Lenvima Special Precautions

Hypertension: Hypertension has been reported in patients treated with lenvatinib (see Adverse Reactions). 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).

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Proteinuria: Proteinuria has been reported in patients treated with lenvatinib (see Adverse Reactions). Monitor urine protein regularly. If urine dipstick proteinuria ≥2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration). 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 (see Adverse Reactions). 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 (see Dosage & Administration).
Cardiac Failure: Cardiac failure and decreased left ventricular ejection fraction have been reported in patients treated with lenvatinib (see Adverse Reactions).
Patients should be monitored for clinical symptoms or signs of cardiac decompensation, as dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
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 (see Adverse Reactions). 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 as previously mentioned). In patients with signs or symptoms of RPLS, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
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 Adverse Reactions). 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 under Adverse Reactions) 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 (see Table 3 Thyroid Cancer, Table 4 RCC, Table 5 HCC and Table 6 EC under Dosage & Administration).
Hemorrhagic Events: Serious hemorrhagic events have been reported in patients treated with lenvatinib (see Adverse Reactions). 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 (see Dosage & Administration).
Arterial Thromboembolic Events (ATEs): Arterial thromboembolic events have been reported in patients treated with lenvatinib (see Adverse Reactions). 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 Adverse Reactions). Fistulas (e.g. gastrointestinal, bronchopleural, tracheo-oesophageal, 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 (see Dosage & Administration).
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 (see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions).
Hypocalcaemia: Hypocalcaemia has been reported in patients treated with lenvatinib (see Adverse Reactions). 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 (see Adverse Reactions).
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.