Date of approval.
Date of revision.
Anrotinib Hydrochloride Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Anrotinib Hydrochloride Capsules
Trade name: Forcovir
English name: Anlotinib Hydrochloride Capsules
Hanyu Pinyin：Yansuan Anluotini Jiaonang
Ingredients
The active ingredient of this product is Anlotinib Hydrochloride.
Chemical name: 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine dihydrochloride
Chemical structure formula.
Molecular formula: C23H22FN3O3-2HCl
Molecular weight: 480.36
Properties】The content of this product is white or off-white powder or granule.
Indications
This product is indicated as a single agent for the treatment of patients with locally advanced or metastatic non-small cell lung cancer that has progressed or recurred after receiving at least 2 prior systemic chemotherapies. For patients with epidermal growth factor receptor (EGFR) mutation or mesenchymal lymphoma kinase (ALK) positivity, progression or relapse after treatment with appropriate targeted agents and progression or relapse after at least 2 prior systemic chemotherapies should be received prior to initiation of treatment with this product.
Specification
As per Anrotinib (C23H22FN3O3): (1) 12mg; (2) 10mg; (3) 8mg.
Dosage]
This product should be used under the guidance of a physician experienced in the use of antineoplastic drugs
(1) Recommended dose and method of administration.
The recommended dose of Anrotinib hydrochloride is 12mg per dose, taken orally once daily before breakfast. The recommended dose of Anrotinib Hydrochloride is 12mg once daily by mouth before breakfast. Take the drug continuously for 2 weeks and stop for 1 week, i.e. 3 weeks (21 days) as a course of treatment. Until disease progression or intolerable adverse reactions occur. If there is a missed dose during the dosing period, no additional dose will be given if the time until the next dose is confirmed to be shorter than 12 hours.
(2) Dose adjustment
Adverse reactions should be closely monitored during the use of this product and adjusted according to the adverse reactions so that the patient can tolerate the treatment. Adverse reactions caused by this product can be managed by symptomatic treatment, suspension of medication and/or dose adjustment. Depending on the degree of adverse reactions, dose adjustment is recommended under the guidance of a physician: ① first dose adjustment: 10mg once daily for 2 weeks and 1 week off; ② second dose adjustment: 8mg once daily for 2 weeks and 1 week off (please refer to Table 1~Table 2 and [Caution] for the dose adjustment method). If the 8mg dose is still not tolerated, the drug will be discontinued permanently.
In case of non-hemorrhagic adverse reactions, dose adjustment should first be made according to the general principles in Table 1. In case of bleeding adverse reactions, dose adjustment should be made according to Table 2.
Table 1 General principles of dose adjustment according to the level of adverse reactions
Adverse reaction level
(NCI-CTC AE4.0) Dosage adjustment principle for dosing time Level 3 is suspended and continued after the adverse reaction has recovered to <2 level down by one dose; if it has not recovered after 2 weeks, consider permanent discontinuation. NCI CTC AE4.0: National Cancer Institute Common Toxic Reaction Classification Criteria Version 4.0.
The latter levels of adverse reactions are defined according to this standard.
Table 2 Dose adjustment principles in case of bleeding adverse reactions
Dose adjustment principles for bleeding events* Grade 2 suspend the drug and take active symptomatic treatment; if the drug can recover to < Grade 2 within 2 weeks, adjust one dose downward to continue the drug; if it occurs again, consider permanent discontinuation of the drug. Grade ≥3 permanent discontinuation and emergency medical intervention treatment. *Hemorrhagic adverse reactions include hemoptysis, gastrointestinal bleeding, nasal bleeding, bronchial bleeding, gingival bleeding, carnal hematuria, fecal occult blood, and cerebral hemorrhage.
Dosage in patients with hepatic and renal insufficiency
There are no data on the effects of this product on patients with hepatic or renal insufficiency. Clinical studies have shown that hepatic injury and proteinuria may occur in patients taking this product for a long period of time.
CYP1A2 and CYP3A4/5 strong inhibitors and inducers
Strong inhibitors of CYP1A2 and CYP3A4/5 (such as ciprofloxacin or ketoconazole) may increase plasma concentrations of this product, and inducers of CYP1A2 and CYP3A4/5 (such as omeprazole or rifampin) may decrease plasma concentrations of this product.
[Adverse Reactions].
This instruction describes the adverse reactions observed in clinical trials judged to be possibly caused by anlotinib and their approximate incidence. Because clinical trials are conducted under a variety of different conditions, the incidence of adverse reactions observed in one clinical trial cannot be directly compared with the incidence of adverse reactions observed in another clinical trial and may not reflect the actual incidence in clinical practice.
To date, safety data have been obtained for a total of 835 patients exposed to anlotinib from 9 clinical trials using a dosing regimen with a starting dose of 12 mg for 2 weeks and a 1-week discontinuation. The most common adverse reactions (≥20%) reported in the pooled safety data from these studies were hypertension, malaise, hand-foot skin reactions, gastrointestinal reactions, abnormal liver function, abnormal thyroid function, hyperlipidemia, and proteinuria.
Information on adverse reactions to anlotinib for advanced non-small cell lung cancer was primarily derived from a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial (ALTER0303, n=437) and a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial (ALTER0302, n=117).
