| Important Precautions | Precaution on Special Populations (N/A) | Precaution Concerning Dosage & Administration (N/A) | Precaution Concerning Use (N/A) |
Important Precautions
Hypertension
Hypertension has been reported in patients treated with lenvatinib. The median time to onset was 16 days in the Thyroid Cancer Study, 34 days in the RCC Study and 26 days in the HCC Study.
Blood pressure should be well controlled prior to treatment with lenvatinib. The early detection and effective management of hypertension are important to minimize the need for lenvatinib dose interruptions and reductions. Serious complications of poorly controlled hypertension, including aortic dissection, have been reported. Blood pressure should be monitored after 1 week of treatment with lenvatinib, then every 2 weeks for the first 2 months and monthly thereafter while on treatment. If a patient develops systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg active management is indicated (see Table 2).
| Table 2 Recommended Management of Hypertension | |
| Blood Pressure Level | Recommended Action |
| Systolic BP ≥140 mmHg up to 160 mmHg or diastolic BP ≥90 mmHg up to 100 mmHg |
Continue lenvatinib and initiate antihypertensive therapy, if not already receiving OR Continue lenvatinib and increase the dose of the current antihypertensive therapy or initiate additional antihypertensive therapy |
| Systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg despite optimal antihypertensive therapy |
1. Withhold lenvatinib 2. When systolic BP ≤150 mmHg, diastolic BP ≤95 mmHg, and patient has been on a stable dose of antihypertensive therapy for at least 48 hours, resume lenvatinib at a reduced dose. |
| Life-threatening consequences (malignant hypertension, neurological deficit, or hypertensive crisis) |
Urgent intervention is indicated. Discontinue lenvatinib and institute appropriate medical management |
Proteinuria
Proteinuria has been reported in patients treated with lenvatinib (see Section 4.8). Monitor urine protein regularly. If urine dipstick proteinuria ≥2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary (see Section 4.2). Discontinue in the event of nephrotic syndrome.
Renal Failure and Impairment/Gastrointestinal toxicity
Renal impairment (including renal failure) has been reported in patients treated with lenvatinib. The primary risk factor identified was dehydration/hypovolemia due to gastrointestinal toxicity. Gastrointestinal toxicity should be actively managed in order to reduce the risk of development of renal impairment or renal failure. Dose interruptions, adjustments, or discontinuation may be necessary.
Cardiac Failure
Cardiac failure and decreased left ventricular ejection fraction have been reported in patients treated with Lenvatinib.
Patients should be monitored for clinical symptoms or signs of cardiac decompensation, as dose interruptions, adjustments, or discontinuation may be necessary.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
Events of reversible posterior leukoencephalopathy syndrome (RPLS) also known as posterior reversible encephalopathy syndrome (PRES) have been reported (<1%) in patients treated with lenvatinib. RPLS is a neurological disorder that can present with headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or neurological disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Appropriate measures should be taken to control blood pressure (see Table 2). In patients with signs or symptoms of RPLS, dose interruptions, adjustments, or discontinuation may be necessary.
Hepatotoxicity
In Thyroid cancer and RCC liver-related adverse reactions most commonly reported in patients treated with lenvatinib included increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood bilirubin (see Section 4.8). Hepatic failure and acute hepatitis (<1%) have been reported in patients with Thyroid cancer and RCC treated with lenvatinib. The hepatic failure events were generally reported in patients with progressive metastatic liver disease.
Liver-related adverse reactions including hepatic encephalopathy and hepatic failure (including fatal reactions) were reported at a higher frequency in lenvatinib treated patients with HCC (see Table 7) than with Thyroid Cancer and RCC. Patients with worse hepatic impairment and/ or greater liver tumor burden at baseline had a higher risk of developing hepatic encephalopathy and hepatic failure. Hepatic encephalopathy also occurred more frequently in patients aged 75 years and older. Approximately half of the events of hepatic failure were reported in patients with disease progression.
Liver function tests should be monitored before initiation of treatment, then every 2 weeks for the first 2 months and monthly thereafter during treatment. Patients with HCC should be monitored for worsening liver function including hepatic encephalopathy. In the case of hepatotoxicity, dose interruptions, adjustments, or discontinuation may be necessary.
Hemorrhagic Events
Serious hemorrhagic events have been reported in patients treated with lenvatinib.
The most frequently reported hemorrhagic event was mild epistaxis. However, serious tumor related bleeds were reported, including fatal hemorrhagic events in lenvatinib-treated patients. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following Lenvatinib therapy.
In the case of bleeding, dose interruptions, adjustments, or discontinuation may be required.
Arterial Thromboembolic Events (ATEs)
Arterial thromboembolic events have been reported in patients treated with lenvatinib.
Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.
Fistula Formation and Gastrointestinal Perforation
Events of fistula formation or gastrointestinal perforation and their sequelae have been reported in patients treated with lenvatinib (see Section 4.8). Fistulas (e.g. gastrointestinal, bronchopleural, tracheooesophageal, oesophageal, cutaneous, pharyngeal, female genital tract fistula) have been reported In lenvatinib clinical trials and in post-marketing experience. In addition, pneumothorax has been reported with and without clear evidence of a bronchopleural fistula. Some reports of gastrointestinal perforation, fistula and pneumothorax occurred in association with tumor regression or necrosis. In most cases of fistula formation or gastrointestinal perforation, risk factors such as prior surgery or radiotherapy were present. In the case of fistula formation or gastrointestinal perforation, dose interruptions, adjustments, or discontinuation may be required.
QT Interval Prolongation
The effect of a single 32 mg dose of lenvatinib on the QT/QTc interval was evaluated in a thorough QT study in healthy subjects. In this study lenvatinib did not prolong the QT/QTc interval. QT/QTc interval prolongation has been reported at a higher rate in patients treated with lenvatinib. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, and drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics.
Monitor and correct electrolyte abnormalities in all patients.
Hypocalcaemia
Hypocalcaemia has been reported in patients treated with lenvatinib. Monitor blood calcium levels periodically and replace calcium as necessary during lenvatinib treatment. Interrupt and adjust lenvatinib dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia.
Thyroid Dysfunction and Impairment of Thyroid Stimulating Hormone Suppression
Hypothyroidism has been reported in patients treated with lenvatinib. Thyroid function, T3, T4 and TSH should be monitored before initiation of, and periodically throughout treatment with lenvatinib. Hypothyroidism should be treated according to standard medical practice to maintain euthyroid state.
Wound Healing Complications
No formal studies of the effect of lenvatinib on wound healing have been conducted. Impaired wound healing has been reported in patients receiving lenvatinib. Temporary interruption of lenvatinib should be considered in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of lenvatinib following a major surgical procedure. Therefore, the decision to resume lenvatinib following a major surgical procedure should be based on clinical judgment of adequate wound healing.
Osteonecrosis of the Jaw (ONJ)
Events of osteonecrosis of the jaw (ONJ) have been observed with lenvatinib. Invasive dental procedures are an identified risk factor for the development of ONJ. An oral dental examination and appropriate preventive dentistry should be considered prior to initiation of lenvatinib. Patients should be advised regarding periodic dental examinations and oral hygiene practice during Lenvatinib therapy. Avoid invasive dental procedures during lenvatinib treatment, if possible. Use caution in patients receiving agents associated with ONJ, such as bisphosphonates and denosumab.
Effects on Ability to Drive and Use Machines
No studies on the effects on the ability to drive and use machines have been performed.