Tarceva

Generic Name: erlotinib hydrochloride

Dosage Form: tablets
FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

Non-Small Cell Lung Cancer (NSCLC)

Tarceva monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen [see Clinical Studies (14.1)].

Results from two, multicenter, placebo-controlled, randomized, Phase 3 trials conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of Tarceva with platinum-based chemotherapy [carboplatin and paclitaxel or gemcitabine and cisplatin] and its use is not recommended in that setting [see Clinical Studies (14.3)].

Pancreatic Cancer

Tarceva in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer [see Clinical Studies (14.3)].

2. DOSAGE AND ADMINISTRATION

Recommended Dose - NSCLC

The recommended daily dose of Tarceva for non-small cell lung cancer is 150 mg taken at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs. There is no evidence that treatment beyond progression is beneficial.

Recommended Dose - Pancreatic Cancer

The recommended daily dose of Tarceva for pancreatic cancer is 100 mg taken at least one hour before or two hours after the ingestion of food, in combination with gemcitabine (see the gemcitabine package insert). Treatment should continue until disease progression or unacceptable toxicity occurs.

Dose Modifications

In patients who develop an acute onset of new or progressive pulmonary symptoms, such as dyspnea, cough or fever, treatment with Tarceva should be interrupted pending diagnostic evaluation. If Interstitial Lung Disease (ILD) is diagnosed, Tarceva should be discontinued and appropriate treatment instituted as necessary [see Warnings and Precautions (5.1)].

Diarrhea can usually be managed with loperamide. Patients with severe diarrhea who are unresponsive to loperamide or who become dehydrated may require dose reduction or temporary interruption of therapy. Patients with severe skin reactions may also require dose reduction or temporary interruption of therapy.

When dose reduction is necessary, the Tarceva dose should be reduced in 50 mg decrements.

In patients who are taking Tarceva with a strong CYP3A4 inhibitor such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice, a dose reduction should be considered if severe adverse reactions occur. Similarly, in patients who are taking Tarceva with an inhibitor of both CYP3A4 and CYP1A2 like ciprofloxacin, a dose reduction of Tarceva should be considered if severe adverse reactions occur. [see Drug Interactions (7)].

Pre-treatment with the CYP3A4 inducer rifampicin decreased erlotinib AUC by about 2/3 to 4/5. Use of alternative treatments lacking CYP3A4 inducing activity is strongly recommended. If an alternative treatment is unavailable, an increase in the dose of Tarceva should be considered as tolerated at two week intervals while monitoring the patient’s safety. The maximum dose of Tarceva studied in combination with rifampicin is 450 mg. If the Tarceva dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other inducers. Other CYP3A4 inducers include, but are not limited to rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital and St. John's Wort. These too should be avoided if possible [see Drug Interactions (7)].

Cigarette smoking has been shown to reduce erlotinib exposure. Patients should be advised to stop smoking. If a patient continues to smoke, a cautious increase in the dose of Tarceva, not exceeding 300 mg may be considered, while monitoring the patient’s safety. However, efficacy and long-term safety (> 14 days) of a dose higher than the recommended starting doses have not been established in patients who continue to smoke cigarettes. If the Tarceva dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking [see Clinical Pharmacology (12.3)].

Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B), patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with Tarceva [see WARNINGS and PRECAUTIONS (5.2 )]. Treatment with Tarceva should be used with extra caution in patients with total bilirubin > 3 x ULN.   Tarceva dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range. In the setting of worsening liver function tests, before they become severe, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. Tarceva dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Warnings and Precautions (5.2 , 5.3 ), Adverse Reactions (6.3) and Use in Specific Populations (8.6 )]. 

3. 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.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

Pulmonary Toxicity

There have been infrequent reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving Tarceva for treatment of NSCLC, pancreatic cancer or other advanced solid tumors. In the randomized single-agent NSCLC study [see CLINICAL STUDIES (14.1)], the incidence of ILD-like events (0.8%) was the same in both the placebo and Tarceva groups. In the pancreatic cancer study - in combination with gemcitabine –  [see Clinical Studies (14.3)], the incidence of ILD-like events was 2.5% in the Tarceva plus gemcitabine group vs. 0.4% in the placebo plus gemcitabine group.