The ALTER0303 study enrolled patients with locally advanced/metastatic non-small cell lung cancer who had progressed or were intolerant after receiving at least 2 systemic chemotherapies, and patients with EGFR mutations or ALK-positive patients who had also progressed or were intolerant after receiving the appropriate targeted agents. The trial excluded patients with bleeding tendency, poorly controlled hypertension, coagulation abnormalities, and 24-hour urine protein quantification >1.0 g. 294 patients were treated with anlotinib at a starting dose of 12 mg orally once daily for 2 weeks and 1 week off for every 3 weeks (21 days). 57.14% (168/294) of subjects received 6 or more cycles of treatment. Dose downregulation (from 12 mg to 10 mg) occurred in 25 patients (8.50%) in the anlotinib group and a second downregulation (from 10 mg to 8 mg) occurred in 3 patients (1.02%). The main adverse reactions that led to dose downregulation were hand-foot skin reactions, hypertension, diarrhea, anorexia, oral mucositis, abnormal liver function, proteinuria, hyperlipidemia, and malaise.
The incidence of all grade adverse reactions was 97.28% and 88.11% in the anrotinib and placebo groups, respectively, and the incidence of grade 3 and higher adverse reactions was 47.28% and 18.18%, respectively. Table 3 lists the adverse reactions with an incidence of ≥10% in the anrotinib group versus the placebo group and the adverse reactions with an incidence of ≥2% of grade 3 and above (according to NCI-CTC AE4.0 classification) in the ALTER0303 study.
Table 3 Adverse reactions with an incidence of ≥10% of all grades in the ALTER0303 study
and ≥2% of grade 3 or higher adverse reactions summary table*
Adverse reactions* Anrotinib (n=294) Placebo (n=143) All grades ≥ grade 3 All grades ≥ grade 3 n (%) n (%) n (%) n (%) General Weakness 150 (51.02) 1 (0.34) 38 (26.57) 0 Loss of appetite 133 (45.24) 3 (1.02) 43 (30.07) 3 (2.10) Decreased body weight 66(22.45) 0 12(8.39) 0 Pain 42(14.29) 2(0.68) 15(10.49) 2(1.40) Gastrointestinal system Diarrhea 103(35.03) 3(1.02) 21(14.69) 0 Oropharyngeal pain 83(28.23) 1(0.34) 10(6.99) 0 Oral mucositis 68(23.13) 3(1.02) 4(2.80) 0 Vomiting 63(21.43) 1(0.34) 19(13.29) 0 Abdominal pain 53(18.03) 1(0.34) 13(9.09) 0 Nausea 52(17.69) 0 19(13.29) 0 Gum pain 40(13.61) 0 2(1.40) 0 Respiratory system Cough 110(37.41) 2(0.68) 33(23.08) 1(0.70) Dyspnea 90(30.61) 6(2.04) 32(22.38) 7(4.90) Hoarseness 66(22.45) 2(0.68) 7(4.90) 1(0.70) Hemoptysis 58(19.73) 9(3.06) 11(7.69) 2(1.40) Coughing up sputum 49 (16.67) 2(0.68) 16(11.19) 1(0.70) Upper respiratory tract infection33(11.22) 0 3(2.10)0 Pulmonary infection28(9.52) 12(4.08) 9(6.29) 3(2.10) Respiratory failure10(3.40) 10(3.40) 3(2.10) 3(2.10) 3(2.10) Cardiovascular system Hypertension 198 (67.35) 40 (13.61) 23 (16.08) 0 Sinus tachycardia 105 (35.71) 047 (32.87) 0 ECG QT interval prolongation 77 (26.19) 7 (2.38) 27 (18.88) 2 (1.40) Skin and subcutaneous tissue Hand and foot skin reactions 128 (43.54) 11 (3.74) 13 (9.09) 0 Rash 35 (11.90) 0 11 (7.69) 1 (0.70) Skeletal muscle and connective tissue Chest pain 54 (18.37) 1 (0.34) 17 (11.89) 3 (2.10) Low back and rib pain 42 (14.29) 0 11 (7.69) 0 Limb pain 39 (13.27) 016 (11.19) 1 (0.70) Renal and urinary system Proteinuria 85(28.91) 7(2.38) 19(13.29) 1(0.70) Hematuria 41(13.95) 0 8(5.59) 0 Urinary tract infection 33(11.22) 0 6(4.20) 0 Endocrine system Hypothyroidism 57(19.39) 1(0.34) 5(3.50) 0 Nervous system Vertigo 33( 11.22) 0 13(9.09) 0 Headache 32(10.88) 0 5(3.50) 0 Laboratory tests Elevated blood thyroid stimulating hormone 137(46.60) 1(0.34) 9(6.29) 0 Elevated triglycerides 126(42.86) 9(3.06) 34(23.78) 0 Elevated cholesterol 119(40.48) 0 20( 13.99) 0 Elevated gamma-glutamyl transferase 87(29.59) 13(4.42) 26(18.18) 9(6.29) Elevated bilirubin 76(25.85) 5(1.70) 21(14.69) 2(1.40) Decreased sodium 66(22.45) 24(8.16) 12(8.39) 5(3.50) Low density lipoprotein Elevated 60(20.41) 2(0.68) 11(7.69) 0 Decreased lymphocyte count 55(18.71) 14(4.76) 27(18.88) 8(5.59) Decreased albumin 53(18.03) 1(0.34) 18(12.59) 1(0.70) Elevated blood alkaline phosphatase 48(16.33) 7(2.38) 18(12.59) 4(2.80) Elevated alanine aminotransferase (ALT) 46(15.65) 2(0.68) 13(9.09) 0 Elevated aspartate aminotransferase (AST) 44(14.96) 3(1.02) 15(10.49) 0 Decreased blood phosphorus 31(10.54) 4(1.36) 10(6.99) 2( 1.40) Decreased blood potassium 31(10.54) 2(0.68) 7(4.90) 0 Decreased platelet count 30(10.20) 3(1.02) 6(4.20) 0 Elevated lipase 17(5.78) 7(2.38) 2(1.40) 1(0.70) *: Adverse events listed in the table are those in the ALTER0303 study that, in the judgment of the investigator as adverse events other than definitely unrelated, and only all levels of adverse reactions with an incidence difference of ≥2% between the incidence in the anrotinib group and the placebo group are listed.
