Tarlonib

TARLONIB 100: Each tablet contains Erlotinib Hydrochloride 109.3 mg (Equivalent to Erlotinib 100 mg).
TARLONIB 150: Each tablet contains Erlotinib Hydrochloride 163.9 mg (Equivalent to Erlotinib 150 mg).
Erlotinib is a kinase inhibitor with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine. Erlotinib has the molecular formula C₂₂H₂₃N₃O₄ and a molecular weight of 393.443 g/mol.

Pharmacology: Pharmacodynamics: Mechanism of action: Erlotinib potently inhibits the intracellular phosphorylation of HER1/EGFR. HER1/EGFR is expressed on the cell surface of normal cells and cancer cells. In non-clinical models, inhibition of EGFR phosphotyrosine results in cell stasis and/or death.
Pharmacokinetics: Absorption: Oral erlotinib is reported to be well absorbed and has an extended absorption phase, with mean peak plasma levels occurring at 4 hours after oral dosing. A reported study in normal healthy volunteers provided an estimate of bioavailability of 59%. The exposure after an oral dose may be increased by food. Following absorption, erlotinib is reported to be highly bound in blood, with approximately 95% bound to blood components, primarily to plasma proteins (i.e. albumin and alpha-1 acid glycoprotein [AAG]), with a free fraction of approximately 5%.
Distribution: Erlotinib has a mean apparent volume of distribution of 232 l and distributes into tumour tissue of humans. The primary active metabolites were present in the tumour at concentrations averaging 160 ng/g tissue, which corresponded to an overall average of 113% of the reported steady-state peak plasma concentrations. Tissue distribution studies using whole body autoradiography following oral administration with [¹⁴C]-labeled erlotinib in athymic nude mice with HN5 tumour xenografts have reported rapid and extensive tissue distribution with maximum concentrations of radio labeled drug (approximately 73% of that in plasma) observed at 1 hour.
Metabolism: Erlotinib is metabolized in humans by hepatic cytochrome P450 enzymes, primarily by CYP3A4 and to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and CYP1B1 in tumour tissue potentially contribute to the metabolic clearance of erlotinib. In vitro studies have reported approximately 80-95% of erlotinib metabolism by the CYP3A4 enzyme. There are three main metabolic pathways identified: 1) O-demethylation of either side chain or both, followed by oxidation to the carboxylic acids; 2) oxidation of the acetylene moiety followed by hydrolysis to the aryl carboxylic acid; and 3) aromatic hydroxylation of the phenyl-acetylene moiety. The primary metabolites of erlotinib produced by O-demethylation of either side chain have comparable potency to erlotinib in preclinical in vitro assays and in vivo tumour models. They are present in plasma at levels that are <10% of erlotinib and display similar pharmacokinetics as erlotinib.
Elimination: The metabolites and trace amounts of erlotinib are reported to be excreted predominantly via the feces (>90%), with renal elimination accounting for only a small amount of an oral dose.
Clearance: A population pharmacokinetic analysis in patients receiving single-agent erlotinib has reported a mean apparent clearance of 4.47 l/hour with a median half-life of 36.2 hours. Therefore, the time to reach steady-state plasma concentration would be expected to occur in approximately 7-8 days. No significant relationships between predicted apparent clearance and patient age, body weight, gender, and ethnicity were observed.
Patient factors, which correlate with erlotinib pharmacokinetics, are serum total bilirubin, AAG concentrations and current smoking. Increased serum concentrations of total bilirubin and AAG concentrations were associated with a slower rate of erlotinib clearance. Smokers had a higher rate of erlotinib clearance (see Interactions).
A second population pharmacokinetic analysis was reported that incorporated erlotinib data from pancreatic cancer patients who received erlotinib plus gemcitabine. This analysis reported that covariates affecting erlotinib clearance in patients from the pancreatic study were very similar to those reported in the prior single-agent pharmacokinetic analysis. No new covariate effects were reported. Co-administration of gemcitabine had reported no effect on erlotinib plasma clearance.
Pharmacokinetics in Special Populations: There have been no specific studies reported in pediatric or elderly patients.
Hepatic impairment: Erlotinib is mainly cleared by the liver. Erlotinib exposure was reported to be similar in patients with moderately impaired hepatic function (Child-Pugh score 7-9) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases.
Renal impairment: Erlotinib and its metabolites are not significantly excreted by the kidneys, as less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.
Smokers: A pharmacokinetic study in nonsmoking and currently cigarette-smoking healthy subjects has reported that cigarette smoking leads to increased clearance of, and decreased exposure to, erlotinib. The AUC_0-infinity in smokers was reported to be about 1/3 of that in never/former smokers. This reduced exposure in current smokers is presumably due to induction of CYP1A1 in lung and CYP1A2 in the liver.

