Erlotinib

Chemical formula: C₂₂H₂₃N₃O₄  Molecular mass: 393.436 g/mol  PubChem compound: 176870

Interactions

Erlotinib interacts in the following cases:

Substrates of UGT1A1

Erlotinib is a potent inhibitor of CYP1A1, and a moderate inhibitor of CYP3A4 and CYP2C8, as well as a strong inhibitor of glucuronidation by UGT1A1 in vitro. The inhibition of glucuronidation may cause interactions with medicinal products which are substrates of UGT1A1 and exclusively cleared by this pathway.

Proteasome inhibitors

Due to the working mechanism, proteasome inhibitors including bortezomib may be expected to influence the effect of EGFR inhibitors including erlotinib. Such influence is supported by limited clinical data and preclinical studies showing EGFR degradation through the proteasome.

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. The safety and efficacy of erlotinib has not been studied in patients with severe hepatic dysfunction (AST/SGOT and ALT/SGPT >5 x ULN). Use of erlotinib in patients with severe hepatic dysfunction is not recommended.

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.

P-glycoprotein inhibitors

Erlotinib is a substrate for the P-glycoprotein active substance transporter. Concomitant administration of inhibitors of Pgp, e.g. cyclosporine and verapamil, may lead to altered distribution and/or altered elimination of erlotinib. The consequences of this interaction for e.g. CNS toxicity have not been established. Caution should be exercised in such situations.

Potent inhibitors of CYP3A4

Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and CYP1B1 in tumour tissue also potentially contribute to the metabolic clearance of erlotinib. Potential interactions may occur with active substances which are metabolised by, or are inhibitors or inducers of, these enzymes.

Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib plasma concentrations. In a clinical study, the concomitant use of erlotinib with ketoconazole (200 mg orally twice daily for 5 days), a potent CYP3A4 inhibitor, resulted in an increase of erlotinib exposure (86% of AUC and 69% of Cmax). Therefore, caution should be used when erlotinib is combined with a potent CYP3A4 inhibitor, e.g. azole antifungals (i.e. ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin or clarithromycin. If necessary the dose of erlotinib should be reduced, particularly if toxicity is observed.

Potent inducers of CYP3A4

Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and CYP1B1 in tumour tissue also potentially contribute to the metabolic clearance of erlotinib. Potential interactions may occur with active substances which are metabolised by, or are inhibitors or inducers of, these enzymes.

Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly decrease erlotinib plasma concentrations. In a clinical study, the concomitant use of erlotinib and rifampicin (600 mg orally once daily for 7 days), a potent CYP3A4 inducer, resulted in a 69% decrease in the median erlotinib AUC. Co-administration of rifampicin with a single 450 mg dose of erlotinib resulted in a mean erlotinib exposure (AUC) of 57.5% of that after a single 150 mg erlotinib dose in the absence of rifampicin treatment. Co-administration of erlotinib with CYP3A4 inducers should therefore be avoided. 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 (including renal and liver functions and serum electrolytes) is closely monitored, and if well tolerated for more than 2 weeks, further increase to 450 mg could be considered with close safety monitoring. Reduced exposure may also occur with other inducers e.g. phenytoin, carbamazepine, barbiturates or St. John’s Wort (hypericum perforatum). Caution should be observed when these active substances are combined with erlotinib. Alternate treatments lacking potent CYP3A4 inducing activity should be considered when possible.

Potent CYP1A2 inhibitors

When erlotinib was co-administered with ciprofloxacin, a moderate CYP1A2 inhibitor, the erlotinib exposure [AUC] increased significantly by 39%, while no statistically significant change in Cmax was found. Similarly, the exposure to the active metabolite increased by about 60% and 48% for AUC and Cmax, respectively. The clinical relevance of this increase has not been established. Caution should be exercised when ciprofloxacin or potent CYP1A2 inhibitors (e.g. fluvoxamine) are combined with erlotinib. If adverse reactions related to erlotinib are observed, the dose of erlotinib may be reduced.

