.

Geriatric Use
Of the 1297 subjects in clinical studies of Erlotinibfor 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.

Females and Males of Reproductive Potential
Contraception

Females
Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use highly effective contraception during treatment with Erlotinib, and for at least 2 weeks after the last dose of Erlotinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Erlotinib.

Patients with Hepatic Impairment
Patients with hepatic impairment (total bilirubin > upper limit of normal (ULN) or Child-Pugh A, B and C) should be closely monitored during therapy with Erlotinib. Treatment with Erlotinibshould be used with extra caution in patients with total bilirubin > 3 x ULN .

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.

Patients with Renal Impairment 
Less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.

OVERDOSAGE

Single oral doses of Erlotinibup to 1,000 mg in healthy subjects and weekly doses up to 1,600 mg in cancer patients have been tolerated. Repeated twice-daily doses of 200 mg single-agent Erlotinibin healthy subjects were poorly tolerated after only a few days of dosing. Based on the data from these studies, an unacceptable incidence of severe adverse reactions, such as diarrhea, rash, and liver transaminase elevation, may occur above the recommended dose. In case of suspected overdose, Erlotinibshould be withheld and symptomatic treatment instituted.

DESCRIPTION

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

Erlotinib hydrochloride has the molecular formula C22H23N3O4.HCl and a molecular weight of 429.90. The molecule has a pKa of 5.42 at 25oC. Erlotinib hydrochloride is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane.

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.

Erlotinibtablets 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, hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate and titanium dioxide. The tablets also contain trace amounts of color additives, including FD&C Yellow #6 (25 mg only) for product identification.

CLINICAL PHARMACOLOGY

Mechanism of Action
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.

Pharmacokinetics

Absorption and Distribution:
Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases. Co-administration of Erlotinibwith omeprazole, a proton pump inhibitor, decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61%, respectively. When  Erlotinibwas administered 2 hours following a 300 mg dose of ranitidine, an H2 receptor antagonist, the erlotinib AUC was reduced by 33% and Cmax by 54%. When Erlotinibwas 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 and Cmax decreased by 15% and 17%, respectively.

Following absorption, erlotinib is approximately 93% protein bound to plasma albumin and alpha-1 acid glycoprotein (AAG). Erlotinib has an apparent volume of distribution of 232 liters.

Metabolism and Excretion:
A population pharmacokinetic analysis in 591 patients receiving the single-agent Erlotinib2nd/3rd line regimen showed a median half-life of 36.2 hours. Time to reach steady state plasma concentration would therefore be 7 – 8 days. No significant relationships of clearance to covariates of patient age, body weight or gender were observed. Smokers had a 24% higher rate of erlotinib clearance.

An additional population pharmacokinetic analysis was conducted in 291 NSCLC patients administered single-agent erlotinib as maintenance treatment. This analysis demonstrated that covariates affecting erlotinib clearance in this patient population were similar to those seen in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified.

A third population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204 pancreatic cancer patients who received erlotinib plus gemcitabine. Similar results were observed to those seen in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified. Co-administration of gemcitabine had no effect on erlotinib plasma clearance.

In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1. 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).

Cigarette smoking reduces erlotinib exposure. In the Phase 3 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 a separate study which evaluated the single-dose pharmacokinetics of erlotinib in healthy volunteers, current smokers cleared the drug faster than former smokers or volunteers who had never smoked. The AUC0-infinity in smokers was about 1/3 to 1/2 of that in never/former smokers. In another study which was conducted in NSCLC patients (N=35) who were current smokers, pharmacokinetic analyses at steady-state indicated a dose-proportional increase in erlotinib exposure when the Erlotinibdose was increased from 150 mg to 300 mg. However, the exact dose to be recommended for patients who currently smoke is unknown.

Special Populations:

Patients with Hepatic Impairment
Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with Erlotinibtreatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment.

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.

Patients with Renal Impairment
Less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year carcinogenicity studies were conducted in mice and rats with erlotinib at oral doses of up to 60 mg/kg/day in mice, 5 mg/kg/day in female rats, and 10 mg/kg/day in male rats. The studies were negative for carcinogenic findings. Exposure in mice at the highest dose tested was approximately 10 times the exposure in humans at the erlotinib dose of 150 mg/day. The highest dose evaluated in male rats resulted in exposures that were twice those in humans and exposures at the highest tested dose in female rats were slightly lower than those in humans.

