Erlonib

Erlonib

erlotinib

Manufacturer:

Camber

Distributor:

Camber
Full Prescribing Info
Contents
Erlotinib.
Description
Each film coated tablet contains Erlotinib Hydrochloride 109.267 mg eq. to 100 mg of Erlotinib.
Each film coated tablet contains Erlotinib Hydrochloride 163.900 mg eq. to 150 mg of Erlotinib.
Excipients/Inactive Ingredients: Lactose monohydrate, Microcrystalline cellulose, Sodium starch glycolate, Sodium lauryl sulphate and Magnesium stearate. The tablet coat contains Hypromellose, Titanium dioxide, Hydroxy propyl cellulose and Macrogol.
Action
Pharmacology: Pharmacodynamics: Erlotinib reversibly inhibits the kinase activity of EGFR, which is expressed on the cell surface of healthy cells and cancer cells, and prevents auto phosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signalling. In some tumour cells, signalling through this receptor plays a role in tumour cell survival and proliferation irrespective of EGFR mutation status. 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/Distribution: Erlotinib is approximately 60 % absorbed and peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent and decreases as pH increases. Erlotinib is approximately 93 % protein bound to plasma albumin and alpha-1 acid glycoprotein. Erlotinib has an apparent volume of distribution of 232 L.
Effect of food: Erlotinib's bioavailability is substantially increased by food to almost 100%.
Metabolism/ Excretion: Erlotinib is metabolized primarily in the liver via CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1. Following a 100mg 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).
Patients receiving single-agent erlotinib second/third-line regimen showed a median half-life of 36.2 hours; time to reach steady-state plasma concentration would therefore be 7 to 8 days.
Indications/Uses
Non-small cell lung cancer (NSCLC): For the first-line treatment of-metastatic non-small cell lung cancer in which tumours have epidermal growth factor receptor (EGFH) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a Food and Drug Administration (FDA)-approved test; maintenance treatment of locally advanced or metastatic non-small cell lung cancer when disease has not progressed after 4 cycles of platinum based first-line chemotherapy; treatment of locally advanced or metastatic non-small cell lung cancer after failure of at least 1 prior chemotherapy regimen.
Pancreatic cancer: First-line treatment of locally advanced, unresectable or metastatic pancreatic cancer in combination with gemcitabine.
Dosage/Direction for Use
Recommended Dose: General dosing considerations: Select patients for the first-line treatment of metastatic non-small cell lung cancer based on the presence of EGFH exon 19 deletions or exon -21 (L858R) substitution mutations in tumour specimens. Information on FDA-approved tests. for the deletion of EGFR mutations is available at http://www.fda.gov/Companion Diagnostics. Dosage reduction may be required for patients with hepatic impairment (see Hepatic Function Impairment).
Adults: Non-small cell lung cancer: 150 mg daily.
Pancreatic cancer: 100 mg daily, in combination with gemcitabine.
Hepatic function impairment: Withhold erlotinib in patients with pre-existing hepatic impairment or biliary obstruction for doubling of bilirubin, or tripling of transaminases values over baseline. Discontinue therapy in patients whose abnormal liver tests do not improve significantly or resolve within 3 weeks. One guideline is shown in. the following table. Monitor patients with hepatic dysfunction closely, especially if total bilirubin is more than 3 times the upper limit of normal (ULN). (See Table 1.)

