Date of approval: Month of year
Date of revision: January
Afatinib maleate tablets instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic Name: Afatinib Maleate Tablets
English name: Afatinib Dimaleate Tablets
Hanyu Pinyin: Malaisuan Afatini Pian
Ingredients
The main ingredient of this product is Afatinib maleate.
Chemical name: (2E)-N-(4-((3-chloro-4-fluorophenylamino)-7-[[(3S)-oxa-3-cyclopentyl]oxy]quinazolin-6-yl]-4-(dimethylamino)but-2-enamide dimaleate
Chemical structure formula.
Molecular formula: C24H25ClFN5O3-2C4H4O4
Molecular weight: 718.08
Excipients: lactose, microcrystalline cellulose, cross-linked povidone, silicon dioxide, magnesium stearate, film-coated premix (gastric soluble type)
Characteristic】
This product is film-coated tablets, white to light yellow after removing the coating.
Indications
This product is indicated for the treatment of patients with.
1. Locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) sensitive mutations, not previously treated with EGFR tyrosine kinase inhibitors (TKI).
2. Locally advanced or metastatic squamous histologic type non-small cell lung cancer (NSCLC) with disease progression during or after platinum-containing chemotherapy
【Specifications】According to C24H25ClFN5O3 (1) 20mg; (2) 30mg; (3) 40mg 【Dosage and Administration
This product should be used under the supervision of an experienced physician. The mutational status of EGFR should be determined using approved assays before starting treatment.
Recommended Dose
The recommended dose of afatinib is 40 mg once daily. There is insufficient evidence to support a greater benefit to patients from a 50 mg dose.
Afatinib should not be taken with food. Take afatinib at least 3 hours after eating or at least 1 hour before eating. (See [Drug Interactions] and [Pharmacokinetics]). The entire tablet should be swallowed with water.
Afatinib should be continued until disease progression occurs or is intolerable to the patient (see Table 1 below).
Dose adjustment for adverse reactions
Symptomatic adverse drug reactions (e.g., with severe/persistent diarrhea or skin-related adverse reactions) can be managed by interrupting therapy and reducing the dose of afatinib as listed in Table 1 (see [Adverse Reactions]; see [Precautions] for more details on managing specific drug-related adverse events (AEs)).
Table 1: Dose adjustment information for adverse reactions.
CTCAEa drug-related adverse event afatinib recommended dosing level 1 or level 2 without interruption b no dose adjustment level 2 (prolonged c or intolerance) or ≥ level 3 interruption until return to level 0/1 b continued in 10 mg decrements da National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 3.0
bIn the event of diarrhea, antidiarrheal medication (e.g., loperamide) should be administered immediately and should be continued until diarrhea ceases for persistent diarrhea.
cDiarrhea>48 hours and/or rash>7 days.
dIf the patient cannot tolerate 20 mg/day, permanent discontinuation of afatinib should be considered.
Interstitial lung disease (ILD) should be considered if the patient experiences acute respiratory symptoms or worsening of symptoms, at which point afatinib therapy should be interrupted and evaluation awaited. If a diagnosis of ILD is confirmed, afatinib should be discontinued and appropriate therapy should be instituted if necessary [see [PRECAUTIONS]].
Missed Doses
If 1 dose of afatinib is missed, patients should take it as soon as they remember on the same day. However, if it is less than 8 hours before the next dose, no additional supplemental dose is required for the missed dose.
Patients with renal impairment
There are no trials specifically studying the safety, pharmacokinetics, and efficacy of afatinib in patients with renal impairment. Based on population pharmacokinetic analysis (see [Pharmacokinetics]), no adjustment of the starting dose is necessary in patients with mild or moderate renal impairment. Afatinib treatment is not recommended for patients with severe renal impairment (creatinine clearance <30mL/min).
Patients with hepatic impairment
Afatinib exposure was not significantly altered in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment (see [Pharmacokinetics]). No adjustment of the starting dose was necessary in patients with mild or moderate hepatic impairment. Afatinib has not been studied in patients with severe (Child Pugh C) hepatic impairment. Afatinib treatment is not recommended for this population.
Age, Race, Gender
No dose adjustment based on patient age, race or sex is necessary (see [Pharmacokinetics]).
Pediatric Population
The safety and efficacy of afatinib have not been studied in pediatric patients. Therefore, treatment with afatinib in children or adolescents is not recommended.