Hemorrhage The primary bleeding event reported in both groups in the ALTER0303 study was hemoptysis, and lethal hemoptysis was reported. Thirteen cases of nasal bleeding (4.42%), 13 cases of lower gastrointestinal bleeding (4.42%, 1 grade 3), and 5 cases of bronchial bleeding (1.70%) were also reported in the anlotinib group, and the incidence of these bleeds was higher than in the placebo group, mostly grade 1/2. In the anrotinib group also reported 4 cases of laryngeal bleeding (1.36%, 2 cases of grade 3), 3 cases of gingival bleeding (1.02 %, 1 case of grade 3),, 2 cases of anal bleeding (0.68%), 2 cases of carnal hematuria (0.68%), 1 case each of uterine bleeding and fundus bleeding (0.34%), all of grade 1-2, none of these bleeding events were reported in the placebo group. Another 1 case (0.34% and 0.70%) each of cerebral hemorrhage events was reported in the anlotinib and placebo groups and was judged to be possibly unrelated to study treatment.
Thrombotic/embolic events In the ALTER0303 study, three (1.02%) pulmonary artery thromboses, one grade 3 and one grade 4, and three (1.02%) vena cava thromboses, two of which were grade 3, were reported in the anrotinib group. No thrombotic/embolic events were reported in the placebo group.
Interstitial lung disease Interstitial lung disease has been reported with similar drugs in clinical use. In the ALTER0303 study, four cases (1.36%) of acute interstitial pneumonia were reported in the anlotinib group, including one case (0.34%) of grade 2 and three cases (1.02%) of grade 3 or higher. No interstitial lung disease events were reported in the placebo group.
Pneumothorax In the ALTER0303 study, 5 (1.70%) pneumothorax adverse events were reported in the anrotinib group, while none were reported in the placebo group.
The Phase II ALTER0302 clinical study included patients similar to ALETR0303, except that patients with an ECOG score of 2 and unclear genetic status were included in the ALTER0302 study. 60 patients were treated with anlotinib 12 mg for 2 weeks with 1 week of discontinuation. The incidence of adverse reactions was 86.67 % (52/60) and 52.63 % (30/57) in the anlotinib and placebo groups, respectively, and the incidence of grade 3/4 adverse reactions was 21.6 % (13/60) and 5.26 % (3/57), respectively. Adverse reactions with an incidence of ≥5% in the anrotinib group were: hypertension (53.33%), skin reactions in hands and feet (25.00%), malaise (18.33%), diarrhea (15.60%), oral mucositis (13.33%), oropharyngeal pain (11.67%), rash (10.00%), cough (8.33%), hoarseness (8.33%) thyroid hypofunction (6.67%) and hemoptysis (5.00%). Laboratory test abnormalities (≥5%) included elevated blood thyroid stimulating hormone (31.67%), elevated blood triglycerides (18.33%), elevated blood cholesterol (16.67%), proteinuria (15.00%), elevated LDL (11.67%), elevated gamma-glutamyl transpeptidase (11.67%), elevated ALT (10.00%), and elevated blood bilirubin (6.67%). The safety profile of the Phase II study was generally similar to that of the Phase III study.
Contraindications
It is contraindicated in patients with central squamous lung cancer or at risk of hemoptysis, in patients with severe hepatic or renal insufficiency, and in women during pregnancy and lactation.
Precautions]
This product must be taken under the supervision of a physician experienced in the use of antineoplastic drugs.
Bleeding VEGFR inhibitors have the potential to increase the risk of bleeding. Clinical studies have shown an increased incidence of bleeding events and reported fatal bleeding with anlotinib relative to the placebo group. the most common bleeding event in the ALTER0303 study was hemoptysis. The incidence of grade 3 or higher hemoptysis was 3.06% (9/294, including 4 grade 4 and 2 grade 5) compared to 1.40% (2/143, 2 grade 3) in the placebo group. This was followed by fecal occult blood, gastrointestinal bleeding, rhinorrhea, bronchial bleeding, gingival bleeding, and hematuria. No increase in the incidence of cerebral hemorrhage was observed. Patients with symptomatic or symptom-controlled brain metastases for less than 2 months were excluded from the clinical study, and anlotinib is not recommended for these patients. Clinicians should closely monitor symptoms associated with the use of the drug. This product should be used with caution in patients with bleeding risk and abnormal coagulation, and prothrombin time and international normalized ratio (INR) should be closely monitored while taking this product.
In the event of a grade 2 bleeding event, the drug should be suspended and continued at one dose downward if recovery to <grade 2 can be achieved within two weeks (see [DOSAGE AND ADMINISTRATION]). If reoccurrence occurs, permanent discontinuation should be considered. Permanently discontinue the drug once a grade 3 or higher bleeding event occurs.