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Dosage adjustment: When restarting, therapy following withholding treatment for a dose-limiting toxicity that has resolved to baseline or grade 1 or less, reduce the dose in 50 mg decrements.
Dermatologic toxicity: Withhold erlotinib for severe rash not responsive to medical management. Discontinue erlotinib for severe bullous, blistering, or exfoliating skin conditions.
GI toxicity: Withhold erlotinib for persistent severe diarrhoea not responsive to medical management (e.g., loperamide). Discontinue erlotinib for GI perforation.
Hepatic toxicity: Withhold erlotinib in patients without pre-existing hepatic impairment for total bilirubin levels greater than 3 times the ULN or transaminases greater than 5 times the ULN, and consider discontinuation. Discontinue erlotinib for severe hepatic toxicity that does not improve significantly or resolve within 3 weeks.
Ophthalmic toxicity: Withhold erlotinib for keratitis of grade 3 to 4 or for grade 2 lasting more than 2 weeks; Withhold erlotinib for acute/worsening ocular disorders, such as eye pain, and consider discontinuation. Discontinue erlotinib for corneal perforation or severe ulceration.
Pulmonary toxicity: Withhold erlotinib during diagnostic evaluation for possible interstitial lung disease. Discontinue erlotinib for interstitial lung disease.
Renal toxicity: Withhold erlotinib for severe (grade 3 to 4) renal toxicity and consider discontinuation.
Concomitant therapy: CYP3A4 inhibitors: Avoid concomitant use, if possible. Reduce the erlotinib dose by 50 mg decrements if severe reactions occur with concomitant use of strong cytochrome P450 (CYP-450) 3A4 inhibitors (e.g., atazanavir, clarithromycin, grapefruit juice, grapefruit, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole) or an inhibitor of CYP3A4 and CYP1A2 (eg, ciprofloxacin).
CYP3A4 inducers: Avoid concomitant use, if possible. Increase erlotinib by 50 mg increments at 2-week intervals to a maximum of 450 mg during concomitant use with CYP3A4 inducers (e.g., rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, St. Johns wort).
Drugs affecting gastric pH: Avoid concomitant use with proton pump inhibitors if possible. If treatment with an H2-receptor antagonist (e.g., ranitidine) is required, give erlotinib 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist. If an antacid is necessary, separate the erlotinib dose and the antacid dose by several hours.
Smokers: Increase erlotinib by 50 mg increments at 2-week intervals to a maximum of 300 mg during concurrent cigarette smoking. Immediately reduce the dose of erlotinib to the recommended dose upon cessation of smoking.
Duration of therapy: Continue treatment until disease progression or unacceptable toxicity occurs. (27)
Mode of Administration: Preparation of administration: Erlotinib is considered a cytotoxic agent. Follow safe handling procedures when preparing, administering, or dispensing erlotinib.
Administration: Administer on an empty stomach at least 1 hour before or 2 hours after food. Administration with food increases bioavailability to almost 100 %, when may cause increased toxicity.
For patients, unable to swallow tablets whole, place tablet in 100 mL of distilled water; do not crush tablet. Stir until dispersed, then have the patient drink the mixture immediately. To ensure that the entire dose is administered, rinse the inside of the container with another 40 mL of water and have the patient drink immediately. The suspension may also be administered via an enteral feeding tube.
Overdosage
The signs and symptoms of an acute overdose are expected to be comparable to those side effects seen with higher dose therapy (eg, diarrhea, rash, and liver transaminase elevation).
Contraindications
Hypersensitivity to erlotinib or to any of the excipients listed in Description.
Special Precautions
Hazardous agent - use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Rare, sometimes fatal. interstitial lung disease (ILD) has occurred; symptoms include acute respiratory distress syndrome, interstitial pneumonia, obliterative bronchiolitis, pneumonitis (including radiation and hypersensitivity), pulmonary fibrosis, and pulmonary infiltrates. The onset of symptoms has been within 5 days to more than 9 months after treatment initiation (median: 39 days). Interrupt treatment for unexplained new or worsening pulmonary symptoms (dyspnea, cough, and fever); permanently discontinue for confirmed ILD.