Dose adjustment due to drug interactions
P-glycoprotein (P-gp) inhibitors
If P-glycoprotein (P-gp) inhibitors are required, they should be administered in staggered doses, i.e., the interval between P-gp inhibitor dosing and afatinib dosing should be as long as possible. P-gp inhibitors should be administered 6 hours (P-gp inhibitors given twice daily) or 12 hours (P-gp inhibitors given once daily) apart from afatinib dosing. For patients requiring P-gp inhibitor therapy that is not tolerated, the daily dose of afatinib may be reduced by 10 mg. After discontinuation of P-gp inhibitor, therapy may be continued at the previous dose as long as it is tolerated (see [Precautions], [Drug Interactions], and [Pharmacokinetics]).
P-glycoprotein (P-gp) inducers
For patients requiring long-term treatment with P-gp inducers, increase the daily dose of afatinib by 10 mg as tolerated and continue treatment with afatinib at the previous dose 2-3 days after discontinuation of P-gp inducers (see [Drug Interactions] and [Pharmacokinetics]).
Alternative dosing methods
If the complete tablet cannot be swallowed, afatinib tablets may be dispersed in approximately 100 mL of non-carbonated drinking water. No other liquids should be used. The tablets should not be crushed when placed in water and should be stirred occasionally for up to 15 minutes until the tablets are dispersed into very small particles. The dispersion should be taken immediately. Rinse the glass with approximately 100 ml of water and drink. The dispersion can also be administered through a gastric tube.
[Adverse Reactions].
Summary of drug safety
The types of adverse reactions (ADRs) are generally related to the mechanism of action of afatinib, i.e., inhibition of EGFR. The most common ADRs were diarrhea and skin-related adverse events, as well as stomatitis and onychomycosis (see Tables 2 and 3). Overall, dose reductions (see [Dosage]) resulted in a lower incidence of common adverse reactions.
For patients treated with afatinib 40 mg (once daily), the proportion of patients who had a dose reduction due to adverse drug reactions was 57% for LUX-Lung3 (1200.32), 33.1% for LUX-Lung6 (1200.34) and 25% for LUX-Lung8 (1200.125). Discontinuations due to diarrhea and rash/acne were 1.3% and 0% (LUX-Lung3), 0% and 2.5% (LUX-Lung6), and 3.8% and 2.0% (LUX-Lung8), respectively.
Clinical Trial Experience
Clinically meaningful adverse effect data for afatinib in the chapter are based on data from 4257 patients enrolled in LUX-Lung3 (n=229), LUX-Lung8 (n=392) and 3636 oncology patients from 42 studies in which afatinib was administered as monotherapy or in combination with other antineoplastic agents at doses ranging from 10 -The mean duration of exposure was 5.5 months. The patient population included multiple tumor types, most commonly non-small cell lung cancer, breast cancer, colorectal cancer, brain cancer and head and neck cancer.
In the pivotal LUX-Lung 3 (1200.32) clinical trial, a total of 229 patients who were not treated with an EGFR TKI received afatinib at a starting dose of 40 mg once daily. A total of 111 patients were treated with pemetrexed/cisplatin. The overall incidence of adverse drug reactions (ADRs) was similar between patients treated with afatinib 40 mg once daily and those treated with pemetrexed/cisplatin (100% versus 96%). Afatinib-treated patients had a higher incidence of diarrhea (95% vs. 15%) and rash/acne (89% vs. 6%) compared with pemetrexed/cisplatin-treated patients. 57% of afatinib-treated patients had a dose reduction due to the occurrence of an ADR. Overall dose reduction resulted in a reduction in the frequency of common adverse events (i.e., the frequency of unexplained diarrhea decreased from 96% to 52% after the first dose reduction).
Fewer patients treated with afatinib 40 mg once daily discontinued treatment due to ADRs compared to those treated with pemetrexed/cisplatin (8% vs. 12%). Among patients treated with afatinib, 1.3% and 0% discontinued treatment due to ADR diarrhea and rash/acne, respectively.
In the LUX-Lung 6 (1200.34) clinical trial, a total of 239 patients not treated with an EGFR TKI received afatinib at a starting dose of 40 mg once daily. A total of 113 patients were treated with gemcitabine/cisplatin. The overall incidence of drug-related adverse reactions (ADRs) was similar in patients treated with afatinib 40 mg once daily and those treated with gemcitabine/cisplatin (98.7% versus 99.1%). Afatinib-treated patients had a higher incidence of diarrhea (90.0% versus 15.0%) and rash/acne (81.2% versus 9.7%) compared with gemcitabine/cisplatin-treated patients. 33.1% of afatinib-treated patients had a dose reduction due to the occurrence of an ADR.
