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Erlotinib

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Erlotinib uses


1 INDICATIONS AND USAGE

Erlotinib is a kinase inhibitor indicated for:


Limitations of Use:

1.1 Non-Small Cell Lung Cancer (NSCLC)

Erlotinib® is 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 .

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

1.2 Pancreatic Cancer

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

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2 DOSAGE AND ADMINISTRATION

2.1 Selection of Patients with Metastatic NSCLC

Select patients for the treatment of metastatic NSCLC with Erlotinib 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: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dose – NSCLC

The recommended daily dose of Erlotinib 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 for pancreatic cancer is 100 mg taken once daily in combination with gemcitabine. Take Erlotinib 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


PulmonaryFor additional information see Warnings and Precautions (5).


Interstitial Lung Disease (ILD)

Discontinue Erlotinib

During diagnostic evaluation for possible ILD

Withhold ErlotinibReduce Erlotinib by 50 mg decrements when restarting therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade ≤ 1.


Hepatic


Severe hepatic toxicity that does not improve significantly or resolve within three weeks

Discontinue Erlotinib

In patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline

Withhold Erlotinib 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 and consider discontinuation

Renal


For severe (CTCAE grade 3 to 4) renal toxicity

Withhold Erlotinib and consider discontinuation

Gastrointestinal


Gastrointestinal perforation

Discontinue Erlotinib

For persistent severe diarrhea not responsive to medical management (e.g., loperamide)

Withhold Erlotinib


Skin


Severe bullous, blistering or exfoliating skin conditions

Discontinue Erlotinib

For severe rash not responsive to medical management

Withhold Erlotinib


Ocular


Corneal perforation or severe ulceration

Discontinue Erlotinib

For keratitis of (NCI-CTC version 4.0) grade 3-4 or for grade 2 lasting more than 2 weeks

Withhold Erlotinib


For acute/worsening ocular disorders such as eye pain


Withhold Erlotinib and consider discontinuation


Drug Interactions


CYP3A4 inhibitorsFor additional information see Drug Interactions (7).


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 For additional information see Clinical Pharmacology (12.3).


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 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 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
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3 DOSAGE FORMS AND STRENGTHS

25 mg tablets: round, biconvex face and straight sides, white film-coated, printed in orange with “T” and “25” on one side and plain on other side.

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 other side.

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 other side.

Tablets: 25 mg, 100 mg, and 150 mg (3)

4 CONTRAINDICATIONS

None.

None. (4)

5 WARNINGS AND PRECAUTIONS

5.1 Interstitial Lung Disease (ILD)

Cases of serious ILD, including fatal cases, can occur with Erlotinib treatment. The overall incidence of ILD in approximately 32,000 TARCEVA-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 Erlotinib therapy.

Withhold Erlotinib for 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 .

5.2 Renal Failure

Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency can occur with Erlotinib treatment. 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 Erlotinib arms and 0.8% in the control arms. The incidence of renal impairment in the pancreatic cancer study was 1.4% in the Erlotinib plus gemcitabine arm and 0.4% in the control arm. Withhold Erlotinib in patients developing severe renal impairment until renal toxicity is resolved. Perform periodic monitoring of renal function and serum electrolytes during Erlotinib treatment .

5.3 Hepatotoxicity with or without Hepatic Impairment

Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with Erlotinib treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. 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 Erlotinib arms and 0% in the control arms. The incidence of hepatic failure in the pancreatic cancer study was 0.4% in the Erlotinib plus 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 Erlotinib 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.

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 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. Withhold Erlotinib in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline. Discontinue Erlotinib in patients whose abnormal liver tests meeting the above criteria do not improve significantly or resolve within three weeks .

5.4 Gastrointestinal Perforation

Gastrointestinal perforation, including fatal cases, can occur with Erlotinib treatment. 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 Erlotinib arms and 0.1% in the control arms. The incidence of gastrointestinal perforation in the pancreatic cancer study was 0.4% in the Erlotinib plus gemcitabine arm and 0% in the control arm. Permanently discontinue Erlotinib in patients who develop gastrointestinal perforation .