Erlotinib did not cause genetic damage in a series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration and mammalian cell mutation) and in the in vivo mouse bone marrow micronucleus test.

Erlotinib did not impair fertility in either male or female rats.

CLINICAL STUDIES

Non-Small Cell Lung Cancer (NSCLC) – First-Line Treatment of Patients with EGFR Mutations
The safety and efficacy of Erlotinibas monotherapy for the first-line treatment of patients with metastatic NSCLC containing EGFR exon 19 deletions or exon 21 (L858R) substitution mutations was demonstrated in a randomized, open-label, clinical trial conducted in Europe (Study 4). One hundred seventy-four (174) White patients were randomized 1:1 to receive erlotinib 150 mg once daily until disease progression (n=86) or four cycles of a standard platinum-based doublet chemotherapy (n=88); standard chemotherapy regimens were cisplatin plus gemcitabine, cisplatin plus docetaxel, carboplatin plus gemcitabine, and carboplatin plus docetaxel. The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. Randomization was stratified by EGFR mutation (exon 19 deletion or exon 21 (L858R) substitution) and ECOG PS (0 vs. 1 vs. 2). EGFR mutation status for screening and enrollment of patients was determined by a clinical trials assay (CTA). Tumor samples from 134 patients (69 patients from the erlotinib arm and 65 patients from the chemotherapy arm) were tested retrospectively by the FDA-approved companion diagnostic, the cobas® EGFR Mutation Test.

The baseline demographics of the overall study population were as follows: female (72%), white (99%), age ≥ 65 years (51%), ECOG PS 1 (53%), with ECOG PS 0 (33%), and ECOG PS 2 (14%), current smoker (11%), past-smoker (20%), and never smoker (69%). The disease characteristics were 93% stage IV and 7% Stage IIIb with pleural effusion as classified by the American Joint Commission on Cancer (AJCC, 6th edition), 93% adenocarcinoma histology, 66% exon 19 mutation deletions and 34% exon 21 (L858R) point mutation by a CTA.

A statistically significant improvement in investigator-determined PFS was demonstrated for patients randomized to erlotinib compared to those randomized chemotherapy (see Table 6 and Figure 1). Similar results for PFS were observed for the subgroup evaluated by an independent-review committee (approximately 75% of patients in Study 4 evaluated) and in the subgroup of 134 patients (77% of the Study 4 population) with EGFR mutations confirmed by the cobas® EGFR Mutation Test.

A protocol-specified analysis of overall survival conducted at the time of the final analysis of PFS showed no statistically significant difference between the Erlotiniband chemotherapy arms. At the time of the data cut-off, 84% of patients in the chemotherapy arm had received at least one subsequent treatment, of whom 97% received an EGFR tyrosine kinase inhibitor. In the Erlotinibarm, 66% of patients had received at least one subsequent treatment.

Figure 1: Kaplan-Meier Plot of Investigator-Assessed PFS in Study 4

In exploratory subgroup analyses based on EGFR mutation subtype, the hazard ratio (HR) for PFS was 0.27 (95% CI 0.17 to 0.43) in patients with exon 19 deletions and 0.52 (95% CI 0.29 to 0.95) in patients with exon 21 (L858R) substitution. The HR for OS was 0.94 (95% CI 0.57 to 1.54) in the exon 19 deletion subgroup and 0.99 (95% CI 0.56 to 1.76) in the exon 21 (L858R) substitution subgroup.

NSCLC - Maintenance Treatment
The efficacy and safety of Erlotinibas maintenance treatment of NSCLC were demonstrated in a randomized, double-blind, placebo-controlled trial conducted in 26 countries, in 889 patients with locally advanced or metastatic NSCLC whose disease did not progress during first-line platinum-based chemotherapy (Study 3). Patients were randomized 1:1 to receive Erlotinib150 mg or placebo orally once daily (438 Erlotinib, 451 placebo) until disease progression or unacceptable toxicity. The primary objective of the study was to determine if the administration of Erlotinibafter standard platinum-based chemotherapy in the treatment of NSCLC resulted in improved progression free survival (PFS) when compared with placebo, in all patients or in patients with EGFR immunohistochemistry (IHC) positive tumors.