Fewer patients treated with afatinib 40 mg once daily discontinued treatment due to ADR compared to patients treated with gemcitabine/cisplatin (10.0% vs. 39.8%). Among patients treated with afatinib, 0% and 2.5% discontinued treatment due to ADR diarrhea and rash/acne, respectively.
In the pivotal LUX-Lung8 (1200.125) clinical trial, a total of 392 patients with squamous NSCLC received afatinib at a starting dose of 40 mg once daily, and a total of 395 patients received erlotinib at 150 mg once daily. The overall incidence of ADRs in patients treated with afatinib or erlotinib was 93% versus 81%, respectively, after the first treatment cycle (28 days), with 39 (10%) patients having their afatinib dose increased to 50 mg. The incidence of diarrhea was higher in afatinib-treated patients than in erlotinib-treated patients (70% vs. 33%), and the incidence of rash/acne was comparable in both groups (67% vs. 67%). Dose reductions were seen in 27% of patients treated with afatinib. Treatment was discontinued due to adverse effects in 11% of patients treated with afatinib and 5% of patients treated with erlotinib.
All NSCLC studies with daily doses of afatinib at 40 mg or 50 mg
In NSCLC clinical trials in patients with EGFR mutations or EGFR mutation enrichment (afatinib 40 mg starting dose in 497 patients with NSCLC not treated with an EGFR TKI including trials 1200.22, 1200.32, 1200.34, 1200.123; afatinib 50 mg starting dose in patients with NSCLC not treated with an EGFR TKI including trials 1200.23, 1200.33, 1200.41, 1200.42 in 1638 patients with NSCLC previously treated with an EGFR TKI) were combined to analyze and evaluate the safety of afatinib monotherapy (starting dose of 40 mg or 50 mg once daily). The predominant histological type in these patient populations was lung adenocarcinoma. Overall, the type of ADR was related to the pattern of EGFR inhibition by afatinib. The ADR profile was consistent with LUX-Lung 3 when patients (afatinib 40 mg or 50 mg once daily) were analyzed in combination. CTCAE grade 1 or 2 ADRs occurred in 58.8% and 53.1% of patients receiving afatinib 40 mg and 50 mg, respectively. for 2 doses in 2 different patient populations, the majority of ADRs were CTCAE grade 1 or 2 and could be handled as described in the [Dosage] and [Precautions] sections. CTCAE grade 3 or 4 ADRs occurred in 38% and 41% of patients treated with afatinib 40 mg and 50 mg, respectively. CTCAE grade 3 ADRs could also be managed as described in the Dosage and Precautions sections, which resulted in a low incidence of treatment discontinuation due to ADRs at both starting doses (7% and 11.7%).
The common ADRs (diarrhea and rash/acne) in the EGFR mutation-positive or mutation-enriched NSCLC patient population treated with afatinib monotherapy in clinical studies are summarized in Table 2.
Table 2: Combined analysis of drug-related diarrhea and rash/acne in EGFR mutation-positive or mutation-enriched NSCLC patients treated with afatinib monotherapy in clinical studies.
EGFR TKI primary treatment
(starting dose 40 mg/day)
N=497 EGFR TKI treated
(starting dose 50mg/day)
N=1638CTCAE Grade 3 rash/acne 14.3%11.8%CTCAE Grade 3 diarrhea 9.9%17.6% Discontinuation of treatment for rash/acne (all grades) 1.2%1.9% Discontinuation of treatment for diarrhea (all grades) 0.6%4.5% Grade 4 rash/acne occurred in 1 (0.2%) of patients receiving the 40 mg starting dose. Grade 4 rash/acne occurred in 1 (0.1%) of patients receiving the 50 mg starting dose, along with grade 4 diarrhea in 3 (0.2%).
The safety of afatinib monotherapy at a starting dose of 40 mg was evaluated in the LUX-Lung8 trial in patients with squamous cell carcinoma of the lung. The most common ADRs were related to the mechanism of action of afatinib EGFR inhibition, and the results were consistent with those of the LUX-Lung 3 study conducted in patients with lung adenocarcinoma. Most ADRs (65%) were CTCAE grade 1 or 2, with a CTCAE grade 3/4 diarrhea incidence of 9.9%/0.5%. The incidence of drug-related CTCAE grade 3 rash was 5.9%. 11% of patients had treatment discontinuation due to ADRs. Treatment discontinuation due to disregarded severity grade diarrhea and rash/acne was 3.8% and 2.0%, respectively.
The incidence of ADRs for afatinib 40 mg or 50 mg as monotherapy in all NSCLC trials is summarized in Table 3. The following terms were used to rank the incidence of ADRs: 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), and very rare (<1/10,000). In each frequency group, ADRs are listed in order of decreasing severity.