The overall incidence of ILD-like events in approximately 4900 Tarceva-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) was approximately 0.7%. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome and lung infiltration. Symptoms started from 5 days to more than 9 months (median 39 days) after initiating Tarceva therapy. In the lung cancer trials most of the cases were associated with confounding or contributing factors such as concomitant/prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections.

In the event of an acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, Tarceva therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, Tarceva should be discontinued and appropriate treatment instituted as needed [see Dosage and Administration (2.3 )].

Patients with Hepatic Impairment

In a pharmacokinetic study in patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 out of 15 patients died on treatment or within 30 days of the last Tarceva dose. 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 suggesting severe hepatic impairment. Treatment with Tarceva should be used with extra caution in patients with total bilirubin > 3 x ULN. Patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with Tarceva. Tarceva dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3 )].

Hepatotoxicity 

Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of Tarceva, particularly in patients with baseline hepatic impairment. Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) is recommended. In the setting of worsening liver function tests, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. Tarceva dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Adverse Reactions (6.3) and Dosage and Administration (2.3 )].

Renal Failure

Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported. Some were secondary to baseline hepatic impairment while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia or concurrent chemotherapy use. In the event of dehydration, particularly in patients with contributing risk factors for renal failure (eg, pre-existing renal disease, medical conditions or medications that may lead to renal disease, or other predisposing conditions including advanced age), Tarceva therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration [see Adverse Reactions (6.3) and Dosage and Administration (2.3 )].

Myocardial infarction/ischemia

In the pancreatic carcinoma trial, six patients (incidence of 2.3%) in the Tarceva/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 1.2%) and one died due to myocardial infarction.

Cerebrovascular accident

In the pancreatic carcinoma trial, six patients in the Tarceva/gemcitabine group developed cerebrovascular accidents (incidence: 2.3%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents.

Microangiopathic Hemolytic Anemia with Thrombocytopenia

In the pancreatic carcinoma trial, two patients in the Tarceva/gemcitabine group developed microangiopathic hemolytic anemia with thrombocytopenia (incidence: 0.8%). Both patients received Tarceva and gemcitabine concurrently. In comparison, in the placebo/gemcitabine group there were no cases of microangiopathic hemolytic anemia with thrombocytopenia.

Use in Pregnancy

Pregnancy Category D

Women of childbearing potential should avoid becoming pregnant while being treated with Tarceva. Erlotinib administered to rabbits during organogenesis at doses that result in plasma drug concentrations of approximately 3 times those in humans (AUCs at 150 mg daily dose) was associated with embryo/fetal lethality and abortion. When erlotinib was administered to female rats prior to mating and through the first week of pregnancy, at doses 0.3 or 0.7 times the clinical dose of 150 mg, on a mg/m2 basis, there was an increase in early resorptions that resulted in a decrease in the number of live fetuses. [see Use in Specific Populations (8.1)]

Elevated International Normalized Ratio and Potential Bleeding

International Normalized Ratio (INR) elevations and infrequent reports of bleeding events including gastrointestinal and non-gastrointestinal bleedings have been reported in clinical studies, some associated with concomitant warfarin administration. Patients taking warfarin or other coumarin-derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR. [see Adverse Reactions (6.3)].

6. ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reactions 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 Tarceva is based on 856 cancer patients who received Tarceva as monotherapy, 308 patients who received Tarceva 100 or 150 mg plus gemcitabine, and 1228 patients who received Tarceva concurrently with other chemotherapies.

There have been reports of serious events, including fatalities, in patients receiving Tarceva for treatment of NSCLC, pancreatic cancer or other advanced solid tumors [see Warnings and Precautions (5) and Dosage and Administration (2.3 )].