5.5 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 Erlotinib treatment . The pooled incidence of bullous and exfoliative skin disorders in the 3 monotherapy lung cancer studies was 1.2% in the Erlotinib arms and 0% in the control arms. The incidence of bullous and exfoliative skin disorders in the pancreatic cancer study was 0.4% in the Erlotinib plus gemcitabine arm and 0% in the control arm. Discontinue Erlotinib treatment if the patient develops severe bullous, blistering or exfoliating conditions .

5.6 Cerebrovascular Accident

In the pancreatic carcinoma trial, seven patients in the TARCEVA/gemcitabine group developed cerebrovascular accidents. 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 Erlotinib arms and not higher than that observed in the control arms.

5.7 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 Erlotinib arms 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 Erlotinib plus gemcitabine arm and 0% in the control arm.

5.8 Ocular Disorders

Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can occur with Erlotinib treatment 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 Erlotinib arms and 4% in the control arms. The incidence of ocular disorders in the pancreatic cancer study was 12.8% in the Erlotinib plus gemcitabine arm and 11.4% in the control arm. Interrupt or discontinue Erlotinib therapy if patients present with acute or worsening ocular disorders such as eye pain .

5.9 Hemorrhage in Patients Taking Warfarin

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

5.10 Embryo-fetal Toxicity

Based on animal data and its mechanism of action, Erlotinib can 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 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.

Advise females of reproductive potential to use effective contraception during therapy and for one month after the last dose of Erlotinib [see Use in Specific Populations (8.1) and ( 8.3 ), Clinical Pharmacology (12.1)].

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6 ADVERSE REACTIONS

The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the labeling:


The most common adverse reactions (≥ 20%) with Erlotinib from a pooled analysis in patients with NSCLC across all approved lines of therapy, with and without EGFR mutations, and in patients with pancreatic cancer were rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, and vomiting. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact OSI Pharmaceuticals, LLC, at 1-800-572-1932 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety evaluation of Erlotinib is based on more than 1200 cancer patients who received Erlotinib as monotherapy, more than 300 patients who received Erlotinib 100 or 150 mg plus gemcitabine, and 1228 patients who received Erlotinib concurrently with other chemotherapies. The most common adverse reactions with Erlotinib are rash and diarrhea usually with onset during the first month of treatment. The incidences of rash and diarrhea from clinical studies of Erlotinib for the treatment of NSCLC and pancreatic cancer were 70% for rash and 42% for diarrhea.

Non-Small Cell Lung Cancer

First-Line Treatment of Patients with EGFR Mutations

The most frequent (≥ 30%) adverse reactions in TARCEVA-treated patients were diarrhea, asthenia, rash, cough, dyspnea, and decreased appetite. In TARCEVA-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 TARCEVA-treated patients were rash and diarrhea.

Dose interruptions or reductions due to adverse reactions occurred in 37% of TARCEVA-treated patients, and 14.3% of TARCEVA-treated patients discontinued therapy due to adverse reactions. In TARCEVA-treated patients, the most frequently reported adverse reactions leading to dose modification were rash (13%), diarrhea (10%), and asthenia (3.6%).

Common adverse reactions in Study 1, occurring in at least 10% of patients who received Erlotinib or chemotherapy and an increase in ≥ 5% in the TARCEVA-treated group, are graded by National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (NCI-CTCAE v3.0) Grade in Table 1. The median duration of Erlotinib treatment was 9.6 months in Study 1.


Erlotinib

N = 84


Chemotherapy Platinum-based chemotherapy (cisplatin or carboplatin with gemcitabine or docetaxel).

N = 83


Adverse Reaction


All Grades

%


Grades 3-4

%


All Grades

%


Grades 3-4

%


Rash Rash as a composite term includes rash, acne, folliculitis, erythema, acneiform dermatitis, dermatitis, palmar-plantar erythrodysesthesia syndrome, exfoliative rash, erythematous rash, rash pruritic, skin toxicity, eczema, follicular rash, skin ulcer.