Non-Small Cell Lung Cancer: TARLONIB 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.
Pancreatic Cancer: TARLONIB in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

Standard Dosage: Non-Small Cell Lung Cancer: The recommended daily dose of erlotinib is 150 mg taken at least one hour before or two hours after the ingestion of food.
Pancreatic Cancer: The recommended daily dose of erlotinib is 100 mg taken at least one hour before or two hours after the ingestion of food, in combination with gemcitabine (see the label of gemcitabine for the pancreatic cancer indication).
Special Dosage Instructions: Concomitant use of CYP3A4 substrates and modulators may require dose adjustment (see Interactions).
When dose adjustment is necessary, it is recommended to reduce in 50 mg steps (see Precautions and Interactions).
Hepatic impairment: Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh score 7-9) compared with patients with adequate hepatic function, caution should be used when administering erlotinib to patients with hepatic impairment. Dose reduction or interruption of erlotinib should be considered if severe adverse reactions occur. Safety and efficacy have not been reported in patients with severe hepatic impairment (see Precautions and Pharmacology: Pharmacokinetics: Pharmacokinetics in special populations under Actions).
Renal impairment: The safety and efficacy of erlotinib has not been studied in patients with renal impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Pediatric use: The safety and efficacy of erlotinib has not been studied in patients under the age of 18 years.
Smokers: Cigarette smoking has been reported to reduce erlotinib exposure by 50-60%. The maximum tolerated dose of erlotinib in NSCLC patients who currently smoke cigarettes was reported as 300 mg. Efficacy and long term safety of a dose higher than the recommended starting doses have not been established in patients who continue to smoke cigarettes (see Interactions and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).

It has been reported that single oral doses of erlotinib up to 1,000 mg in healthy subjects, and up to 1,600 mg given as a single dose once weekly in cancer patients, have been tolerated. Repeated twice daily doses of 200 mg in healthy subjects were poorly tolerated after only a few days of dosing. Based on the data from these studies, severe adverse reactions such as diarrhea, rash and possibly liver transaminase elevation may occur above the recommended dose.
In case of suspected overdose, erlotinib should be withheld and symptomatic treatment administered.

TARLONIB is contraindicated in patients with severe hypersensitivity to erlotinib or to any of the excipients.

Interstitial Lung Disease: Cases of interstitial lung disease (ILD)-like events, including fatalities, have been reported uncommonly in patients receiving erlotinib for treatment of NSCLC (non-small cell lung carcinoma), pancreatic cancer or other advanced solid tumours. In a reported study in NSCLC, the incidence of serious ILD-like events was 0.8% in each of the placebo and erlotinib arms. In the reported pancreatic cancer study in combination with gemcitabine, the incidence of ILD-like events was 2.5% in the erlotinib plus gemcitabine group versus 0.4% in the placebo plus gemcitabine treated group. The overall incidence in patients treated with erlotinib from all reported studies (including uncontrolled studies and studies with concurrent chemotherapy) was reported as approximately 0.6%. Some examples of 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, lung infiltration and alveolitis. These ILD-like events started from a few days to several months after initiating erlotinib therapy. Most of the cases were associated with confounding or contributing factors such as concomitant or prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections.
In patients who develop acute onset of new and/or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever, erlotinib therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, erlotinib should be discontinued and appropriate treatment initiated as necessary (see Adverse Reactions).
Diarrhea, dehydration, electrolyte imbalance and renal failure: Diarrhea has reported in patients on erlotinib and moderate or severe diarrhea should be treated with loperamide. In some cases, dose reduction may be necessary. In the event of severe or persistent diarrhea, nausea, anorexia or vomiting associated with dehydration, erlotinib therapy should be interrupted and appropriate measures should be taken to treat the dehydration (see Adverse Reactions). There have been rare reports of hypokalemia and renal failure (including fatalities). Some reports of renal failure were secondary to severe dehydration due to diarrhea, vomiting and/or anorexia while others were confounded by concomitant chemotherapy. In more severe or persistent cases of diarrhea, or cases leading to dehydration, particularly in groups of patients with aggravating risk factors (concomitant medications, symptoms or diseases or other predisposing conditions including advanced age), erlotinib therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patients intravenously. In addition, renal function and serum electrolytes including potassium should be monitored in patients at risk of dehydration.
Hepatitis, hepatic failure: Rare cases of hepatic failure (including fatalities) have been reported during use of erlotinib. Confounding factors have included pre-existing liver disease or concomitant hepatotoxic medications. Therefore, in such patients, periodic liver function testing should be considered. Erlotinib dosing should be interrupted if changes in liver function are severe (see Adverse Reacions).
Gastrointestinal perforation: Patients receiving erlotinib are at increased risk of developing gastrointestinal perforation, which was observed uncommonly (including some cases with a fatal outcome). Patients receiving concomitant antiangiogenic agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. Erlotinib should be permanently discontinued in patients who develop gastrointestinal perforation (see Adverse Reactions).
Bullous and exfoliative skin disorders: Bullous, blistering and exfoliative skin conditions have been reported, including very rare cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal (see Adverse Reactions). Erlotinib treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.
Ocular disorders: Very rare cases of corneal perforation or ulceration have been reported during use of erlotinib. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been reported with erlotinib treatment which are also risk factors for corneal perforation/ulceration. Erlotinib therapy should be interrupted or discontinued if patients present with acute/worsening ocular disorders such as eye pain (see Adverse Reactions).
Interactions: Erlotinib has a potential for clinically significant drug-drug interactions (see Interactions).
Excipients: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Ability to drive and use machines: No studies on the effects on the ability to drive and use machinery have been reported. However, erlotinib is not associated with impairment of mental ability.