Non-Small Cell Lung Cancer

Adverse events, regardless of causality, that occurred in at least 10% of patients treated with single-agent Tarceva at 150 mg and at least 3% 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 1.

The most common adverse reactions in patients receiving single-agent Tarceva 150 mg were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6%, respectively, in Tarceva-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of Tarceva-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. 

Table 1: Adverse Reactions Occurring More Frequently (≥ 3%) in the Single Agent Tarceva Group than in the Placebo Group and in ≥10% of Patients in the Tarceva Group.

	Tarceva 150 mg N = 485			Placebo N = 242
NCI-CTC Grade	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
MedDRA Preferred Term	%	%	%	%	%	%
Rash	75	8	<1	17	0	0
Diarrhea	54	6	<1	18	<1	0
Anorexia	52	8	1	38	5	<1
Fatigue	52	14	4	45	16	4
Dyspnea	41	17	11	35	15	11
Cough	33	4	0	29	2	0
Nausea	33	3	0	24	2	0
Infection	24	4	0	15	2	0
Vomiting	23	2	<1	19	2	0
Stomatitis	17	<1	0	3	0	0
Pruritus	13	<1	0	5	0	0
Dry skin	12	0	0	4	0	0
Conjunctivitis	12	<1	0	2	<1	0
Keratoconjunctivitis sicca	12	0	0	3	0	0
Abdominal pain	11	2	<1	7	1	<1

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent Tarceva 150 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 Tarceva and placebo treated patients, respectively. Grade 3 (>5.0 – 20.0 x ULN) elevations were not observed in Tarceva-treated patients. Tarceva dosing should be interrupted or discontinued if changes in liver function are severe. [see Dosage and Administration (2.3)]

Pancreatic Cancer

Adverse events, regardless of causality, that occurred in at least 10% of patients treated with Tarceva 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer are summarized by NCI-CTC (version 2.0) Grade in Table 2.

The most common adverse reactions in pancreatic cancer patients receiving Tarceva 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the Tarceva plus gemcitabine arm, Grade 3/4 rash and diarrhea were each reported in 5% of Tarceva plus gemcitabine-treated 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 Tarceva plus gemcitabine. 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. 

Table 2: Adverse Reactions Occurring in ≥ 10% of Tarceva-treated Pancreatic Cancer Patients: 100 mg cohort

*Includes all MedDRA preferred terms in the Infections and Infestations System Organ Class
	Tarceva + Gemcitabine 1000 mg/m2 IV N=259			Placebo + Gemcitabine 1000 mg/m2 IV N=256
NCI-CTC Grade	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
MedDRA Preferred Term	%	%	%	%	%	%
Fatigue	73	14	2	70	13	2
Rash	69	5	0	30	1	0
Nausea	60	7	0	58	7	0
Anorexia	52	6	<1	52	5	<1
Diarrhea	48	5	<1	36	2	0
Abdominal pain	46	9	<1	45	12	<1
Vomiting	42	7	<1	41	4	<1
Weight decreased	39	2	0	29	<1	0
Infection*	39	13	3	30	9	2
Edema	37	3	<1	36	2	<1
Pyrexia	36	3	0	30	4	0
Constipation	31	3	1	34	5	1
Bone pain	25	4	<1	23	2	0
Dyspnea	24	5	<1	23	5	0
Stomatitis	22	<1	0	12	0	0
Myalgia	21	1	0	20	<1	0
Depression	19	2	0	14	<1	0
Dyspepsia	17	<1	0	13	<1	0
Cough	16	0	0	11	0	0
Dizziness	15	<1	0	13	0	<1
Headache	15	<1	0	10	0	0
Insomnia	15	<1	0	16	<1	0
Alopecia	14	0	0	11	0	0
Anxiety	13	1	0	11	<1	0
Neuropathy	13	1	<1	10	<1	0
Flatulence	13	0	0	9	<1	0
Rigors	12	0	0	9	0	0

In the pancreatic carcinoma trial, 10 patients in the Tarceva/gemcitabine group developed deep venous thrombosis (incidence: 3.9%). In comparison, 3 patients in the placebo/gemcitabine group developed deep venous thrombosis (incidence 1.2%). The overall incidence of grade 3 or 4 thrombotic events, including deep venous thrombosis, was similar in the two treatment arms: 11% for Tarceva plus gemcitabine and 9% for placebo plus gemcitabine.