85

14

5

0

Diarrhea


62

5

21

1

Cough


48

1

40

0

Dyspnea

45

8

30

4

Dry skin


21

1

2

0

Back pain


19

2

5

0

Chest pain


18

1

12

0

Conjunctivitis

18

0

0

0

Mucosal inflammation


18

1

6

0

Pruritus


16

0

1

0

Paronychia

14

0

0

0

Arthralgia


13

1

6

1

Musculoskeletal pain

11

1

1

0

Hepatic Toxicity: One TARCEVA-treated patient experienced fatal hepatic failure and four additional patients experienced grade 3-4 liver test abnormalities in Study 1 .

Maintenance Treatment

Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single-agent Erlotinib at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial (Study 3) are summarized by NCI-CTCAE v3.0 Grade in Table 2.

The most common adverse reactions in patients receiving single-agent Erlotinib 150 mg were rash and diarrhea. Grade 3-4 rash and diarrhea occurred in 9% and 2%, respectively, in TARCEVA-treated patients. Rash and diarrhea resulted in study discontinuation in 1% and 0.5% of TARCEVA-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5% and 3% of patients, respectively. In TARCEVA-treated patients the median time to onset of rash was 10 days, and the median time to onset of diarrhea was 15 days.


Adverse Reaction


Erlotinib

N = 433


PLACEBO

N = 445


Any Grade


Grade 3


Grade 4


Any Grade


Grade 3


Grade 4


%


%


%


%


%


%


Rash Rash as a composite term includes: rash, acne, acneiform dermatitis, skin fissures, erythema, papular rash, rash generalized, pruritic rash, skin exfoliation, urticaria, dermatitis, eczema, exfoliative rash, exfoliative dermatitis, furuncle, macular rash, pustular rash, skin hyperpigmentation, skin reaction, skin ulcer.


60

9

0

9

0

0

Diarrhea

20

2

0

4

0

0

Liver test abnormalities including ALT elevations were observed at Grade 2 or greater severity in 3% of TARCEVA-treated patients and 1% of placebo-treated patients. Grade 2 and above bilirubin elevations were observed in 5% of TARCEVA-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 Erlotinib at 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 v2.0 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 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.


Adverse Reaction


Erlotinib 150 mg

N=485


Placebo

N=242


Any Grade


Grade 3


Grade 4


Any Grade


Grade 3


Grade 4


%


%


%


%


%


%


Rash Rash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, acne, skin disorder, pigmentation disorder, erythema, skin ulcer, exfoliative dermatitis, papular rash, skin desquamation.


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

Nausea

33

3

0

24

2

0

Infection

24

4

0

15

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

Liver function test abnormalities [including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin] were observed in patients receiving single-agent Erlotinib 150 mg. These elevations were mainly transient or associated with liver metastases. Grade 2 [> 2.5 – 5.0 x upper limit of normal (ULN)] ALT elevations occurred in 4% and < 1% of Erlotinib and placebo treated patients, respectively. Grade 3 (> 5.0 – 20.0 x ULN) elevations were not observed in TARCEVA-treated patients. Erlotinib dosing should be interrupted or discontinued if changes in liver function are severe .

Pancreatic Cancer - Erlotinib Administered 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 by intravenous infusion) in patients with locally advanced, unresectable or metastatic pancreatic cancer (Study 5). 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 Erlotinib 100 mg plus gemcitabine in the randomized trial of patients with pancreatic cancer (Study 5) were graded according to NCI-CTC v2.0 in Table 4.

The most common adverse reactions in pancreatic cancer patients receiving Erlotinib 100 mg plus gemcitabine were fatigue, rash, nausea, anorexia and diarrhea. In the Erlotinib plus 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 Erlotinib plus gemcitabine. Severe adverse reactions (≥ Grade 3 NCI-CTC) in the Erlotinib 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 .

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.