Because clinical trials have excluded patients with signs or history of bleeding, any bleeding event ≥ CTCAE grade 3 within 4 weeks prior to dosing, unhealed wounds, ulcers, or fractures, arterial/venous thrombotic events such as cerebrovascular accidents (including temporary ischemic attacks), deep vein thrombosis, and pulmonary embolism within 6 months, patients at risk for these events should be used under the supervision of a physician, and patients who are co-administering warfarin Patients on warfarin should be monitored every 1-2 weeks for changes in prothrombin time, INR values and clinical signs of bleeding.
Clinical studies have shown that anlotinib may increase the risk of thrombotic/embolic events. It should be used with caution in patients with a history of thrombosis/stroke, in patients taking anticoagulant drugs, or in patients with related conditions. Close monitoring should be performed during administration and suspension of the drug is recommended if thrombosis-related adverse reactions occur; discontinuation of the drug is recommended if they recur after resumption of dosing.
Elevated blood pressure Elevated blood pressure is the most common adverse effect of VEGFR inhibitor drugs. The incidence of hypertension was significantly increased by the administration of anlotinib in clinical studies. 64.63% and 13.99% of patients in the anlotinib and placebo groups, respectively, developed hypertension in the ALTER0303 clinical study, with 39 cases (13.27%) in the anlotinib group reporting grade 3 hypertension and 1 case (0.34%) grade 4 hypertension. It mostly appeared within 2 weeks after starting the drug and was controlled by conventional antihypertensive drugs such as diuretics, β-blockers and calcium channel antagonists.
Blood pressure should be monitored daily for the first 6 weeks of drug initiation. Blood pressure should be monitored 2 to 3 times a week during the follow-up period, and any increase in blood pressure or headache and dizziness should be actively communicated with the physician and treated with antihypertensive medication, suspension of anrotinib therapy or dose adjustment under the physician’s guidance.
If Grade 3/4 hypertension (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg) occurs, medication should be suspended; if Grade 3/4 blood pressure rises again after resumption of medication, medication should be continued at a lower dose (see [Dosage and Administration] Table 1). If grade 3/4 hypertension persists, discontinuation of the drug is recommended.
Patients who develop hypertensive crisis should discontinue the drug immediately and receive specialized cardiovascular care.
QT interval prolongation
Anrotinib prolongs the QT/QTc interval. 2.38% of the anrotinib group in the ALTER0303 study experienced prolongation of the ECG QT interval to grade 3 or greater compared with 1.40% in the placebo group. Patients with clinically significant arrhythmias (including QTc interval >480 ms) were excluded from enrollment in this clinical trial.
A prolonged QTc interval can lead to an increased risk of ventricular tachyarrhythmias (such as tip-twist ventricular tachycardia) or sudden death.
Avoid this product in patients with congenital long QT interval syndrome. Patients with congestive heart failure, electrolyte abnormalities, or on medications known to prolong the QTc interval should receive regular (every 3-6 weeks) monitoring of electrocardiogram (ECG) and electrolytes (sodium, magnesium, potassium, and calcium). Patients with two consecutive independent ECG tests suggesting a QTc interval >500 ms should be temporarily discontinued until the QTc interval is ≤480 ms or returns to baseline levels (e.g., baseline QTc interval >480 ms), at which time the drug may be resumed, but the dose should be adjusted downward by one dose and the ECG should be monitored closely.
The drug should be permanently discontinued in patients presenting with QTc interval prolongation of any grade (≥450 ms) with any of the following: tip-twisting ventricular tachycardia, polymorphic ventricular tachycardia, signs or symptoms of severe arrhythmias, and should receive prompt vascular specialist care.
Patients with abnormal underlying cardiac function should have cardiac function tests every 6 weeks and should discontinue the drug in the presence of grade III/IV cardiac insufficiency or in patients with a left ventricular ejection fraction <50% on cardiac ultrasonography.
Hepatic Function Abnormalities Anrotinib can cause elevated transaminases or elevated total bilirubin in the ALTER0303 study. It is contraindicated in patients with severe hepatic function. Patients with mild to moderate hepatic insufficiency should be administered with caution weighing the risks of benefit under the guidance of a physician. Hepatic transaminases and bilirubin should be monitored while taking anlotinib [monitoring of liver function (ALT, AST, bilirubin) prior to treatment initiation, during each treatment cycle, and as clinically indicated is recommended. The frequency of testing should be increased when patients develop grade 2 liver function abnormalities. If grade 3/4 aminotransferases or total bilirubin elevations occur, the drug should be suspended and serum aminotransferases and total bilirubin should be monitored 2 to 3 times per week, and the drug may be resumed within 2 weeks after recovery to grade 2 or less.
Proteinuria and Renal Abnormalities Proteinuria is one of the common adverse effects of VEGFR inhibitors. Anrotinib can cause proteinuria, with 7 cases (2.38%) of grade 3 proteinuria in the anrotinib group and 1 case (0.7%) in the placebo group in the ALTER0303 study. Grade 4 proteinuria was not reported. Grade 3 and higher creatinine elevations were not reported. Anrotinib should be used with caution and closely monitored under the guidance of a physician in patients with renal insufficiency. Patients are advised to check urine routine every 6 weeks. For 2 consecutive urine protein ≥++, 24-hour urine protein measurement must be performed and treatment measures including suspension of drug, dose adjustment and permanent discontinuation should be taken according to the grade of adverse reactions (see [DOSAGE AND ADMINISTRATION] Table 1).