Table 3: Summary of ADRs in each frequency group
Physical system very common
(≥1/10) Common
(≥1/100 to <1/10) Uncommon
(≥1/1,000 to < 1/100) Infections and infestations Nail fungus1 Cystitis Metabolic and nutritional disorders Loss of appetite Dehydration
Hypokalemia Neurologic disorders Taste disorders Eye disorders Conjunctivitis
Dry eye keratitis Respiratory, thoracic, and mediastinal diseases Epistaxis Nasal overflow Interstitial lung disease Gastrointestinal disorders Diarrhea
Stomatitis2
Nausea
Vomiting Indigestion
Labyrinthitis Pancreatitis Hepatobiliary disease Elevated alanine aminotransferase (ALT)
Elevated aspartate aminotransferase (AST) Skin and subcutaneous tissue disorders Rash3
Acne-like dermatitis4
Pruritic skin5
Dry skin6 Palmar-plantar sensory loss erythema syndrome
Nail disorders8 Stevens-Johnson syndrome7
Toxic epidermolysis bullosa7 Musculoskeletal and connective tissue disorders Muscle spasms Renal and urinary disorders Renal impairment/
Renal failure Systemic and administration site disorders Fever Examination Weight loss 1 Including nail infections, nail infections, nail bed infections
2 Includes stomatitis, aphthous stomatitis, mucosal inflammation, oral ulceration, oral mucosal erosion, mucosal erosion, mucosal ulceration
3 Including the group of diseases for which the preferred term is rash
4 Including acne, pustular acne, acneiform dermatitis
5 including pruritus, generalized pruritus
6 Includes dry skin, chapped skin
7 Based on post-marketing experience
8 Includes nail disorders, nail detachment, nail toxicity, nail breakage, ingrown nails, nail depression, nail loss, nail discoloration, nail dystrophy, nail striae and nail curvature
Post-marketing experience
The following adverse reactions were identified in post-marketing use of afatinib and because these adverse reactions were actively reported by an uncertain sample size of the population, it was not possible to estimate their incidence or to determine a causal relationship with drug exposure.
Pancreatitis
Toxic epidermal necrolysis relaxation syndrome/Stevens-Johnson syndrome
[Contraindicated].
Afatinib is contraindicated in patients with known hypersensitivity to afatinib or any of the excipients.
Precautions】
Diarrhea
Diarrhea, including severe diarrhea, has been reported during afatinib treatment (see [ADVERSE REACTIONS]). Diarrhea can lead to dehydration with or without renal impairment, and in rare cases can lead to fatal outcomes. Diarrhea usually occurs within the first 2 weeks of treatment. grade 3 diarrhea most often occurs within the first 6 weeks of treatment. Active management of diarrhea (including adequate rehydration combined with antidiarrheal agents, especially during the first 6 weeks of treatment) is important and should be initiated at the initial onset of diarrheal symptoms. Antidiarrheal agents (e.g., loperamide) should be administered, and if necessary, the dose should be escalated to the highest approved recommended dose. Antidiarrheal agents should be readily available to patients so that treatment can be started at the first onset of diarrhea and continued until the diarrhea has stopped for 12 hours. Patients with severe diarrhea (Grade 2 or Grade 3 diarrhea lasting more than 48 hours) require dose interruption and reduction or discontinuation of afatinib therapy (see [DOSAGE]). Patients who are dehydrated may require electrolytes and fluids given intravenously.
Skin-related adverse reactions
Rash/acne has been reported in patients treated with afatinib (see [ADVERSE REACTIONS]). Overall, the rash has presented as a mild or moderate erythematous and acne-like rash that can occur or worsen at sun-exposed sites. For sun-exposed patients, protective clothing and/or sunscreens are recommended. Early intervention for dermatologic reactions (e.g., emollients, antibiotics) is beneficial for continued afatinib treatment.
Patients with persistent or severe skin reactions may also require temporary treatment interruption, dose reduction (see [Dosage]), additional therapeutic intervention, and referral to a specialist with experience in managing these dermatologic reactions. Herpetic, herpetic, and exfoliative dermatoses have been reported, with rare cases of Stevens-Johnson syndrome and toxic epidermolysis bullosa. If a patient develops severe herpetic, herpetic, or exfoliative skin disease, treatment with afatinib should be permanently discontinued.
Females, low body weight, and potential renal impairment
Higher afatinib exposure has been observed in female patients, in lower weight patients, and in patients with potential renal impairment (see [Pharmacokinetics]). This can lead to a higher risk of EGFR-mediated adverse events such as diarrhea, rash/acne, and stomatitis. Close monitoring of patients with these risk factors is recommended.