Severe renal impairment

The safety and efficacy of erlotinib has not been studied in patients with renal impairment (serum creatinine concentration >1.5 times the upper normal limit). Based on pharmacokinetic data no dose adjustments appear necessary in patients with mild or moderate renal impairment. Use of erlotinib in patients with severe renal impairment is not recommended.

Proton pump inhibitors (PPIs), H2-receptor antagonists

Erlotinib is characterised by a decrease in solubility at pH above 5. Medicinal products that alter the pH of the upper Gastro-Intestinal (GI) tract may alter the solubility of erlotinib and hence its bioavailability. Co-administration of erlotinib with omeprazole, a proton pump inhibitor (PPI), decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61%, respectively. There was no change to Tmax or half-life. Concomitant administration of erlotinib with 300 mg ranitidine, an H2-receptor antagonist, decreased erlotinib exposure [AUC] and maximum concentrations [Cmax] by 33% and 54%, respectively. 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 maximum concentrations [Cmax] decreased only by 15% and 17%, respectively.

The effect of antacids on the absorption of erlotinib has not been investigated but absorption may be impaired, leading to lower plasma levels. In summary, the combination of erlotinib with proton pump inhibitors should be avoided. If the use of antacids is considered necessary during treatment with erlotinib, they should be taken at least 4 hours before or 2 hours after the daily dose of erlotinib. If the use of ranitidine is considered, it should be used in a staggered manner; i.e. erlotinib must be taken at least 2 hours before or 10 hours after ranitidine dosing.

Coumarin-derived anticoagulants

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 Tarceva. Patients taking coumarin-derived anticoagulants should be monitored regularly for any changes in prothrombin time or INR.

Statins

The combination of erlotinib and a statin may increase the potential for statin-induced myopathy, including rhabdomyolysis, which was observed rarely.

Fertility

Studies in animals have shown no evidence of impaired fertility. However, an adverse effect on the fertility can not be excluded as animal studies have shown effects on reproductive parameters. The potential risk for humans is unknown.

Capecitabine

Capecitabine may increase erlotinib concentrations. When erlotinib was given in combination with capecitabine, there was a statistically significant increase in erlotinib AUC and a borderline increase in Cmax when compared with values observed in another study in which erlotinib was given as single agent. There were no significant effects of erlotinib on the pharmacokinetics of capecitabine.

Carboplatin, paclitaxel

Erlotinib increases platinum concentrations. In a clinical study, the concomitant use of erlotinib with carboplatin and paclitaxel led to an increase of total platinum AUC0-48 of 10.6%. Although statistically significant, the magnitude of this difference is not considered to be clinically relevant. In clinical practice, there may be other co-factors leading to an increased exposure to carboplatin like renal impairment. There were no significant effects of carboplatin or paclitaxel on the pharmacokinetics of erlotinib.

Interstitial lung disease (ILD)

Cases of interstitial lung disease (ILD)-like events, including fatalities, have been reported uncommonly in patients receiving erlotinib for treatment of non-small cell lung cancer (NSCLC), pancreatic cancer or other advanced solid tumours. In the pivotal study BR.21 in NSCLC, the incidence of ILD (0.8%) was the same in both the placebo and erlotinib groups. In a meta-analysis of NSCLC randomised controlled clinical trials (excluding phase I and single-arm phase II studies due to lack of control groups), the incidence of ILD-like events was 0.9% on erlotinib compared to 0.4% in patients in the control arms.

In the 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. 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 (ARDS), alveolitis, and lung infiltration. Symptoms started from a few days to several months after initiating erlotinib therapy. Confounding or contributing factors such as concomitant or prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections were frequent. A higher incidence of ILD (approximately 5% with a mortality rate of 1.5%) is seen among patients in studies conducted in Japan.

In patients who develop acute onset of new and/or progressive unexplained pulmonary symptoms such as dyspnoea, cough and fever, erlotinib therapy should be interrupted pending diagnostic evaluation. Patients treated concurrently with erlotinib and gemcitabine should be monitored carefully for the possibility to develop ILD-like toxicity. If ILD is diagnosed, erlotinib should be discontinued and appropriate treatment initiated as necessary.