Hypothyroidism In the ALTER0303 study, 57 cases (19.39%) in the anrotinib group developed hypothyroidism, of which 1 case (0.34%) was grade 3; 4 cases (2.80%) in the placebo group developed grade 1 hypothyroidism. Patients should have their thyroid function checked prior to initial dosing, and patients with underlying hypo- or hyperthyroidism should be given the appropriate standard therapy prior to treatment with this product. All patients should be closely monitored for signs and symptoms of decreased thyroid function, including chills, decreased appetite, and edema, while receiving this product. Thyroid function [thyroid stimulating hormone (TSH), triiodothyronine (T3) and tetraiodothyronine (T4)] should be tested every 3-6 weeks in patients with signs and symptoms of thyroid insufficiency and seen in the endocrinology department for standard treatment.
Hand-foot skin reactions Hand-foot skin reactions are one of the common clinical adverse reactions to VEGFR inhibitor drugs. In the ALTER0303 clinical study, 127 patients (43.20%,Grade 3 3.74%) and 13 patients (9.09%, Grade 3 0%) in the anlotinib and placebo groups, respectively, experienced hand-foot skin reactions.
Patients with grade 1 hand-foot skin reactions can continue to be observed. patients with grade 2 hand-foot skin reactions should be treated with symptomatic therapy, including intensive skin care, keeping the skin clean, avoiding secondary infection, avoiding pressure and friction; topical application of lotions or lubricants containing urea and corticosteroid ingredients; topical treatment with antifungal drugs or antibiotics in case of infection, which is recommended to be used under the guidance of a dermatologist. If skin reactions of ≥ grade 3 occur in the hands and feet, the dose should be adjusted downward by one dose and continued (see [DOSAGE AND ADMINISTRATION] Table 1). If adverse reactions persist, the drug should be discontinued.
Gastrointestinal Adverse Events In the ALTER0303 clinical study, diarrhea was the most frequently reported treatment-related gastrointestinal adverse event. 86 cases (29.25%) in the anlotinib group had diarrhea, of which 3 cases (1.02%) were grade 3. Other gastrointestinal adverse events included oropharyngeal pain, stomatitis, vomiting, nausea, and abdominal pain. Supportive care for gastrointestinal adverse events requiring treatment may include oral care, antiemetic and antidiarrheal.
If grade 3/4 diarrhea occurs while taking this product, suspension of the drug is recommended; if grade 3/4 diarrhea occurs again after resumption of dosing, the drug may be continued at one dose downward (see [DOSAGE AND ADMINISTRATION] Table 1), and discontinuation of the drug is recommended if adverse reactions persist.
Hyperlipidemia Anrotinib caused elevated triglycerides and cholesterol in the ALTER0303 study, and patients with hyperlipidemia are advised to adjust to a low-fat diet. grade 2 or higher hypercholesterolemia (≥7.75 mmol/L), or grade 2 or higher hypertriglyceridemia (≥2.5 x upper limit of normal), should be treated with hydroxymethylglutaryl coenzyme A (HMG-CoA) Reducing enzyme inhibitor (atorvastatin, etc.) lipid-lowering medication.
Seizures Three patients (1.02%) on anlotinib in the ALTER0303 clinical trial developed seizures (all of these patients had brain metastases at baseline). It is uncertain whether this product can cause seizures or increase the risk of seizures and should be used with caution in patients with a prior history of seizures.
Reversible posterior leukoencephalopathy syndrome (RPLS) Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in tumors treated with VEGFR inhibitors and is potentially fatal.RPLS is a neurological disorder that may be accompanied by headache, seizures, drowsiness, confusion, blindness, and other visual and neurological deficits. It may be accompanied by mild to severe hypertension. The best identified diagnostic method for RPLS is MRI. No such events have been reported in the anrotinib studies. During actual use, the associated signs and symptoms should be monitored closely and patients who develop RPLS should be permanently discontinued.
Delayed Wound Healing Slow wound healing has been reported in tumors treated with VEGFR inhibitors. No complications of delayed wound healing were observed in patients treated with anlotinib in clinical studies. Patients undergoing major surgical procedures are advised to withhold dosing to prevent this phenomenon. There is limited clinical experience regarding when to initiate treatment after major surgery. Therefore, reintroduction should be left to the discretion of the clinician depending on the degree of recovery of the patient following major surgery.
For Pregnant and Lactating Women
Pregnant women
There are no studies of anlotinib in women during pregnancy. Animal studies have shown reproductive toxicity including teratogenicity, and it is speculated that Anrotinib may inhibit fetal angiogenesis.
Women of childbearing potential should use effective contraception during and for at least 6 months after treatment with this product.
It is contraindicated in women during pregnancy. If pregnancy is detected during use, discontinuation of the product and consultation with an obstetrician/gynecologist is recommended.
Lactating women
There is no information on the use of Anrotinib in women who are breastfeeding. It is not known that this product and/or its metabolites can be secreted into human breast milk. Because many drugs can be secreted into human breast milk and because of the potential for serious adverse effects on the breastfed child, anrotinib hydrochloride is contraindicated in nursing women.
Pediatric Use
There is no information on the safety and efficacy of anlotinib in patients under 18 years of age.
Geriatric Use
In the ALTER0303 study, 19.2% (84/437) of elderly patients were 65 years of age or older. There was no significant difference in the safety and efficacy of treatment with anlotinib in patients 65 years of age or older compared to patients 65 years of age or younger. No dose adjustment according to the patient’s age (65 years or older) is required.