Demographic characteristics were balanced between the two treatment groups.

Baseline demographics of the overall study population were as follows: male (74%), age < 65 years (66%), ECOG PS 1 (69%), ECOG PS 0 (31%), white (84%), Asian (15%), current smoker (55%), past-smoker (27%), and never smoker (17%). Disease characteristics were as follows: Stage IV (75%), Stage IIIb with effusion (25%) as classified by AJCC (6th edition) with histologic subtypes of adenocarcinoma including bronchioalveolar (45%), squamous (40%) and large cell (5%); and EGFR IHC positive (70%), negative (14%), indeterminate (4%), and missing (12%).

Figure 2 depicts the Kaplan-Meier Curves for Overall Survival (ITT Population).

Figure 2: Kaplan - Meier Curve for Overall Survival of Patients by Treatment Group in Study 3

Note: HR is from a univariate Cox regression model.

The PFS and OS Hazard Ratios, respectively, in patients with EGFR IHC-positive tumors were 0.69 (95% CI: 0.58, 0.82) and 0.77 (95% CI: 0.64, 0.93). The PFS and OS Hazard Ratios in patients with IHC-negative tumors were 0.77 (95% CI: 0.51, 1.14) and 0.91 (95% CI: 0.59, 1.38), respectively.

Patients with adenocarcinoma had an OS Hazard Ratio of 0.77 (95% CI: 0.61, 0.97) and patients with squamous histology had an OS Hazard Ratio of 0.86 (95% CI: 0.68, 1.10).

NSCLC –Second/Third Line Treatment
The efficacy and safety of single-agent Erlotinibwas assessed in a randomized, double blind, placebo-controlled trial in 731 patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapy regimen (Study 1). Patients were randomized 2:1 to receive Erlotinib150 mg or placebo (488 Erlotinib, 243 placebo) orally once daily until disease progression or unacceptable toxicity. Study endpoints included overall survival, response rate, and progression-free survival (PFS). Duration of response was also examined. The primary endpoint was survival. The study was conducted in 17 countries.

Baseline demographics of the overall study population were as follows: male (65%), white (78%), Asian (12%), black (4%), age < 65 years (62%), ECOG PS 1 (53%), ECOG PS 0 (13%), ECOG PS 2 (25%), ECOG PS 3 (9%), current or ex-smoker (75%), never smoker (20%), and exposure to prior platinum therapy (93%). Tumor characteristics were as follows: adenocarcinoma (50%), squamous (30%), undifferentiated large cell (9%), and mixed non-small cell (2%).

The results of the study are shown in Table 8.

Survival was evaluated in the intent-to-treat population. Figure 3 depicts the Kaplan-Meier curves for overall survival. The primary survival and PFS analyses were two-sided Log-Rank tests stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.

Figure 3: Kaplan - Meier Curve for Overall Survival of Patients by Treatment Group in Study 1

Note:HR is from Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. P-value is from two-sided Log-Rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.

NSCLC – Lack of Efficacy of ErlotinibAdministered Concurrently with Chemotherapy
Results from two, multicenter, placebo-controlled, randomized, trials in over 1000 patients conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of Erlotinibwith platinum-based chemotherapy [carboplatin and paclitaxel (Erlotinib, N = 526) or gemcitabine and cisplatin (Erlotinib, N = 580)].

Pancreatic Cancer - ErlotinibAdministered Concurrently with Gemcitabine
The efficacy and safety of Erlotinibin combination with gemcitabine as a first-line treatment was assessed in a randomized, double blind, placebo-controlled trial in 569 patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 2). Patients were randomized 1:1 to receive Erlotinib(100 mg or 150 mg) or placebo once daily on a continuous schedule plus gemcitabine IV (1000 mg/m2, Cycle 1 - Days 1, 8, 15, 22, 29, 36 and 43 of an 8 week cycle; Cycle 2 and subsequent cycles - Days 1, 8 and 15 of a 4-week cycle [the approved dose and schedule for pancreatic cancer, see the gemcitabine package insert]). Erlotinibor placebo was taken orally once daily until disease progression or unacceptable toxicity. The primary endpoint was survival. Secondary endpoints included response rate, and progression-free survival (PFS). Duration of response was also examined. The study was conducted in 18 countries. A total of 285 patients were randomized to receive gemcitabine plus Erlotinib(261 patients in the 100 mg cohort and 24 patients in the 150 mg cohort) and 284 patients were randomized to receive gemcitabine plus placebo (260 patients in the 100 mg cohort and 24 patients in the 150 mg cohort). Too few patients were treated in the 150 mg cohort to draw conclusions.