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. Erlotinib treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions. Patients with bullous and exfoliative skin disorders should be tested for skin infection and treated according to local management guidelines.

Ulcerative keratitis

Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist. If a diagnosis of ulcerative keratitis is confirmed, treatment with erlotinib should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Erlotinib should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.Very rare cases of corneal perforation or ulceration have been reported during use of erlotinib.

Diarrhoea, dehydration, electrolyte imbalance

Diarrhoea (including very rare cases with a fatal outcome) has occurred in approximately 50% of patients on erlotinib and moderate or severe diarrhoea should be treated with e.g. loperamide. In some cases dose reduction may be necessary. In the clinical studies doses were reduced by 50 mg steps. Dose reductions by 25 mg steps have not been investigated. In the event of severe or persistent diarrhoea, nausea, anorexia, or vomiting associated with dehydration, erlotinib therapy should be interrupted and appropriate measures should be taken to treat the dehydration.

There have been rare reports of hypokalaemia and renal failure (including fatalities). Some cases were secondary to severe dehydration due to diarrhoea, vomiting and/or anorexia, while others were confounded by concomitant chemotherapy. In more severe or persistent cases of diarrhoea, or cases leading to dehydration, particularly in groups of patients with aggravating risk factors (especially concomitant chemotherapy and other 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.

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 anti-angiogenic 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.

Low expression levels of UGT1A1, genetic glucuronidation disorders

Erlotinib is a potent inhibitor of CYP1A1, and a moderate inhibitor of CYP3A4 and CYP2C8, as well as a strong inhibitor of glucuronidation by UGT1A1 in vitro. Patients with low expression levels of UGT1A1 or genetic glucuronidation disorders (e.g. Gilbert’s disease) may exhibit increased serum concentrations of bilirubin and must be treated with caution.

Smoker

Cigarette smoking has been shown to reduce erlotinib exposure by 50-60%. The maximum tolerated dose of erlotinib in NSCLC patients who currently smoke cigarettes was 300 mg. The 300 mg dose did not show improved efficacy in second line treatment after failure of chemotherapy compared to the recommended 150 mg dose in patients who continue to smoke cigarettes. Safety data were comparable between the 300 mg and 150 mg doses; however, there was a numerical increase in the incidence of rash, interstitial lung disease and diarrhoea, in patients receiving the higher dose of erlotinib. Current smokers should be advised to stop smoking.

Results of a pharmacokinetic interaction study indicated a significant 2.8-, 1.5- and 9-fold reduced AUCinf, Cmax and plasma concentration at 24 hours, respectively, after administration of erlotinib in smokers as compared to non-smokers. Therefore, patients who are still smoking should be encouraged to stop smoking as early as possible before initiation of treatment with erlotinib, as plasma erlotinib concentrations are reduced otherwise. Based on the data from the CURRENTS study, no evidence was seen for any benefit of a higher erlotinib dose of 300 mg when compared with the recommended dose of 150 mg in active smokers. Safety data were comparable between the 300 mg and 150 mg doses; however, there was a numerical increase in the incidence of rash, interstitial lung disease and diarrhoea, in patients receiving the higher dose of erlotinib.

Pregnancy

There are no adequate data for the use of erlotinib in pregnant women. Studies in animals have shown no evidence of teratogenicity or abnormal parturition. However, an adverse effect on the pregnancy can not be excluded as rat and rabbit studies have shown increased embryo/foetal lethality. The potential risk for humans is unknown.

Nursing mothers

It is not known whether erlotinib is excreted in human milk. No studies have been conducted to assess the impact of erlotinib on milk production or its presence in breast milk. As the potential for harm to the nursing infant is unknown, mothers should be advised against breast-feeding while receiving erlotinib and for at least 2 weeks after the final dose.

Carcinogenesis, mutagenesis and fertility

Women of childbearing potential

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 foetus.