Interstitial Lung Disease (ILD)
Interstitial lung disease or ILD-like adverse reactions (e.g., pulmonary infiltrates, pneumonia, acute respiratory distress syndrome, or allergic alveolitis) occurred in 1.6% of 4257 patients treated with afatinib in different clinical trials, of whom 0.4% died. Asian patients (2.3%; 38/1657) had a higher incidence of ILD compared with white patients (1.0%; 23/2241). In LUX-Lung3, the incidence of grade 3 or higher ILD in afatinib-treated patients was 1.3% and resulted in 1% of deaths. In LUX-Lung8, the incidence of grade 3 or higher ILD in afatinib-treated patients was 0.9% and resulted in 0.8% of deaths. Patients with a history of ILD have not been studied. All patients presenting with an acute onset and/or unexplained worsening of pulmonary symptoms (dyspnea, cough, fever) should be carefully evaluated to rule out ILD. afatinib therapy should be interrupted and these symptoms should be studied. If ILD is diagnosed, afatinib should be permanently discontinued and appropriate therapy should be instituted if necessary (see [DOSAGE AND ADMINISTRATION]).
Severe hepatic impairment
Hepatic failure, including death, has been reported in less than 1% of patients during afatinib treatment. In these patients, confounding factors include preexisting liver disease and/or comorbidities associated with the progression of an underlying malignancy. For patients with preexisting liver disease, periodic liver function checks are recommended. Patients who experience deterioration in liver function may require interruption of afatinib therapy (see [DOSAGE]). Afatinib should be discontinued in patients who develop severe hepatic impairment during the administration of afatinib.
Keratitis
Symptoms of acute or worsening ocular inflammation, tearing, photosensitivity, blurred vision, eye pain, and/or red eyes should be promptly referred to an ophthalmologist. If the diagnosis confirms ulcerative keratitis, afatinib treatment should be interrupted or discontinued. If the diagnosis is keratitis, the benefits and risks of continuing treatment should be carefully considered. Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye disease. Contact lens use is also a risk factor for keratitis and ulceration (see [Adverse Reactions]).
Left ventricular function
Left ventricular insufficiency has been associated with HER2 inhibition. Available clinical trial data do not suggest that afatinib causes adverse effects on cardiac contractility. However, afatinib has not been studied in patients with abnormal left ventricular ejection fraction (LVEF) or a history of severe cardiac disease. Cardiac monitoring (both at baseline and during afatinib treatment to assess LVEF) should be considered in patients with cardiac risk factors and conditions that affect LVEF. Cardiac monitoring (including LVEF assessment) should be considered for patients who develop relevant cardiac signs/symptoms during treatment.
Cardiology consultation and interruption or discontinuation of afatinib therapy should be considered for patients with ejection fractions below the lower limit of normal.
P-glycoprotein (P-gp) interactions
If a strong inhibitor of P-gp is given prior to afatinib, it may result in increased afatinib exposure and should therefore be used with caution. If a P-gp inhibitor is required, it should be administered concurrently with or after afatinib. Concomitant treatment with P-gp strong inducers may reduce afatinib exposure (see [DOSAGE], [DRUG INTERACTIONS], and [PHARMACOLOGY]).
Effects on driving and machine handling ability
Afatinib has a small effect on driving and machine-operating ability. During treatment, some patients reported ocular adverse reactions (conjunctivitis, dry eye, keratitis), which may affect the patient’s ability to drive or operate machinery.
Pregnant women and nursing mothers
Pregnancy
Non-clinical studies with afatinib have shown no teratogenicity when maternal lethal dose levels are reached (included). Adverse changes were limited to the occurrence of significantly toxic dose levels (see [Pharmacologic Toxicology])
There are no studies with afatinib in pregnant women. Therefore the potential risk to humans is unknown. Women of childbearing potential should be advised to avoid pregnancy while receiving afatinib. Adequate contraception should be used during treatment and for at least 2 weeks after the last dose. If afatinib is used during pregnancy or if the patient becomes pregnant while receiving afatinib, the patient should be informed of the potential hazard of the drug to the fetus.
Lactation
Based on non-clinical data (see [Pharmacologic Toxicology]), it is possible that afatinib may be excreted into human breast milk and the risks associated with nursing a child cannot be excluded. Mothers should be advised to discontinue breast-feeding while on afatinib treatment.
Fertility
The effects of afatinib on human fertility have not been studied. The available non-clinical toxicology data have identified effects on reproductive organs at higher doses (see [Pharmacologic Toxicology]). Therefore, an adverse effect of afatinib treatment on human fertility cannot be excluded.