Adverse Reaction


Erlotinib + Gemcitabine

1000 mg/m2 IV

N=259


Placebo + Gemcitabine

1000 mg/m2 IV

N=256


Any Grade


Grade 3


Grade 4


Any Grade


Grade 3


Grade 4


%


%


%


%


%


%


Rash Rash as a composite term includes: rash, palmar-plantar erythrodysesthesia syndrome, pigmentation disorder, acneiform dermatitis, folliculitis, photosensitivity reaction, Stevens-Johnson syndrome, urticaria, erythematous rash, skin disorder, skin ulcer.


70

5

0

30

1

0

Diarrhea

48

5

<1

36

2

0

Decreased weight

39

2

0

29

<1

0

Infection Infections as a composite term include infections with unspecified pathogens as well as bacterial (including chlamydial, rickettsial, mycobacterial and mycoplasmal), parasitic (including helminthic, ectoparasitic and protozoal), viral and fungal infectious disorders.


39

13

3

30

9

2

Pyrexia

36

3

0

30

4

0

Stomatitis

22

<1

0

12

0

0

Depression

19

2

0

14

<1

0

Cough

16

0

0

11

0

0

Headache

15

<1

0

10

0

0

Ten patients (4%) in the TARCEVA/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 Erlotinib plus gemcitabine and 9% for placebo plus gemcitabine.

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


Erlotinib + Gemcitabine

1000 mg/m2 IV

N=259


Placebo + Gemcitabine

1000 mg/m2 IV

N=256


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

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.

6.2 Post-Marketing Experience

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

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

Eye Disorders: ocular inflammation including uveitis

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7 DRUG INTERACTIONS

CYP3A4 Inhibitors

Co-administration of Erlotinib with a strong CYP3A4 inhibitor or a combined CYP3A4 and CYP1A2 inhibitor increased erlotinib exposure. Erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2. Increased erlotinib exposure may increase the risk of exposure-related toxicity .

Avoid co-administering Erlotinib with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or a combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin). Reduce the Erlotinib dosage when co-administering with a strong CYP3A4 inhibitor or a combined CYP3A4 and CYP1A2 inhibitor if co-administration is unavoidable .

CYP3A4 Inducers

Pre-treatment with a CYP3A4 inducer prior to Erlotinib decreased erlotinib exposure . Increase the Erlotinib dosage if co-administration with CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital and St. John's wort) is unavoidable .

CYP1A2 Inducers and Cigarette Smoking

Cigarette smoking decreased erlotinib exposure. Avoid smoking tobacco (CYP1A2 inducer) and avoid concomitant use of Erlotinib with moderate CYP1A2 inducers (e.g., teriflunomide, rifampin, or phenytoin). Increase the Erlotinib dosage in patients that smoke tobacco or when co-administration with moderate CYP1A2 inducers is unavoidable .

Drugs the Increase Gastric pH

Co-administration of Erlotinib with proton pump inhibitors (e.g., omeprazole) and H-2 receptor antagonists (e.g., ranitidine) decreased erlotinib exposure . For proton pump inhibitors, avoid concomitant use if possible. For H-2 receptor antagonists and antacids, modify the dosing schedule . Increasing the dose of Erlotinib when co-administered with gastric PH elevating agents is not likely to compensate for the loss of exposure.

Anticoagulants

Interaction with coumarin-derived anticoagulants, including warfarin, leading to increased International Normalized Ratio (INR) and bleeding adverse reactions, which in some cases were fatal, have been reported in patients receiving Erlotinib. Regularly monitor prothrombin time or INR in patients taking coumarin-derived anticoagulants. Dose modifications of Erlotinib are not recommended .