[Drug Interactions].
No formal drug interaction studies have been conducted with this product.
Effects of CYP1A2 and CYP3A4/5 inducers and inhibitors on Anrotinib
Anrotinib is mainly metabolized by CYP1A2 and CYP3A4/5.
CYP3A4/5 inducers (rifampicin, rifabutin, rifapentine, dexamethasone, phenytoin, carbamazepine or phenobarbital, etc.), and CYP1A2 inducers (montelukast, omeprazole, morethizine, etc.) may accelerate the metabolism of anlotinib and decrease the plasma concentration of anlotinib.
Strong inhibitors of CYP3A4/5 (ketoconazole, itraconazole, clarithromycin, voriconazole, telithromycin, saquinavir, ritoprevir, etc.), and strong inhibitors of CYP1A2 (ciprofloxacin, enoxacin, and fluvoxamine), may slow down the metabolism of anlotinib and increase the plasma concentration of anlotinib.
Combination with inhibitors and inducers of CYP1A2 and CYP3A4 is recommended to be avoided.
Effects of Anrotinib on other drugs
Anrotinib has a moderately strong inhibitory effect (IC50 in the range of 1-10µM) on CYP3A4, CYP2B6, CYP2C8, CYP2C9 and CYP2C19, with no significant induction effect on CYP1A2, CYP2B6 and CYP3A4. Concomitant application of Anrotinib with drugs of narrow therapeutic range metabolized by these enzymes, such as alfentanil and ergotamine metabolized by CYP3A4 and warfarin metabolized by CYP2C9, should be avoided.
[Drug overdose].
The recommended dose of this product is 12 mg once daily for 2 weeks with 1 week off, every 21 days. in the phase I tolerability study, 4 patients who were given 10 mg uninterruptedly, 2 developed grade 3 hypertension, and under the dosing regimen of 16 mg for 2 weeks with 1 week off, 3 patients developed 1 case of grade 3 hypertension and 1 case of grade 3 weakness. Therefore, anlotinib should be administered strictly in accordance with the dosing regimen of 2 weeks every 3 weeks with 1 week of discontinuation.
There is no antidote for anrotinib. If overdose is suspected, the drug should be discontinued immediately and the patient should be treated with appropriate symptomatic support.
[Clinical Trials].
Locally advanced/metastatic non-small cell lung cancer
The efficacy and safety of anlotinib alone in locally advanced/metastatic non-small cell lung cancer were evaluated in two randomized controlled clinical trials.
ALTER0303 is a multicenter, randomized, double-blind, placebo-parallel-controlled phase III clinical trial enrolling 437 patients with advanced/metastatic non-small cell lung cancer who had failed after at least two systems of chemotherapy (EGFR mutation and ALK-positive patients who had also progressed after treatment with appropriate targeted agents). The primary study endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and objective remission rate (ORR). Patients were randomized 2:1 into two groups: the trial group was given anlotinib 12 mg once daily for 2 weeks with 1 week of discontinuation (n=294); the control group was given placebo (n=143).
Of the 437 subjects, 55.6% were under 60 years of age; 65.2% were male; 20.1% had an ECOG score of 0 and 79.3% had a score of 1; 5.0% had stage IIIB and 94.5% had stage IV; 76.9% had adenocarcinoma, 19.7% had squamous or adenosquamous carcinoma, and 3.4% had other subtypes; 31.6% had EGFR mutations, 1.6% were ALK-positive, and 96.4% of patients with positive mutations received the corresponding targeted therapy; 52.9% received two systemic chemotherapy regimens and 43.0% received three or more systemic chemotherapy regimens; 41.9% had received prior radiation therapy. Baseline gender, age, stage, ECOG score, histological type, gene mutation status, and previous treatment history were comparable between the two groups. The median duration of treatment was 6 cycles in the anlotinib group and 2 cycles in the placebo group.
The study was analyzed for validity of the primary endpoint at the time of 292 survival events (66.82%). Median overall survival was 9.46 months (95% CI 8.05 to 10.45) in the anlotinib group and 6.37 months (95% CI 4.93 to 7.98) in the placebo group, with a prolonged median overall survival in the anlotinib group compared to the placebo group, with a risk ratio (HR) of 0.70, 95% CI 0.55 to 0.89, p = 0.002, and compared to placebo, anlotinib reduced the risk of death by 30%. The 1-year survival rate for patients treated with anlotinib was 39.53% compared to 27.79% in the placebo group. Key effectiveness data are shown in Table 4.
Table 4 Key effectiveness results of ALTER0303 (FAS)
Index Anlotinib group (n=294) Placebo group (n=143) Overall survival Median (mOS, months) 9.46 (8.05 to 10.45) 6.37 (4.93 to 7.98) HR (95% CI) 0.70 (0.55 to 0.89, p=0.002) Progression-free survival (PFS) Median (mPFS, months) 5.37 ( 4.40 to 5.63) 1.40 (1.07 to 1.50) HR (95% CI) 0.25 (0.19 to 0.31, p< 0.0001) Objective remission rate (CR+PR) 9.18% – Disease control rate (CR+PR+SD) 80.95% 37.06% Note: Based on 30.4 days per month.
FAS: full analysis set; mOS: median overall survival; mPFS: median progression-free survival; CR: complete remission; PR: partial remission; SD: stable disease.