Pediatric Dosage]
The safety and efficacy of afatinib have not been studied in pediatric patients. Therefore, treatment with afatinib in children or adolescents is not recommended.
Geriatric Use]
No dose adjustment based on patient age, race or sex is necessary (see [Pharmacokinetics]).
Drug Interactions
Interaction with P-glycoprotein (P-gp)
Afatinib is a substrate for P-gp based on in vitro data. Based on clinical data, concomitant administration with P-gp inhibitors or inducers may alter afatinib exposure. Results of drug interaction trials confirm that P-gp inhibitors (e.g., ritonavir) can be safely co-administered with afatinib as long as they are administered concurrently with or after afatinib. P-gp strong inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) may increase exposure to afatinib if administered prior to afatinib and should be used with caution (see [DOSAGE], [PRECAUTIONS], and [PHARMACOLOGY]).
Strong inducers of P-gp (including but not limited to rifampin, carbamazepine, phenytoin, phenobarbital, or onychomycin) may reduce afatinib exposure. (See [Precautions] and [Pharmacokinetics]).
Effect of Food on Afatinib
Coadministration of afatinib with a high-fat meal results in a significant reduction in afatinib exposure, with an approximate 50% reduction in Cmax and an approximate 39% reduction in AUC0-∞. Afatinib should not be taken with food (see [DOSAGE] and [PHARMACOLOGY]).
[Drug Overdose].
Symptoms
The highest doses of afatinib studied in a limited number of patients in phase I clinical trials were 160 mg once daily for 3 days and 100 mg once daily for 2 weeks. Adverse reactions at this dose were primarily dermatologic (rash/acne) and gastrointestinal events (particularly diarrhea).Overdose-related adverse reactions in 2 healthy adolescents who each ingested 360 mg afatinib (as part of a mixed dose) were nausea, vomiting, malaise, dizziness, headache, abdominal pain, and elevated amylase (<1.5 times ULN).Both subjects recovered from these adverse events. recovery.
Treatment
There is no specific antidote for afatinib drug overdose. When an overdose is suspected, administration of afatinib should be discontinued and supportive therapy instituted.
If indicated, unabsorbed afatinib may be removed by induced vomiting or gastric lavage.
[Pharmacology and Toxicology
Pharmacological effects
Afatinib binds covalently to the kinase regions of EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4), irreversibly inhibiting tyrosine kinase autophosphorylation and leading to downregulation of ErbB signaling.
At concentrations reached by patients afatinib inhibited autophosphorylation and exhibited inhibitory effects on the in vitro proliferation of selected cell lines expressing wild-type EGFR, or expressing selective EGFR exon 19 deletion mutations or exon 21 L858R mutations (including certain cell lines expressing secondary T790M mutations). In addition, afatinib inhibited the proliferation of HER2 overexpressing cell lines in vitro. Tumor growth was inhibited by afatinib administration in tumor-bearing nude mice, models that either overexpressed wild-type EGFR or HER2 or had EGFR L858R/7790M double mutations.
Toxicological studies
Repeated administration toxicity test: In a repeated oral administration toxicity test (up to 26 weeks in rats and up to 52 weeks in minipigs), the main toxic target organs were skin (dermal changes, epithelial atrophy, and folliculitis in rats), gastrointestinal tract (diarrhea, gastric erosion, epithelial atrophy in rats and minipigs), and kidney (renal papillary necrosis in rats). These changes can occur below, within, or above clinically treatment-related exposures. Pharmacologically mediated epithelial atrophy was seen in multiple organs in both animal species.
Genotoxicity: Afatinib was positive in one bacterial test strain at the upper end of the response range in the Ames assay; afatinib was negative in the in vitro chromosomal aberration assay at non-cytotoxic concentrations, the in vivo bone marrow micronucleus assay, the in vivo comet assay, and the mutagenicity assay in MutaTM mice administered orally for 4 weeks.
Reproductive toxicity: In a fertility assay, afatinib was administered orally to male and female rats at 4, 6 or 8 mg/kg/day. males showed an increased incidence of reduced sperm count or azoospermia at 6 mg/kg (approximately the AUC level at the recommended human dose of 40 mg/day) or higher, but overall fertility was not affected; general toxicology tests showed an increased incidence of testicular apoptosis and seminal vesicle and prostate A mild increase in luteal count in females at 8 mg/kg (approximately 0.63 times the AUC at the recommended human dose of 40 mg/day) was accompanied by a mild increase in post-arrest loss due to early absorption. In a 4-week toxicity test with repeated dosing, ovarian weights were reduced in female rats in each dosing group and had not fully recovered by the end of the 2-week recovery period.