Pregnancy: There are no adequate or well controlled studies reported in pregnant women using erlotinib. Studies in animals have reported some reproductive toxicity. The potential risk for humans is unknown. Women of childbearing potential must be advised to avoid pregnancy while on erlotinib. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the fetus.
Lactation: It is not reported whether erlotinib is excreted in human milk. Because of the potential harm to the infant, mothers should be advised against breastfeeding while receiving erlotinib.

Adverse reactions reported with monotherapy: Cardiovascular: Chest pain, peripheral edema.
Central nervous system: Anxiety, dizziness, fatigue, headache, insomnia, neurotoxicity, pain, paresthesia, voice disorder.
Dermatologic: Acne vulgaris, acneiform eruption, alopecia, bullous dermatitis, dermatitis, erythema, erythematous rash, exfoliative dermatitis, folliculitis, hypertrichosis, nail disease, palmar-plantar erythrodysesthesia, paronychia, pruritus, skin fissure, skin rash, xeroderma.
Endocrine & metabolic: Weight loss.
Gastrointestinal: Abdominal pain, anorexia, constipation, decreased appetite, diarrhea, dyspepsia, mucositis, nausea, stomatitis, taste disorder, vomiting, xerostomia.
Genitourinary: Urinary tract infection.
Hematologic & oncologic: Anemia, leukopenia, lymphocytopenia, thrombocytopenia.
Hepatic: Hepatic failure, hyperbilirubinemia, increased gamma-glutamyl transferase, increased serum ALT.
Infection: Increased susceptibility to infection.
Neuromuscular and skeletal: Arthralgia, back pain, muscle spasm, musculoskeletal pain (including chest), ostealgia, weakness.
Ophthalmic: Conjunctivitis, keratoconjunctivitis sicca, ophthalmic signs and symptoms.
Otic: Tinnitus.
Renal: Increased serum creatinine, renal failure.
Respiratory: Cough, dyspnea, epistaxis, nasopharyngitis, pneumonitis, pulmonary embolism, pulmonary fibrosis, respiratory tract infection.
Miscellaneous: Fever.
Rare but important or life-threatening: Interstitial lung disease.
Adverse reactions reported with combination (erlotinib plus gemcitabine) therapy: Cardiovascular: Cardiac arrhythmia, cerebrovascular accident (including cerebral hemorrhage), deep vein thrombosis, edema, myocardial infarction, syncope, thrombosis.
Central nervous system: Anxiety, depression, dizziness, fatigue, headache.
Dermatologic: Alopecia, skin rash.
Gastrointestinal: Abdominal pain, anorexia, diarrhea, dyspepsia, flatulence, intestinal obstruction, nausea, pancreatitis, stomatitis, vomiting, weight loss.
Hematologic & oncologic: Hemolytic anemia, microangiopathic hemolytic anemia with thrombocytopenia.
Hepatic: Hyperbilirubinemia, increased serum ALT, increased serum AST.
Infection: Increased susceptibility to infection.
Neuromuscular & skeletal: Myalgia, neuropathy, ostealgia, rigors.
Renal: Renal failure, renal insufficiency .
Respiratory: Cough, dyspnea, interstitial lung disease.
Miscellaneous: Fever.
Rare but important or life-threatening: Bullous dermatitis, exfoliative dermatitis, hepatic failure.
Mono- or combination therapy: Rare but important or life-threatening: Acute peptic ulcer with hemorrhage, bronchiolitis, corneal perforation, corneal ulcer, episcleritis, gastritis, gastrointestinal hemorrhage, gastrointestinal perforation, hearing loss, hematemesis, hematochezia, hepatorenal syndrome, hepatotoxicity, hirsutism, hyperpigmentation, hypokalemia, keratitis, melena, myopathy (in combination with statin therapy), peptic ulcer, rhabdomyolysis (in combination with statin therapy), skin photosensitivity, skin rash (acneiform; sparing prior radiation field), Stevens-Johnson syndrome, toxic epidermal necrolysis, tympanic membrane perforation.