Hepatic failure and hepatorenal syndrome have been reported, particularly in patients with baseline hepatic impairment (although have also been observed in patients with normal hepatic function). Monitor liver function (transaminases, bilirubin, and alkaline- phosphatase); patients with any hepatic impairment (total bilirubin >ULN; Child Pugh class A, B, or C) should be closely monitored, including those with hepatic disease due to tumor burden. Dosage reduction, interruption, or discontinuation may be recommended for changes in hepatic function. Use with extreme caution in patients with total bilirubin >3 times ULN. Interrupt therapy if total bilirubin is >3 times ULN or transaminases are >5 times ULN in patients without pre-existing hepatic impairment. In patients with baseline hepatic dysfunction or biliary obstruction, interrupt therapy if bilirubin doubles or transaminases triple from baseline values. Increased monitoring or liver function is required in patients with pre-existing hepatic impairment or biliary obstruction. Acute renal failure, renal insufficiency, and hepatorenal syndrome have been reported, either secondary to hepatic impairment at baseline or due to severe dehydration; use with caution in patients with or at risk for renal impairment. Monitor closely for dehydration; monitor renal function and electrolytes in patients at risk for dehydration. If severe renal impairment develops, interrupt therapy until toxicity resolves. Gastrointestinal perforation has been reported with use; risk for perforation is increased with concurrent anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based-therapy, and patients with history of peptic ulcers or diverticular disease; permanently discontinue in patients who develop perforation.
Bullous, blistering, or exfoliating skin conditions, some suggestive of Stevens-Johnson or toxic epidermal necrolysis (TEN) have been reported. An acne-like rash commonly appears on the face, back, and upper chest. Generalized or severe acneiform, erythematous or maculopapular rash may occur. Skin rash may correlate treatment response and prolonged survival; management of skin rashes that are not serious should include alcohol-free lotions, topical antibiotics, or topical corticosteroids, or if necessary, oral antibiotics and systemic corticosteroids; avoid sunlight. Reduce dose or temporarily interrupt treatment for severe skin reactions; discontinue treatment for bullous, blistering or exfoliative skin toxicity.(Corneal perforation and ulceration have been reported with use; decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca, or keratitis have also been reported and are known risk factors for corneal ulceration/perforation. Interrupt or discontinue treatment in patients presenting with eye pain or other acute or worsening ocular symptoms. Consider a baseline ophthalmologic exam and reassess for ocular toxicities at 4 to 8 weeks after treatment initiation.
MI, CVA, and microangiopathic hemolytic anemia with thrombocytopenia have been reported (rarely) with erlotinib in combination with gemcitabine. Elevated INR and bleeding events (including fatal hemorrhage) have been reported: monitor prothrombin time and INR closely. Erlotinib levels may be lower in patients who smoke; advise patients to stop smoking. Smokers treated with 300 mg/day exhibited steady-state erlotinib levels comparable to former- and never-smokers receiving 150 mg/day.Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Avoid concomitant use with proton pump inhibitors. If taken with an H2-receptor antagonist (eg, ranitidine), administer erlotinib 10 hours after the H2-receptor antagonist dose and at least 2 hours prior to the next H2-receptor dose. If an antacid is necessary, separate dosing by several hours. In patients with NSCLC, EGFR mutations, specifically exon 19 deletions and exon 21 mutation (L858R), are associated with better response to erlotinib; erlotinib treatment is not recommended in patients with K-ras mutations; they are not likely to benefit from erlotinib treatment. Concurrent erlotinib plus platinum-based chemotherapy is not recommended for first line treatment of locally advanced or metastatic NSCLC due to a lack of clinical benefit. The cobas EGFR mutation test has been approved to detect EGFR mutation for first-line NSCLC treatment. Product may contain lactose; avoid use in patients with Lapp lactase deficiency, glucose-galactose malabsorption, or glucose intolerance.
Use In Pregnancy & Lactation
Pregnancy Risk Factor D.
Pregnancy Considerations: Adverse events were observed in animal reproduction studies. Based on the mechanism of action, may cause fetal harm if administered in pregnancy. Females of reproductive potential should be advised to avoid pregnancy; highly effective contraception is recommended during treatment and for at least 2 weeks after treatment has been completed.
Breast-Feeding Considerations: It is not known if erlotinib is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the decision to discontinue breast-feeding or discontinue Erlotinib should take into account the benefits of treatment to the mother.
Adverse Reactions
Common adverse reactions: The most common adverse reactions are rash (70%) and diarrhoea (42%), usually with onset during the first month of treatment.
Non-small cell lung cancer: First line treatment of patient with EGFR mutations: Adverse reactions (30 % or more): Asthenia, cough, decreased appetite, diarrhoea, dyspnea, and rash. In erlotinib-treated patients, the median time to onset of rash was 15 days and the median time to onset of diarrhoea was 32 days. The most frequent grade 3/4 adverse reactions in erlotinib-treated patients were rash and diarrhea. (See Table 2.)