No differences in Grade 3 or Grade 4 hematologic laboratory toxicities were detected between the Tarceva plus gemcitabine group compared to the placebo plus gemcitabine group.

Severe adverse events (≥grade 3 NCI-CTC) in the Tarceva plus 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 [see Warnings and Precautions (5)].

Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) have been observed following the administration of Tarceva plus gemcitabine in patients with pancreatic cancer. Table 3 displays the most severe NCI-CTC grade of liver function abnormalities that developed. Tarceva dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration (2.3)].

Table 3: Liver Function Test Abnormalities (most severe NCI-CTC grade) in Pancreatic Cancer Patients: 100 mg Cohort

	Tarceva + Gemcitabine 1000 mg/m2 IV N = 259			Placebo + Gemcitabine 1000 mg/m2 IV N = 256
NCI-CTC Grade	Grade 2	Grade 3	Grade 4	Grade 2	Grade 3	Grade 4
Bilirubin	17 %	10%	<1%	11%	10%	3%
ALT	31%	13%	<1%	22%	9%	0%
AST	24%	10%	<1%	19%	9%	0%

NSCLC and Pancreatic Cancer Indications

During the NSCLC and the combination pancreatic cancer trials, infrequent cases of gastrointestinal bleeding have been reported, some associated with concomitant warfarin or NSAID administration. [see Warnings and Precautions (5.9)]. These adverse events were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, hematochezia, melena and hemorrhage from possible colitis. Cases of acute renal failure or renal insufficiency, including fatalities, with or without hypokalemia have been reported. [see Warnings and Precautions (5.4)].  Cases of Grade 1 epistaxis were also reported in both the single-agent NSCLC and the pancreatic cancer clinical trials.

NCI-CTC Grade 3 conjunctivitis and keratitis have been reported infrequently in patients receiving Tarceva therapy in the NSCLC and pancreatic cancer clinical trials. Corneal ulcerations may also occur. [see Patient Counseling Information (17)].

 Hair and nail disorders including alopecia, hirsutism, eyelash/eyebrow changes, paronychia and brittle and loose nails have been reported in clinical trials and during post-marketing use of Tarceva.

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. Associated symptoms may include itching, tenderness and/or burning. Dry skin with or without digital skin fissures may occur.

Hepatic failure has been reported in patients treated with single-agent Tarceva or Tarceva combined with chemotherapy in clinical studies and during post-marketing use of Tarceva [see Warnings and Precautions (5.3 )]; it is not possible to reliably estimate the frequency or establish a causal relationship to Tarceva treatment.

In general, no notable differences in the safety of Tarceva monotherapy or in combination with gemcitabine could be discerned between females or males and between patients younger or older than the age of 65 years [see Use in Specific Populations (8.4)]. The safety of Tarceva appears similar in Caucasian and Asian patients.

7. DRUG INTERACTIONS

Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increases erlotinib AUC by 2/3. When Tarceva was 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. Caution should be used when administering or taking Tarceva with ketoconazole and other strong CYP3A4 inhibitors such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole and grapefruit or grapefruit juice. [see Dosage and Administration (2.3 )].

Pre-treatment with the CYP3A4 inducer rifampicin for 7 days prior to Tarceva decreased erlotinib AUC by about 2/3 to 4/5, which is equivalent to a dose of about 30 to 50 mg in NSCLC patients. In a separate study, treatment with rifampicin for 11 days, with co-administration of a single 450 mg dose of Tarceva on day 8 resulted in a mean erlotinib exposure (AUC) that was 57.6% of that observed following a single 150 mg Tarceva dose in the absence of rifampicin treatment [see Dose Modifications (2.3