Formulation and Specifications: Capsules: 8mg, 10mg, 12mg
Indications: For the treatment of patients with adenoidal soft tissue sarcoma, clear cell sarcoma, and other advanced soft tissue sarcomas that have progressed or recurred after at least one prior treatment with an anthracycline-containing chemotherapy regimen.
Key points for rational drug use:
1. The recommended dose of anlotinib is 12 mg orally once daily before breakfast. Take the drug continuously for 2 weeks and stop for 1 week, i.e. 3 weeks (21 days) as a treatment cycle 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 to the next dose is confirmed to be shorter than 12 hours.
2. Adverse reactions due to Anrotinib may be managed by symptomatic treatment, suspension of dosing and/or dose adjustment. Depending on the degree of adverse reactions, dose adjustment is recommended as follows: (1) First dose adjustment: 10 mg once daily for 2 weeks with 1 week of discontinuation. (2) Second dose adjustment: 8mg once daily for 2 weeks and 1 week off. If the 8mg dose is still not tolerated, the drug will be discontinued permanently. In the event of a non-hemorrhagic adverse reaction, refer to the general principles in Table 8 for dose adjustment.
Table 8 General Principles of Dose Adjustment for Anrotinib According to Adverse Reaction Class
| Duration of administration | Dose adjustment principles | |
| Level 3 | Suspend dosing until adverse reactions return to | Continue dosing after one dose down; consider permanent discontinuation if recovery does not occur after 2 weeks |
|
Suspend medication until adverse reactions return to | Continue dosing after one dose reduction; consider permanent discontinuation if recovery does not occur after 2 weeks; or consider permanent discontinuation based on physician’s judgment |
|
NCI CTCAE 5.0: National Cancer Institute Common Toxic Drug Reaction Classification Criteria Version 5.0
If a grade 2 bleeding event occurs, the drug should be suspended and continued at a lower dose if it returns to a grade 2 level within 2 weeks; if it occurs again, permanent discontinuation should be considered. Once a grade 3 or higher bleeding event occurs, discontinue the drug permanently. Refer to Table 9 for dose adjustment when adverse events of bleeding occur.
Table 9 Dose Adjustment Principles for Anlotinib When Bleeding Adverse Reactions Occur Dose Adjustment for Anlotinib
| Hemorrhagic events* | Dose adjustment principles |
| Level 2 | Suspension of medication and aggressive symptomatic management; if recovery to |
| Grade ≥3 | Permanent discontinuation with emergency medical intervention |
*Hemorrhagic adverse reactions include: hemoptysis, gastrointestinal bleeding, rhinorrhea, bronchial bleeding, gingival bleeding, carnal hematuria, fecal occult blood, and cerebral hemorrhage.
Patients with any bleeding event ≥ CTCAE grade 3 within 4 weeks prior to dosing, the presence of unhealed wounds, ulcers or fractures and arterial/venous thrombotic events such as cerebrovascular accidents (including transient ischemic attacks), deep vein thrombosis and pulmonary embolism within 6 months should be dosed under the direction of a physician, and prothrombin time and INR values should be monitored every 1 to 2 weeks in patients co-administering warfarin and clinical The patient should be monitored every 1 to 2 weeks for prothrombin time and INR values and clinical signs of bleeding.
Hypertension is the most common adverse effect of Anrotinib and should be monitored closely during the drug administration. Hypertension mostly occurs within 2 weeks after the start of the drug, and can be controlled by diuretics, β-blockers and calcium channel antagonists, and other conventional hypotensive drugs. Blood pressure should be monitored daily for the first 6 weeks after starting the medication, and 2 to 3 times a week during the subsequent medication period. If elevated blood pressure or headache and dizziness symptoms are detected, you should actively communicate with your physician and receive antihypertensive medication under the guidance of your physician, suspend Anrotinib treatment or dose adjustment. When grade 3 to 4 hypertension (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg) occurs, medication should be suspended; if grade 3 to 4 hypertension occurs again after resuming medication, medication should be continued after downward adjustment of one dose. If grade 3 to 4 hypertension persists, discontinuation of the drug is recommended. Patients who develop hypertensive crisis should stop the drug immediately and receive cardiovascular specialist treatment.
Anrotinib may prolong the QTc interval, which can lead to ventricular tachyarrhythmias (e.g., tip-twisting ventricular tachycardia) and an increased risk of death. Patients with congenital long QTc interval syndrome should avoid the drug. Patients with congestive heart failure, blood electrolyte abnormalities, or on drugs known to prolong the QTc interval should receive periodic (every 3 to 6 weeks) electrocardiogram and blood electrolyte testing. Patients with QTc intervals >500ms on two consecutive independent ECG tests should have their medication suspended until the QTc interval is ≤480ms or until it falls to baseline levels (when the baseline QTc interval is >480ms), the medication should be adjusted downward by one dose. Patients with QTc interval prolongation of any grade (≥450ms) with tip-twist ventricular tachycardia, polymorphic ventricular tachycardia, or severe arrhythmias should be permanently discontinued and promptly seen by a cardiovascular specialist.