8 USE IN SPECIFIC POPULATIONS

Lactation: Do not breastfeed

8.1 Pregnancy

Risk Summary

Based on animal data and its mechanism of action, Erlotinib can cause fetal harm when administered to a pregnant woman. Limited available data on use of Erlotinib in pregnant women are not sufficient to inform a risk of major birth defects or miscarriage. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at exposures approximately 3 times the exposure at the recommended human daily dose of 150 mg. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Erlotinib has been shown to cause maternal toxicity resulting in embryo-fetal lethality and abortion in rabbits when given during the period of organogenesis at doses that result in plasma drug concentrations approximately 3 times those achieved at the recommended dose in humans (AUCs at 150 mg daily dose). During the same period, there was no increase in the incidence of embryo-fetal lethality or abortion in rabbits or rats at doses resulting in exposures approximately equal to those in humans at the recommended daily dose. In an independent fertility study female rats treated with 30 mg/m2/day or 60 mg/m2/day (0.3 or 0.7 times the recommended daily dose, on a mg/m2 basis) of erlotinib had an increase in early resorptions that resulted in a decrease in the number of live fetuses.

No teratogenic effects were observed in rabbits or rats dosed with erlotinib during organogenesis at doses up to 600 mg/m2/day in the rabbit (3 times the plasma drug concentration seen in humans at 150 mg/day) and up to 60 mg/m2/day in the rat (0.7 times the recommended dose of 150 mg/day on a mg/m2 basis).

8.2 Lactation

Risk Summary

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

8.3 Females and Males of Reproductive Potential

Contraception

Females

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

8.4 Pediatric Use

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

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

8.5 Geriatric Use

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

8.6 Hepatic Impairment

Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with Erlotinib treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment . Monitor patients with hepatic impairment (total bilirubin greater than upper limit of normal (ULN) or Child-Pugh A, B and C) during therapy with Erlotinib. Treatment with Erlotinib should be used with increased monitoring in patients with total bilirubin greater than 3 x ULN .

10 OVERDOSAGE

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

11 DESCRIPTION

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

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.

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

14.2 NSCLC – Lack of Efficacy of Erlotinib in Maintenance Treatment of Patients without EGFR Mutations

Lack of efficacy of Erlotinib for the maintenance treatment of patients with NSCLC without EGFR activating mutations was demonstrated in Study 2. Study 2 was a multicenter, placebo-controlled, randomized trial of 643 patients with advanced NSCLC without an EGFR exon 19 deletion or exon 21 L858R mutation who had not experienced disease progression after four cycles of platinum-based chemotherapy. Patients were randomized 1:1 to receive Erlotinib 150 mg or placebo orally once daily (322 Erlotinib, 321 placebo) until disease progression or unacceptable toxicity. Following progression on initial therapy, patients were eligible to enter an open-label phase. Baseline characteristics were as follows: median age 61 years (35% age ≥ 65 years), 75% male, 77% White, 21% Asian, 28% ECOG PS 0, 72% ECOG PS 1, 16% never smokers, 58% current smokers, 57% adenocarcinoma, 35% squamous cell carcinoma, 22% stage IIIB disease not amenable to combined modality treatment, and 78% stage IV disease. Fifty percent of patients randomized to Erlotinib entered the open-label phase and received chemotherapy, while 77% of patients randomized to placebo entered the open-label phase and received Erlotinib.

The main efficacy outcome was overall survival (OS). Median OS was 9.7 months in the Erlotinib arm and 9.5 months in the placebo arm; the hazard ratio for OS was 1.02 (95% CI 0.85, 1.22). Median PFS was 3.0 months in the Erlotinib arm and 2.8 months in the placebo arm; the hazard ratio for PFS was 0.94 (95% CI 0.80, 1.11).

14.3 NSCLC – Maintenance Treatment or Second/Third Line Treatment

Two randomized, double-blind, placebo-controlled trials, Studies 3 and 4, examined the efficacy and safety of Erlotinib administered to patients with metastatic NSCLC as maintenance therapy after initial treatment with chemotherapy or with disease progression following initial treatment with chemotherapy (Study 4). Determination of EGFR mutation status was not required for enrollment.

Study 3

The efficacy and safety of Erlotinib as maintenance treatment of NSCLC were demonstrated in Study 3, a randomized, double-blind, placebo-controlled trial conducted in 26 countries, in 889 patients with metastatic NSCLC whose disease did not progress during first-line platinum-based chemotherapy. Patients were randomized 1:1 to receive Erlotinib 150 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 Erlotinib after 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.