Erlotinib is metabolized in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP1A2, and the pulmonary isoform CYP1A1. Potential interactions may occur with drugs which are metabolized by, or are inhibitors or inducers of, these enzymes.
Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib plasma concentrations. Inhibition of CYP3A4 metabolism by ketoconazole (200 mg p.o. BID for 5 days) has reported to increase exposure to erlotinib (86% in median erlotinib exposure [AUC]) and a 69% increase in C_max when compared to erlotinib alone. When erlotinib was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum concentration (C_max) has reported to increase by 39% and 17%, respectively. Therefore caution should be used when administering erlotinib with potent CYP3A4 or combined CYP3A4/CYP1A2 inhibitors. In these situations, the dose of erlotinib should be reduced if toxicity is observed.
Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly decrease erlotinib plasma concentrations. Induction of CYP3A4 metabolism by rifampicin (600 mg p.o. QD for 7 days) has reported a 69% decrease in the median erlotinib AUC, following a 150 mg dose of erlotinib, as compared to erlotinib alone.
Pre-treatment and co-administration of rifampicin with a single 450 mg dose of erlotinib has reported in a mean erlotinib exposure (AUC) of 57.5% of that after a single 150 mg erlotinib dose in the absence of rifampicin treatment. Alternative treatments lacking potent CYP3A4 inducing activity should be considered when possible. For patients who require concomitant treatment with erlotinib and a potent CYP3A4 inducer such as rifampicin an increase in dose to 300 mg should be considered while their safety (see Precautions) is closely monitored, and if well tolerated for more than 2 weeks, further increase to 450 mg could be considered with close safety monitoring. Higher doses have not been reported in this setting.
Pre-treatment or co-administration of erlotinib did not alter the clearance of the prototypical CYP3A4 substrates midazolam and erythromycin. Significant interactions reported with the clearance of other CYP3A4 substrates are therefore unlikely. Oral availability of midazolam did appear to decrease by up to 24%, which was however not attributed to effects on CYP3A4 activity.
The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases. Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and hence its bioavailability. Co-administration of erlotinib with omeprazole, a proton pump inhibitor, has been reported to decrease the erlotinib exposure [AUC] and C_max by 46% and 61%, respectively. No change to T_max or half-life has been reported. Concomitant administration of erlotinib with 300 mg ranitidine, an H₂-receptor antagonist, has been reported to decrease erlotinib exposure [AUC] and C_max by 33% and 54%, respectively. Therefore, co-administration of drugs reducing gastric acid production with erlotinib should be avoided where possible. Increasing the dose of erlotinib when co-administered with such agents is not likely to compensate for this loss of exposure. However, when erlotinib was dosed in a staggered manner 2 hours before or 10 hours after ranitidine 150 mg b.i.d., erlotinib exposure [AUC] and C_max decreased only by 15% and 17%, respectively. If patients need to be treated with such drugs, then an H₂-receptor antagonist such as ranitidine should be considered and used in a staggered manner. Erlotinib must be taken at least 2 hours before or 10 hours after the H₂-receptor antagonist dosing.
Interaction with coumarin-derived anticoagulants, including warfarin, leading to increased International Normalized Ratio (INR) and bleeding events, which in some cases were fatal, have been reported in patients receiving erlotinib. Patients taking coumarin-derived anticoagulants should be monitored regularly for any changes in prothrombin time or INR.
The combination of erlotinib and a statin may increase the potential for statin-induced myopathy, including rhabdomyolysis, which was reported rarely.
Smokers should be advised to stop smoking as cigarette smoking, which is known to induce CYP1A1 and CYP1A2, has been reported to reduce erlotinib exposure by 50-60% (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
In a reported study, there were no significant effects of gemcitabine on the pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the pharmacokinetics of gemcitabine.

Do not store above 30°C.

Targeted Cancer Therapy

L01EB02 - erlotinib ; Belongs to the class of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Used in the treatment of cancer.

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