6. Patients with abnormal underlying cardiac function should have cardiac function tests every 6 weeks. Patients with grade III-IV cardiac insufficiency or cardiac ultrasound showing left ventricular ejection fraction <50% should discontinue the drug.
7. There is a risk of spontaneous pneumothorax in tumor patients with regressed lung and subpleural lesions. Sudden onset of symptoms such as chest pain or dyspnea during or after treatment with Anrotinib should be sought immediately, and closed chest drainage or other medical intervention should be performed after confirmation of pneumothorax.
8. Anrotinib may cause an increase in transaminases or total bilirubin. It should be used with caution in patients with mild to moderate hepatic impairment and is contraindicated in patients with severe hepatic impairment. Aminotransferases and bilirubin should be monitored while taking anlotinib. It is recommended that liver function (ALT, AST, bilirubin) be tested prior to the start of treatment, at each treatment cycle, and as clinically indicated. When grade 2 liver function abnormalities occur in patients, the frequency of testing should be increased. When grade 3-4 transaminases or total bilirubin elevation occurs in patients, the drug should be suspended, while transaminases and total bilirubin should be tested 2 to 3 times a week, and the drug can be continued at a lower dose after recovery to
10. Baseline thyroid function testing is recommended before the start of anlotinib treatment. During treatment, all patients should be closely observed for signs and symptoms of hypothyroidism, and laboratory monitoring of thyroid function should be performed regularly to standardize treatment for patients with hypothyroidism.
11. Anrotinib can cause diarrhea. Take care to assess for dehydration or electrolyte imbalance and consider intravenous rehydration and treatment with loperamide, probiotics and montelukast if necessary. Prophylactic antibiotic therapy with growth inhibitors may also be considered in severe cases. In patients with severe or persistent diarrhea or even dehydration, other causes of diarrhea need to be identified (intestinal flora disorders, immune deficiency, carcinoid syndrome, etc.), and measures may be taken to suspend the drug, adjust one dose downward until permanent discontinuation, and treat the patient aggressively according to the cause of diarrhea.
12. Oral pain, oral mucositis and toothache can occur with Anrotinib treatment. Patients with gum and mouth swelling and pain should keep the mouth clean, relieve pain, prevent multiple infections, and prevent further aggravation of oral mucositis. Symptomatic treatment with rinses or coatings containing lidocaine, sodium bicarbonate or chlorhexidine is recommended to promote oral mucosal healing. Pay attention to balanced nutrition and water intake, individualize diet, avoid hot and spicy food, avoid smoking and alcohol, prohibit alcohol-containing rinses, and visit a dental specialist if necessary. When gum and mouth swelling and pain occur, take measures to suspend the medication, adjust a dose downward until permanent discontinuation.
13. Hand-foot syndrome mostly appears within 2 weeks of anlotinib administration and is manifested as a combination of swelling, peeling, blistering, cracking, bleeding or erythema of the skin on the palmar area of the hands and feet, often accompanied by pain. 2 grade hand-foot syndrome patients should be treated symptomatically, including strengthening skin care, keeping the skin clean, avoiding secondary infection, avoiding pressure and friction; topical application of lotions or lubricants containing urea and glucocorticoids; topical application of lotions or lubricants containing urea and glucocorticoids in case of infection. or lubricants; topical treatment with antifungals or antibiotics in case of infection, which is recommended to be used under the guidance of a dermatologist. In case of Grade ≥3 hand-foot syndrome, continue the drug after adjusting the dose downward by one dose. If adverse reactions persist, the drug should be discontinued.
14. Patients presenting with hyperlipidemia are advised to adjust to a low-fat diet. Grade ≥2 hypercholesterolemia (≥7.75 mmol/L) or grade ≥2 hypertriglyceridemia (≥2.5 times ULN) should be treated with lipid-lowering drugs such as hydroxymethylglutaryl coenzyme A reductase inhibitors.
15. It is uncertain whether anlotinib can cause epilepsy or increase the risk of epilepsy and should be used with caution in patients with a prior history of epilepsy.
16. Reversible posterior leukoencephalopathy syndrome has been reported in tumors treated with VEGFR inhibitors and can be fatal. Such events have not been reported in studies of anlotinib. During actual use, signs and symptoms should be monitored closely and patients with reversible posterior leukoencephalopathy syndrome should be permanently discontinued.
17. Anrotinib may affect wound healing in patients. Patients preparing for surgical procedures are advised to withhold dosing to prevent delayed postoperative wound healing, and when to resume dosing after surgery is determined by the clinician on a patient-by-patient basis.
There is a lack of information on the safety and efficacy of anlotinib in patients under 18 years of age. No dose adjustment is required for the use of Anrotinib in elderly patients ≥65 years of age.
19. Women of childbearing potential should use effective contraception during and for at least 6 months after treatment with anlotinib, and it is contraindicated in women during pregnancy and lactation.
20. It is recommended that anlotinib be avoided in combination with strong inhibitors of CYP1A2 and CYP3A4/5 and strong inducers.
*21. Anrotinib is recommended as a second-line treatment for advanced or unresectable soft tissue sarcoma and as a first-line treatment for advanced or unresectable adenoidal soft tissue sarcoma.