In a rabbit embryo-fetal development toxicity assay, pregnant rabbits given afatinib at 5 mg/kg (approximately 0.2 times the AUC at the recommended human dose of 40 mg/day) or higher showed increased post-arrival loss and late gestational abortion in animals that developed maternal toxicity. At a dose of 10 mg/kg (approximately 0.7 times the AUC of the recommended human dose of 40 mg/day), reduced fetal weight and increased incidence of fetal shortening, visceral and skin lesions were observed. In the rat embryo-fetal developmental toxicity test, skeletal variation (including incomplete or delayed ossification) and fetal weight loss were observed at 16 mg/kg (approximately twice the AUC of the recommended human dose of 40 mg/day).
Results of a rat radiological study showed that afatinib could enter breast milk, with mean concentrations in breast milk at 1h and 6h post-dose approximately 80 and 150 times the corresponding plasma concentrations.
Carcinogenicity: Carcinogenicity tests have not been performed.
Phototoxicity: In vitro 3T3 phototoxicity assay suggests that afatinib is phototoxic.
Pharmacokinetics]
Absorption and distribution
The maximum blood concentration (Cmax) of afatinib was observed approximately 2-5 hours after oral administration of afatinib. There was a slight out-of-proportion increase in mean Cmax and AUC0-∞ values for afatinib doses ranging from 20 mg to 50 mg. Systemic exposure to afatinib was reduced by 50% (Cmax) and 39% (AUC0-∞ ) when administered with a high-fat meal compared to fasting status. Based on population pharmacokinetic data from clinical trials with various tumor types, a mean reduction in AUCτ,ss of 26% was observed when meals were consumed within 3 hours prior to or 1 hour after afatinib administration. Therefore, meals should not be consumed at least 3 hours before and at least 1 hour after afatinib administration. (See [DOSAGE AND ADMINISTRATION] and [DRUG INTERACTIONS]). Following administration of afatinib, the mean relative bioavailability was 92% compared to oral solution (corrected AUC0-∞ geometric mean ratio).
In vitro, the binding of afatinib to human plasma proteins was approximately 95%.
Metabolism and excretion
Afatinib has a negligible enzymatic metabolic response in vivo. The major circulating metabolite of afatinib is protein covalent adducts.
After administration of 15 mg of afatinib oral solution, 85.4% of the dose is recovered in the feces and 4.3% in the urine. The parent compound afatinib accounted for 88% of the recovered dose. The apparent terminal half-life was 37 hours. Afatinib reached steady-state plasma concentrations within 8 days after multiple dosing, resulting in a 2.77-fold (AUC) and 2.11-fold (Cmax) drug accumulation.
Impairment of renal function
Afatinib is excreted via the kidney in less than 5% of single doses. The safety, pharmacokinetics and efficacy of afatinib have not been studied specifically in patients with renal impairment. Based on population pharmacokinetic data from clinical trials in various tumor types, no dose adjustment is required for patients with mild or moderate renal impairment (see “Population Pharmacokinetic Analysis in Special Populations” and [Dosage]).
Hepatic Impairment
Afatinib is primarily eliminated by biliary/fecal excretion. After a single dose of afatinib 50 mg, subjects with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment were exposed at similar levels compared to healthy volunteers. This is consistent with population pharmacokinetic data from clinical trials in various tumor types (see “Population Pharmacokinetic Analysis in Specific Populations”). No adjustment of the starting dose is required for patients with mild or moderate hepatic impairment (see [DOSAGE]). The pharmacokinetics of afatinib have not been studied in patients with severe (Child Pugh Class C) hepatic insufficiency (see [Precautions]).
Population Pharmacokinetic Analysis in Special Populations
Population pharmacokinetic analysis was performed in 927 cancer patients (764 with NSCLC) receiving afatinib monotherapy. No adjustment of the starting dose was required for any of the following covariates that were tested
Age
No significant effect of age (range: 28-87 years) on the pharmacokinetics of afatinib was observed.
Body weight
Plasma exposure (AUCτ,ss) was increased by 26% in 1 patient at 42 kg (2nd.5th percentile) and decreased by 22% in 1 patient at 95 kg (97.5th percentile) relative to 1 patient at 62 kg (median weight of the overall patient population).
Gender
Plasma exposure (AUCτ,ss, corrected for body weight) was 15% higher in female patients than in male patients.