Figure 1 Comparative analysis of the efficacy of survival (OS, months) in the two groups in the phase III clinical study (FAS set)
ALTER0302 was a multicenter, randomized, double-blind, placebo-parallel-controlled phase II clinical study enrolling patients with advanced (stage IIIB/IV) non-small cell lung cancer who had received treatment at third line and above or were intolerant to treatment. Patients were randomized 1:1 to receive either anlotinib (n=60) or placebo (n=57), with anlotinib administered in the same manner and at the same dose as ALTER0303. The primary efficacy measure was progression-free survival (PFS), with median progression-free survival of 4.83 months (95% CI 3.47 to 6.40) and 1.23 months (95% CI 0.70 to 1.60), HR=0.32 (95% CI 0.20 to 0.51), p<0.0001. Table 5 presents the primary effectiveness data of the study.
Table 5 Key effectiveness results of ALTER0302
Index Anrotinib group (n=60) Placebo group (n=57) Progression-free survival (PFS) Median (mPFS, months) 4.83 (3.47 to 6.40) 1.23 (0.70 to 1.60) HR (95% CI) 0.32 (0.20 to 0.51, p<0.0001) Overall survival (OS) Median (mOS, months) 9.33 (6.80 to 15.07) 6.30 (4.27 to 10.53) HR (95% CI) 0.78 (0.51 to 1.18, p = 0.2316) Objective remission rate (CR+PR) 10.00% 0.00% Disease control rate (CR+PR+SD) 83.33% 31.58% Note: Based on 30.0 days per month.
FAS: full analysis set; mOS: median overall survival; mPFS: median progression-free survival; CR: complete remission; PR: partial remission; SD: stable disease.
Subgroup analysis based on EGFR gene mutation status.
In the ALTER0303 study, 31.6% (138/437) of patients were EGFR mutation positive, and OS benefit was observed in both positive and negative patients. Consistent benefit trends were also observed in the EGFR mutation-positive (21 patients) and negative or unknown status subgroups (96 patients) in the ALTER0302 study, and data from the subgroup analysis of patients with EGFR mutations in the ALTER0303 trial are presented in Table 6.
Table 6 Analysis of EGFR mutation subgroups in the ALTER0303 study
Gene status group Number of cases (n) mOS (m) p-value HR (95% CI) EGFR (-) Anrotinib 201 8.75 p = 0.0290.73
(0.55 to 0.97) Placebo98 6.38 EGFR(+) Anrotinib93 10.56 p =0.0240.59
(0.37 to 0.93) Placebo45 6.18 Note: Based on 30.4 days per month.
T790M resistance mutations were not tested in the ALTER0303 study in EGFR mutation-positive patients who progressed after receiving prior targeted drug therapy, and further studies are needed to confirm the benefit for T790M-positive patients. Studies of anlotinib in this population are ongoing.
Pharmacology and Toxicology]
Pharmacological effects
Anlotinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor. The kinase inhibition assay showed that anlotinib inhibited the kinase activity of VEGFR1 (IC50 26.9 nM), VEGFR2 (IC50 0.2 nM), VEGFR3 (IC50 0.7 nM), c-Kit (IC50 14.8 nM), and PDGFRβ (IC50 115 nM).
In vitro assays showed that anlotinib inhibited the proliferation of various tumor cell lines (786-Q, A375, A549, Caki-1, U87MG, MDA-MB-231, HT-29, NCI-H526, HMC-1) with IC50 ranging from 3.0 to 12.5 μM; in HUVECs cells it significantly inhibited the VEGFR2 Phosphorylation of VEGFR2 and downstream related proteins in HUVECs, c-Kit and downstream related proteins in Mo7e cells, PDGFR and downstream related proteins in U87MG cells, proliferation, migration and tubule formation in VEGF-A stimulated HUVECs, and the formation of rat arterial inhibited the formation of annular microvascular-like structures in rat arteries.
Toxicological studies
General toxicology: SD rats were administered orally 0.2, 0.8 and 3.0 mg/kg for 26 weeks, and the no adverse effect dose (NOAEL) was 0.8 mg/kg, which was approximately 0.65 times the clinical dose (12 mg/person) based on body surface area; significant toxicity was observed at 3.0 mg/kg, and the toxic target organs were teeth and kidneys. In Beagle dogs given orally for 39 weeks at 0.02, 0.08 and 0.32 mg/kg, with 6 weeks of recovery from discontinuation, the NOAEL was <0.02 mg/kg, approximately 0.05 times the clinical dose (12 mg/person) on a body surface area basis, with small artery/microarteritis and its secondary changes as the major toxic effects.
Genotoxicity: The results of the Ames test for anlotinib, the Chinese hamster lung fibroblast (CHL) chromosomal aberration test, and the mouse bone marrow micronucleus test were all negative.
Reproductive toxicity: In the fertility and early embryonic development toxicity test, oral administration of anlotinib at 0.25, 1.0 and 4.0 mg/kg in rats resulted in a decrease in the volume of bilateral epididymis (1/24), slight to mild prostate atrophy (10/24) and slight to moderate seminal vesicle gland atrophy (13/24) in males; in females, a decrease in the number of corpus luteum, number of glandular implantation, pregnancy rate, conception rate, placenta, uterus In female rats, decreased weight or coefficients of ovaries, atrophy of uterine glands, corpus luteum of pregnancy and luteal cysts, increased number of absorbed fetuses, pre/post-implantation/total loss rate, and decreased number of live fetuses were observed. The NOAEL for this test was 1 mg/kg (approximately 0.8 times the clinical dose of 12 mg/person based on body surface area).