Fertility

Studies in animals have shown no evidence of impaired fertility. However, an adverse effect on the fertility can not be excluded as animal studies have shown effects on reproductive parameters. The potential risk for humans is unknown.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed; however erlotinib is not associated with impairment of mental ability.

Adverse reactions


Safety evaluation of erlotinib is based on the data from more than 1500 patients treated with at least one 150 mg dose of erlotinib monotherapy and more than 300 patients who received erlotinib 100 or 150 mg in combination with gemcitabine.

The incidence of adverse drug reactions (ADRs) from clinical trials reported with erlotinib alone or in combination with chemotherapy are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 1. The listed ADRs were those reported in at least 10% (in the erlotinib group) of patients and occurred more frequently (≥3%) in patients treated with erlotinib than in the comparator arm. Other ADRs including those from other studies are summarized below.

Adverse drug reactions from clinical trials (Table 1) are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Non-small cell lung cancer (erlotinib administered as monotherapy)

First-Line Treatment of Patients with EGFR Mutations

In an open-label, randomised phase III study, ML20650 conducted in 154 patients, the safety of erlotinib for first-line treatment of NSCLC patients with EGFR activating mutations was assessed in 75 patients; no new safety signals were observed in these patients.

The most frequent ADRs seen in patients treated with erlotinib in study ML20650 were rash and diarrhoea (any Grade 80% and 57%, respectively), most were Grade ½ in severity and manageable without intervention. Grade 3 rash and diarrhoea occurred in 9% and 4% of patients, respectively. No Grade 4 rash or diarrhoea was observed. Both rash and diarrhoea resulted in discontinuation of erlotinib in 1% of patients. Dose modifications (interruptions or reductions) for rash and diarrhoea were needed in 11% and 7% of patients, respectively.

Maintenance treatment

In two other double-blind, randomised, placebo-controlled Phase III studies BO18192 (SATURN) and B025460 (IUNO); erlotinib was administered as maintenance after first-line chemotherapy. These studies were conducted in a total of 1532 patients with advanced, recurrent or metastatic NSCLC following first-line standard platinum-based chemotherapy, no new safety signals were identified.

The most frequent ADRs seen in patients treated with erlotinib in studies B018192 and B025460 were rash (B018192: all grades 49.2%, grade 3: 6.0%; B025460: all grades 39.4%, grade 3: 5.0%) and diarrhoea (B018192: all grades 20.3%, grade 3: 1.8%; B025460: all grades 24.2%, grade 3: 2.5%). No Grade 4 rash or diarrhoea was observed in either study. Rash and diarrhoea resulted in discontinuation of erlotinib in 1% and <1% of patients, respectively, in study B018192, while no patients discontinued for rash or diarrhoea in B025460. Dose modifications (interruptions or reductions) for rash and diarrhoea were needed in 8.3% and 3% of patients, respectively, in study B018192 and 5.6% and 2.8% of patients, respectively, in study B025460.

Second and Further Line Treatment

In a randomised double-blind study (BR.21; erlotinib administered as second line therapy), rash (75%) and diarrhoea (54%) were the most commonly reported adverse drug reactions (ADRs). Most were Grade ½ in severity and manageable without intervention. Grade ¾ rash and diarrhoea occurred in 9% and 6%, respectively in erlotinib-treated patients and each resulted in study discontinuation in 1% of patients. Dose reduction for rash and diarrhoea was needed in 6% and 1% of patients, respectively.

In study BR.21, the median time to onset of rash was 8 days, and the median time to onset of diarrhoea was 12 days.

In general, rash manifests as a mild or moderate erythematous and papulopustular rash, which may occur or worsen in sun exposed areas. For patients who are exposed to sun, protective clothing, and/or use of sunscreen (e.g. mineral-containing) may be advisable.

Pancreatic cancer (erlotinib administered concurrently with gemcitabine)

The most common adverse reactions in pivotal study PA.3 in pancreatic cancer patients receiving erlotinib 100 mg plus gemcitabine were fatigue, rash and diarrhoea. In the erlotinib plus gemcitabine arm, Grade ¾ rash and diarrhoea were each reported in 5% of patients. The median time to onset of rash and diarrhoea was 10 days and 15 days, respectively. Rash and diarrhoea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving erlotinib plus gemcitabine.