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Hepatic: One erlotinib-treated patient experienced fatal hepatic failure and 4 additional patients experienced grade 3 to 4 liver test abnormalities. (See Table 3.)

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(See Table 4.)

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Pancreatic cancer: Common adverse reactions: Anorexia, diarrhoea, fatigue, nausea, and rash; grade 3/4 rash and diarrhoea were each reported in 5 % of erlotinib plus gemcitabine-treated patients. The median time to onset of rash and diarrhoea was 10 and 15 days, respectively.
Severe adverse reactions: Severe adverse reactions (grade 3 or higher) with incidences less than 5 % included arrhythmias, cerebrovascular accidents including cerebral haemorrhage, haemolytic anaemia including microangiopathic haemolytic anaemia with thrombocytopenia, ileus, MI/ischemia, pancreatitis, renal insufficiency, and syncope. (See Table 5.)

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Lab test abnormalities: Non-small cell lung cancer: Maintenance study: Liver function 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 greater bilirubin elevations were observed in 5 % of Erlotinib-treated patients and in less than 1 % in the placebo group.
Second/Third-line study: Liver function test abnormalities (including elevated ALT, AST, and bilirubin) were observed in patients receiving single agent Erlotinib 150 mg. These elevations were mainly transient or associated with liver matastases. Grade 2 (more than 2.5 to 5 times ULN) ALT elevations occurred in 4 % and less than 1 % of Erlotinib-and placebo-treated patients, respectively. Grade 3 (more than 5 to 20 times ULN) elevations were not observed in Erlotinib-treated patients.
Pancreatic Cancer: See Table 6.

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Post marketing: Musculoskeletal: Myopathy, including rhabdomyolysis, in combination with statin therapy.
Drug Interactions
Metabolism/Transport: Substrate of CYP1A2 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential.
Based on in vitro assays, erlotinib metabolism is primarily by CYP3A4 and, to a lesser extent, by CYP1A2 and the extrahepatic CYP1A1 isoform. Therefore, drugs that are substrates for or induce or inhibit 1 or more of these pathways may result in clinically important drug interactions. Drugs that induce these enzyme systems may increase erlotinib metabolism, decreasing erlotinib plasma concentrations and efficacy. Drugs that inhibit these enzyme systems may interfere with erlotinib metabolism, elevating erlotinib plasma concentrations and increasing the pharmacologic effects and risk of adverse reactions.
In patients receiving erlotinib, clinically important interactions may occur when an interacting drug is started or stopped and, in many instances, when the dose of either agent is changed. Monitoring the patient's clinical response and making the appropriate adjustments in dose is important in minimizing the risk of a drug interaction, especially with drugs that have a narrow therapeutic index (e.g., warfarin).
Cigarette smoking: See Dosage & Administration. (See Table 7.)

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Drug/Herb: St. John's wort may increase metabolism and decrease erlotinib concentrations.
Management: Avoid St. John's wort.
Drug/Food interactions: Erlotinib bioavailability is increased with food. Grapefruit or grapefruit juice may decrease metabolism and increase erlotinib plasma concentrations. Management: Take on an empty stomach at least 1 hour before or 2 hours after the ingestion of food. Avoid grapefruit and grapefruit juice. Maintain adequate nutrition and hydration, unless instructed to restrict fluid intake.
Storage
Store below 30°C and protect from moisture.
Patient Counseling Information
Advice to patients to contact their health care provider if the following signs or symptoms occur; severe or persistent diarrhea, nausea, anorexia or vomiting; eye irritation; onset or worsening of skin rash or development of bullous lesions or desquamation; onset or worsening of unexplained shortness of breath or cough; any changes in smoking status. Inform patients that if they develop a skin rash, it commonly occurs on the face, upper chest and back, may occur or worsen in sun exposed areas.
Inform patients 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. Discuss the management of rash with the patient. This may include topical corticosteroids or antibiotics with anti-inflammatory properties. 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.
Inform patients that hyperpigmentation or dry skin, with or without digital skin fissures, may occur and that take majority of case were associated with rash.
Inform patients that hair and nail disorders, including hirsutism and brittle and lose nails, may occur.
Advise patients who smoke to stop smoking while taking erlotinib because cigarette smoking reduces plasma concentrations of erlotinib.
Advise patients to take erlotinib at least 1 hour before or 2 hours after food intake.
Advise breast feeding mothers to discontinue breast feeding while receiving the erlotinib.
ATC Classification
L01EB02 - erlotinib ; Belongs to the class of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Used in the treatment of cancer.
Presentation/Packing
FC tab 100 mg (white coloured, round biconvex debossed with "H" on one side and "21" on the other side) x 10's, 3 x 10's, 6 x 10's. 150 mg (white coloured, round biconvex debossed with "H" on one side and "22" on the other side) x 10's, 3 x 10's, 6 x 10's.
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