Ethnicity
There were no statistically significant differences in afatinib pharmacokinetics between Asian and Caucasian patients. No significant differences in pharmacokinetics were also detected between American Indian/Alaska Native or black patients (based on limited data from these populations, 6 and 9 of 927 patients were included in the analysis, respectively)
Impairment of renal function
Exposure to afatinib increased moderately as creatinine clearance (CrCL) decreased, i.e., exposure to afatinib (AUCτ,ss) increased by 13% and 42% in patients with a CrCL of 60 or 30 mL/min compared with patients with a CrCL of 79 mL/min (the median CrCL for the overall patient population analyzed), while patients with a CrCL of 90 or 120 mL/min reduced exposure by 6% and 20%, respectively.
Liver function impairment
Patients with mild and moderate hepatic impairment detected by abnormal liver function test results did not have any significant change in afatinib exposure.
Other patient characteristics/intrinsic factors
Other patient characteristics/intrinsic factors that had a significant effect on afatinib exposure included: ECOG functional status score, lactate dehydrogenase level, alkaline phosphatase level, and total protein level. The individual effects of these covariates were not clinically significant.
History of smoking, alcohol consumption, or liver metastases did not significantly affect the pharmacokinetics of afatinib.
Pharmacokinetic Interactions
Drug transport proteins.
P-glycoprotein (P-gp)
Effects of P-glycoprotein inhibitors and inducers on afatinib
Two trials were conducted to assess the effect of ritonavir, a strong inhibitor of P-gp, on the pharmacokinetics of afatinib. In one trial, the relative bioavailability of afatinib was studied when ritonavir (200 mg twice daily for 3 days) was administered concurrently with or 6 hours after a single dose of 40 mg afatinib. The relative bioavailability of afatinib was 119% (AUC0-∞) and 104% (Cmax) when administered concomitantly with ritonavir and 111% (AUC0-∞) and 105% (Cmax) when ritonavir was administered 6 hours after afatinib. In trial 2, exposure to afatinib was increased by 48% (AUC0-∞) and 39% (Cmax) when ritonavir (200 mg twice daily for 3 days) was administered 1 hour prior to a single dose of 20 mg afatinib (see [Dosage], [Precautions], and [Drug Interactions]).
Pretreatment (600 mg daily for 7 days) with rifampin, a strong inducer of P-gp, reduced afatinib plasma exposure by 34% (AUC0-∞) and 22% (Cmax) after a single dose of 40 mg afatinib (see [Precautions] and [Drug Interactions]).
Afatinib’s effect on P-gp substrates
Based on in vitro trial data, afatinib is a moderate inhibitor of P-gp. Afatinib treatment is therefore unlikely to cause changes in plasma concentrations of other P-gp substrates.
Breast cancer resistance protein (BCRP)
In vitro studies have shown afatinib to be a substrate and inhibitor of the transporter protein BCRP.
Drug uptake transporter system
In vitro data suggest that afatinib drug-drug interactions due to inhibition of OATB1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and OCT3 transport are unlikely.
Drug metabolizing enzymes.
Cytochrome P450 (CYP) enzymes
CYP enzyme inducers and inhibitors on afatinib
In vitro data suggest that CYP enzyme inhibition or induction due to concomitant dosing is unlikely to cause afatinib drug-drug interactions. Human studies have found negligible effects of enzymatic metabolic reactions on afatinib metabolism. Approximately 2% of the afatinib dose is metabolized via FMO3, and the amount of CYP3A4-dependent N-demethylation is too low to be quantified.
Afatinib’s effect on CYP enzymes
Afatinib is not an inhibitor or inducer of CYP enzymes. Therefore, afatinib is unlikely to affect the metabolism of other CYP enzyme-dependent drugs.
UDP-glucuronosyltransferase 1A1 (UGT1A1)
In vitro data suggest that afatinib drug-drug interactions due to UGT1A1 inhibition are unlikely.
[Storage].
Seal and store below 30℃
Package
Aluminum-plastic packaging, plus desiccant, outer laminated film bag, 10 tablets/plate/bag/box.
Expiration date
18 months
Execution Standard
Approval number】
【Drug marketing license holder
Company Name: Jiangsu Haosen Pharmaceutical Group Co.
Address: Lianyungang Economic and Technological Development Zone, Jiangsu Province
Manufacturer
Manufacturer Name: Jiangsu Haosen Pharmaceutical Group Co.
Production Address: No. 8 Lushan Road, Lianyungang Economic and Technological Development Zone
Postal code: 222047
Customer service telephone: 4008285227 Monday to Friday 9:00-17:00 (except holidays)
Web address: http://www.hansoh.cn