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%).


Efficacy Parameter


Erlotinib

(N = 438)


Placebo

(N = 451)


Progression-Free Survival (PFS) based on investigator assessment


Number of Progression or Deaths (%)

349 (80%)

400 (89%)

Median PFS in Months (95% CI)


2.8 (2.8, 3.1)

2.6 (1.9, 2.7)

Hazard Ratio (95% CI) Univariate Cox regression model.


0.71 (0.62, 0.82)

p-value (stratified log-rank test) Unstratified log-rank test.


p < 0.0001

Overall Survival (OS)


Number of Deaths

298 (68%)

350 (78%)

Median OS in Months (95% CI)

12.0 (10.6, 13.9)

11.0 (9.9, 12.1)

Hazard Ratio (95% CI)


0.81 (0.70, 0.95)

p-value (stratified log-rank test)


0.0088

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

Note: HR is from a univariate Cox regression model.

Study 4

The efficacy and safety of single-agent Erlotinib was assessed in Study 4, a randomized, double blind, placebo-controlled trial in 731 patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapy regimen. Patients were randomized 2:1 to receive Erlotinib 150 mg or placebo (488 Erlotinib, 243 placebo) orally once daily until disease progression or unacceptable toxicity. Efficacy outcome measures 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.


Efficacy Parameter


Erlotinib

(N = 488)


Placebo

(N = 243)


Overall Survival (OS)


Number of Deaths

378 (77%)

209 (86%)

Median OS in Months (95% CI)


6.7 (5.5, 7.8)

4.7 (4.1, 6.3)

Hazard Ratio (95% CI) Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.


0.73 (0.61, 0.86)

p-value (stratified log-rank test) Two-sided log-rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.


p < 0.001

Progression-Free Survival (PFS)


Number of Progression or Deaths (%)

402 (82%)

211 (87%)

Median PFS in Months (95% CI)

2.3 (1.9, 3.3)

1.8 (1.8, 1.9)

Hazard Ratio (95% CI)


0.59 (0.50, 0.70)

Objective Response


Objective Response Rate (95% CI)

8.9% (6.4, 12.0)

0.9% (0.1, 3.4)

Figure 3 depicts the Kaplan-Meier curves for overall survival.

Figure 2: Kaplan-Meier Curves for Overall Survival of Patients by Treatment Group in Study 3 Figure 3: Kaplan-Meier Curves for Overall Survival of Patients by Treatment Group in Study 4

14.4 NSCLC – Lack of Efficacy of Erlotinib Administered 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 Erlotinib with platinum-based chemotherapy [carboplatin and paclitaxel (TARCEVA, N = 526) or gemcitabine and cisplatin (TARCEVA, N = 580)].

14.5 Pancreatic Cancer - Erlotinib Administered Concurrently with Gemcitabine

The efficacy and safety of Erlotinib in combination with gemcitabine as a first-line treatment was assessed in Study 5, a randomized, double-blind, placebo-controlled trial in 569 patients with locally advanced, unresectable or metastatic pancreatic cancer. Patients were randomized 1:1 to receive Erlotinib (100 mg or 150 mg) or placebo once daily on a continuous schedule plus gemcitabine by intravenous infusion (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]). Erlotinib or 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 Erlotinib arm (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.


Efficacy Parameter


Erlotinib + Gemcitabine

(N = 261)


Placebo + Gemcitabine

(N = 260)


Overall Survival (OS)


Number of Deaths

250

254

Median OS in Months (95% CI)


6.5 (6.0, 7.4)

6.0 (5.1, 6.7)

Hazard Ratio (95% CI) Cox regression model with the following covariates: ECOG performance status and extent of disease.


0.81 (0.68, 0.97)

p-value (stratified log-rank test) Two-sided log-rank test stratified by ECOG performance status and extent of disease.