In the 100 mg cohort, baseline demographics of the overall study population were as follows: male (52%), white (88%), Asian (7%), black (2%), age < 65 years (53%), ECOG PS 1 (51%), ECOG PS 0 (32%), and ECOG PS 2 (17%). There was a slightly larger proportion of females in the Erlotinibarm (51%) compared with the placebo arm (44%). The median time from initial diagnosis to randomization was approximately 1.0 month. The majority of the patients (76%) had distant metastases at baseline and 24% had locally advanced disease.

The results of the study are shown in Table 9.

Survival was evaluated in the intent-to-treat population. Figure4 depicts the Kaplan-Meier curves for overall survival in the 100 mg cohort. The primary survival and PFS analyses were two-sided Log-Rank tests stratified by ECOG performance status and extent of disease.

Figure 4: Kaplan - Meier Curve for Overall Survival: 100 mg Cohort in Study 2

Note: HR is from Cox regression model with the following covariates: ECOG performance status and extent of disease. The p-value is from two-sided Log-Rank test stratified by ECOG performance status and extent of disease.

HOW SUPPLIED/STORAGE AND HANDLING

25 mg Tablets
Round, biconvex face and straight sides, white film-coated, printed in orange with a “T” and “25” on one side and plain on the other side; supplied in:
Bottles of 30

100 mg Tablets
Round, biconvex face and straight sides, white film-coated, printed in gray with “T” and “100” on one side and plain on the other side; supplied in:
Bottles of 30

150 mg Tablets
Round, biconvex face and straight sides, white film-coated, printed in maroon with “T” and “150” on one side and plain on the other side; supplied in:
Bottles of 30

Store at 25°C (77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). See USP Controlled Room Temperature.

PATIENT COUNSELING INFORMATION

Advise patients to contact their health care provider for:

• Severe or persistent diarrhea, nausea, anorexia, or vomiting
• Onset or worsening of unexplained shortness of breath or cough
• Eye irritation
• Onset or worsening of skin rash or development of bullous lesions or desquamation
• Any changes in smoking status

Advise patients on the presentation of skin, hair and nail disorders.

• In patients who develop skin rash, the appearance of the rash is typically erythematous and maculopapular and it may resemble acne with follicular pustules, but is histopathologically different. This skin reaction commonly occurs on the face, upper chest and back, but may be more generalized or severe (NCI-CTC Grade 3 or 4) with desquamation. Skin reactions may occur or worsen in sun exposed areas. Symptoms associated with rash may include itching, tenderness and/or burning.
• Hyperpigmentation or dry skin, with or without digital skin fissures, have been reported and in the majority of cases were associated with rash.
• Hair and nail disorders, including hirsutism and brittle and loose nails, have been reported.

Instruct patients on initial management of rash or diarrhea.

• Given that skin reactions are anticipated when taking Erlotinib, proactive intervention may include alcohol-free emollient cream and use of sunscreen or avoidance of sun exposure
• Management of rash may include topical corticosteroids or antibiotics with anti-inflammatory properties. These approaches were used in the NSCLC and pancreatic pivotal clinical trials. Acne preparations with drying properties may aggravate the dry skin and erythema. Treatment of rash has not been formally studied and should be based on rash severity.
• Diarrhea can usually be managed with loperamide.

Counsel patients on pregnancy planning and prevention.

• Advise females of reproductive potential to use highly effective contraception during treatment with Erlotinib, and for at least 2 weeks after the last dose of Erlotinib.
• Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Erlotinib
• Advise breast-feeding mothers to discontinue nursing while receiving Erlotinib

Advise patients to stop smoking. Advise patients that the dose of Erlotinibmay need to be adjusted if they smoke.