Table 1. ADRs occurring in ≥10% of patients in BR.21 (treated with erlotinib) and PA.3 (treated with erlotinib plus gemcitabine) studies and ADRs occurring more frequently (≥3%) than placebo in BR.21 (treated with erlotinib) and PA.3 (treated with erlotinib plus gemcitabine) studies:

 Erlotinib (BR.21) N=485Erlotinib (PA.3) N=259Frequency category of highest incidence
NCI-CTC GradeAny Grade3 4Any Grade3 4
MedDRA Preferred Term% % % % % %
Infections and infestations
Infection* 24 4 0 31 3<1 very common
Metabolism and nutrition disorders
Anorexia5281- - - very common
Weight decreased- - - 3920very common
Eye disorders
Keratoconjunctivitis sicca1200- - - very common
Conjunctivitis12<1 0- - - very common
Psychiatric disorders
Depression- - - 19 2 0 very common
Nervous system disorders
Neuropathy- - - 131<1very common
Headache- - - 15<1 0very common
Respiratory, thoracic and mediastinal disorders
Dyspnoea411711- - - very common
Cough33401600very common
Gastrointestinal disorders
Diarrhoea** 546<1485<1very common
Nausea3330- - - very common
Vomiting232<1- - - very common
Stomatitis17<1022<10very common
Abdominal pain112<1- - - very common
Dyspepsia- - - 17<10very common
Flatulence- - - 1300very common
Skin and subcutaneous tissue disorders
Rash*** 758<16950very common
Pruritus13<10- - - very common
Dry skin1200- - - very common
Alopecia- - - 1400very common
General disorders and administration site conditions
Fatigue5214473142very common
Pyrexia- - - 3630very common
Rigors- - - 1200very common

* Severe infections, with or without neutropenia, have included pneumonia, sepsis, and cellulitis.
** Can lead to dehydration, hypokalemia and renal failure.
*** Rash included dermatitis acneiform.
- corresponds to percentage below threshold.

Summary of ADRs per frequency category:

Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000)

Eye disorders

Common: Keratitis, Conjunctivitis1

Uncommon: Eyelash changes2

Very rare: Corneal perforations, Corneal ulcerations, Uveitis

Respiratory, thoracic and mediastinal disorders

Common: Epistaxis

Uncommon: Interstitial lung disease (ILD)3

Gastrointestinal disorders

Very common: Diarrhoea7

Common: Gastrointestinal bleeding4,7

Uncommon: Gastrointestinal perforations7

Hepatobiliary disorders

Very common: Liver function test abnormalities5

Rare: Hepatic failure6

Skin and subcutaneous tissue disorders

Very common: Rash

Common: Alopecia, Dry skin1, Paronychia, Folliculitis, Acne/Dermatitis acneiform, Skin fissures

Uncommon: Hirsutism, Eyebrow changes, Brittle and Loose nails, Mild skin reactions such as hyperpigmen tation

Rare: Palmar plantar erythrodysaesthesia syndrome

Very rare: Stevens-Johnson syndrome/Toxic epidermal necrolysis7

Renal and urinary disorders

Common: Renal insufficiency1

Uncommon: Nephritis1, Proteinuria1

1 In clinical study PA.3.
2 Including in-growing eyelashes, excessive growth and thickening of the eyelashes.
3 Including fatalities, in patients receiving erlotinib for treatment of NSCLC or other advanced solid tumours. A higher incidence has been observed in patients in Japan.
4 In clinical studies, some cases have been associated with concomitant warfarin administration and some with concomitant NSAID administration.
5 Including increased alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin. These were very common in clinical study PA.3 and common in clinical study BR.21. Cases were mainly mild to moderate in severity, transient in nature or associated with liver metastases.
6 Including fatalities. Confounding factors included pre-existing liver disease or concomitant hepatotoxic medications.
7 Including fatalities.

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