0.028

Progression-Free Survival (PFS)


Number of Progression or Deaths (%)

225

232

Median PFS in Months (95% CI)

3.8 (3.6, 4.9)

3.6 (3.3, 3.8)

Hazard Ratio (95% CI)


0.76 (0.64, 0.92)

Objective Response


Objective Response Rate (95% CI)

8.6% (5.4, 12.9)

7.9% (4.8, 12.0)

Survival was evaluated in the intent-to-treat population. Figure 4 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.

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.

Figure 4: Kaplan-Meier Curves for Overall Survival: 100 mg Cohort in Study 5

16 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: NDC 50242-062-01

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: NDC 50242-063-01

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: NDC 50242-064-01

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

17 PATIENT COUNSELING INFORMATION

Skin rash, bullous and exfoliative skin disorders


Diarrhea

Advise patients that diarrhea can usually be managed with loperamide and to contact their healthcare provider for severe or persistent diarrhea .

Interstitial lung disease

Advise patients of the risk of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new of worsening unexplained shortness of breath or coughing .

Renal failure

Advise patients of the risk of developing renal failure. Inform patients of the need for the healthcare provider to monitor kidney function and electrolytes .

Hepatotoxicity

Advise patients to immediately report signs or symptoms of hepatotoxicity .

Gastrointestinal perforations

Advise patients that Erlotinib can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain .

Cerebrovascular accident

Advise patients of the risk of cerebrovascular accident and see immediate medical attention .

Ocular disorders

Advise patients promptly to contact their healthcare provider if they develop eye signs or symptoms, lacrimation, light sensitivity, blurred vision, eye pain, red eye, or changes in vision .

Hemorrhage in patients taking warfarin

Advise patients who are receiving warfarin of the need to monitor INR or other coumarin-derivative anticoagulants .

Hair and nail disorders

Advise patients that hair and nail disorders, including hirsutism and brittle and loose nails, have been reported .

Embryo-fetal toxicity


Lactation


Smoking


Manufactured for:

OSI Pharmaceuticals, LLC, Northbrook, IL 60062

an affiliate of Astellas Pharma US, Inc.

Product of Japan or Italy – See bottle label for origin

Distributed by:

Genentech USA, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990

For further information please call 1-877-TARCEVA (1-877-827-2382).

Erlotinib® is a registered trademark of OSI Pharmaceuticals, LLC. Other trademarks listed belong to their respective owners.

©2016 Astellas Pharma US, Inc., and Genentech, Inc. All rights reserved.

15J080-TAR-SPL

Logo

Erlotinib pharmaceutical active ingredients containing related brand and generic drugs:


Erlotinib available forms, composition, doses:

Price
Tablets; Oral; Erlotinib Hydrochloride 100 mg
Tablets; Oral; Erlotinib Hydrochloride 150 mg
Tablets; Oral; Erlotinib Hydrochloride 25 mg
Tarceva 100 mg tablet144.98 USD
Tarceva 150 mg tablet163.98 USD
Tarceva 25 mg tablet52.78 USD

Erlotinib destination | category:


Erlotinib Anatomical Therapeutic Chemical codes:


Erlotinib pharmaceutical companies:


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References

  1. Dailymed."TARCEVA (ERLOTINIB HYDROCHLORIDE) TABLET [GENENTECH, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "Erlotinib". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "Erlotinib". http://www.drugbank.ca/drugs/DB0053... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Erlotinib?

Depending on the reaction of the Erlotinib after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Erlotinib not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Erlotinib addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Erlotinib, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Erlotinib consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

One visitor reported frequency of use

How often in a day do you take the medicine?
Are you taking the Erlotinib drug as prescribed by the doctor?
Few medications can be taken Once in a day more than prescribed when the doctor's advice mentions the medicine can be taken according to frequency or severity of symptoms. Most times, be very careful and clear about the number of times you are taking the medication. The report of sdrugs.com website users about the frequency of taking the drug Erlotinib is mentioned below.
Visitors%
Once in a day1
100.0%

Visitor reported doses

No survey data has been collected yet

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

Visitor reported age

No survey data has been collected yet

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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