In the embryo-fetus developmental toxicity test, oral administration of anlotinib 0.3, 0.6 and 1.8 mg/kg to pregnant rats showed reduced live placental weight, increased early fetal resorption, increased loss after implantation, reduced gestational uterine weight, small individual fetal development, and a significant increase in the number of malformed fetuses and the number of litters in which malformations occurred (179/200, 22/22 litters), with the main malformations manifested as edema The main malformations were edema, short tail or no tail, curly tail, increased incidence of ventricular enlargement in fetuses, reduced ossification points of caudal vertebrae, sternal stalk, glabella, metacarpals and proximal phalanges, increased incidence of sternal, cranial, lumbar and thoracic vertebral hypoplasia in fetuses, and increased incidence of rib malformation. The NOAEL for this test was <0.3 mg/kg (approximately 0.25 times the clinical dose of 12 mg/person based on body surface area).
Pregnant rabbits given orally with anrotinib 0.15, 0.3, 0.9 mg/kg showed decreased gestational uterus, placental uterus, placental weight and uterine and ovarian organ weights/factors, decreased number of corpus luteum, number of implanted glands, pregnancy rate, increased percentage of pregnant rabbits with resorbed fetuses, decreased number of live fetuses, increased number of resorbed fetuses, increased loss rate, retarded fetal development (decreased weight, decreased number/degree of skeletal ossification), and The rate of appearance, visceral and skeletal variability or malformation was increased. The NOAEL in this test was <0.15 mg/kg (approximately 0.25 times the clinical dose of 12 mg/person based on body surface area).
In the perinatal reproductive toxicity test, rats were given orally 0.3, 0.6 and 1.8 mg/kg of anlotinib, which showed an increase in the number of absorbed fetuses, the number of stillbirths, the percentage of pregnant rats with stillbirths, and a decrease in body weight, food intake and pregnancy rate; and a decrease in the birth survival rate, nursing survival rate and body weight of offspring rats. The NOAEL for parental female rats and F1 generation rats was 0.6 mg/kg (approximately 0.5 times the clinical dose of 12 mg/person, based on body surface area). Anrotinib can be secreted into breast milk, and its concentration in breast milk is about 30~50% of the blood concentration.
Carcinogenicity: Anrotinib has not been studied for carcinogenicity.
[Pharmacokinetics].
Absorption.
In 12 healthy subjects who took 5mg of Anrotinib capsules orally on an empty stomach, the average peak time of Anrotinib plasma concentration was 9.3 hours, and the elimination in vivo was slow with an average elimination half-life of 113 hours. A high-fat diet reduces the oral bioavailability of Anrotinib Hydrochloride Capsules, and the total in vivo exposure of Anrotinib when taken concomitantly with high-fat foods is approximately 80% of that given on an empty stomach. The effect of a low-to-moderate fat diet on the bioavailability of this product is unknown.
In 19 patients with solid tumors, the mean time to peak plasma concentration of the prodrug was approximately 6-11 h after a single fasting oral dose of 10, 12, and 16 mg of anlotinib capsules; the mean elimination half-life was 95-116 h. In vivo exposure levels of anlotinib were positively correlated with the administered dose in the 10-16 mg dose range, but the linear relationship was uncertain. No significant gender differences were observed. 15 patients with solid tumors were dosed with a 12 mg dose once daily for 2 weeks with 1 week off for one dosing cycle, and plasma drug concentrations of the prodrug in the subjects peaked after the 14th day of continuous dosing. After the first cycle of 14 days of dosing, the plasma drug concentration of anlotinib reached 21.1~121 ng/mL, and decreased to 5.05~28.5 ng/mL after one week of discontinuation; after the second cycle of 14 days of dosing, the plasma drug concentration of anlotinib reached 22.1~101 ng/mL. concentrations did not show significant changes.
Distribution.
The mean apparent volume of distribution was 2061~3312 L after a single fasting oral dose of 12 mg and 16 mg Anrotinib hydrochloride capsules in subjects with advanced tumors. 93% Anrotinib human plasma protein binding was measured by equilibrium dialysis (in vitro), with no concentration dependence in the range of 300~1200 ng/mL.
Metabolism.
Anrotinib is primarily metabolized by CYP1A2 and CYP3A4/5, and to a lesser extent by CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6; Anrotinib is not a substrate for P-glycoprotein.
Excretion.
In a human trial of 14C-labeled anrotinib substance balance, cumulative excretion of anrotinib and its major metabolites via feces and urine was detected in oncology patient subjects after a single oral dose of 12 mg anrotinib hydrochloride capsules for 2648 hours (110 days) at approximately 62.04% of the dose administered, with excretion via feces at 48.52% of the dose and excretion via urine at 13.52% of the dose.
Special Populations
No pharmacokinetic studies have been conducted in special populations such as those with hepatic or renal insufficiency.
Storage】Store under 25℃ under light and airtight.
Packaging
Polyamide/aluminum/polyvinyl chloride cold pressed solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.
7 capsules/plate, 14 capsules/plate; 1 plate/box, 2 plates/box, 4 plates/box or 8 plates/box.
Effective period】18 months
Execution Standard
Approval number】
【Manufacturing Company】 【Approval Number
Company Name: Zhengda Tianqing Pharmaceutical Group Co.
Production Address: No. 8 North Julong Road, Lianyungang City, Jiangsu Province
Postal Code: 2226
Telephone number: 0518-85804002
Fax number: 0518-85806524
Web address: http://www.cttq.com