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Lenvima

Lenvima Adverse Reactions

lenvatinib

Manufacturer:

Eisai

Distributor:

DKSH
/
Agencia Lei Va Hong
Full Prescribing Info
Adverse Reactions
The following adverse reactions are discussed in Precautions: Hypertension; Cardiac Dysfunction; Arterial Thromboembolic Events; Hepatotoxicity; Renal Failure and Impairment; Proteinuria; Diarrhea; Fistula Formation and Gastrointestinal Perforation; QT Interval Prolongation; Hypocalcemia; Reversible Posterior Leukoencephalopathy Syndrome; Hemorrhagic Events; Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction; Impaired Wound Healing. (See Precautions.)
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data in Precautions reflect exposure to LENVIMA as a single agent in 261 patients with DTC (SELECT) and 476 patients with HCC (REFLECT), LENVIMA with pembrolizumab in 94 patients with endometrial carcinoma (Study 111), and LENVIMA with everolimus in 62 patients with RCC (Study 205). Safety data obtained in 1823 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize the risks of serious adverse reactions. Among the 1823 patients who received LENVIMA as a single agent, the median age was 61 years (20 to 89 years), the dose range was 0.2 mg to 32 mg daily, and the median duration of exposure was 5.6 months.
The data as follows reflect exposure to LENVIMA in 893 patients enrolled in randomized, active-controlled trials (REFLECT; Study 205), a randomized, placebo-controlled trial (SELECT) and a single arm trial (Study 111). The median duration of exposure to LENVIMA across these four studies ranged from 6 to 16 months. The demographic and exposure data for each clinical trial population are described in the subsections as follows.
Differentiated Thyroid Cancer: The safety of LENVIMA was evaluated in SELECT, in which patients with radioactive iodine-refractory differentiated thyroid cancer were randomized (2:1) to LENVIMA (n=261) or placebo (n=131) [see Pharmacology: Pharmacodynamics: Clinical Studies: Differentiated Thyroid Cancer under Actions]. The median treatment duration was 16.1 months for LENVIMA. Among 261 patients who received LENVIMA, median age was 64 years, 52% were females, 80% were White, 18% were Asian, and 2% were Black; and 4% were Hispanic/Latino.
The most common adverse reactions observed in LENVIMA-treated patients (≥30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).
Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA; 18% of patients discontinued LENVIMA for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).
Table 7 presents adverse reactions occurring at a higher rate in LENVIMA-treated patients than patients receiving placebo in the double-blind phase of the study. (See Table 7.)

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A clinically important adverse reaction occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of <5% was pulmonary embolism (3%, including fatal reports vs 2%, respectively).
Laboratory abnormalities with a difference of ≥ 2% in Grade 3 - 4 events and at a higher incidence in the LENVIMA arm are presented in Table 8. (See Table 8.)

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The following laboratory abnormalities (all Grades) occurred in >5% of LENVIMA-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia.
Renal Cell Carcinoma: The safety of LENVIMA was evaluated in Study 205, in which patients with unresectable advanced or metastatic renal cell carcinoma (RCC) were randomized (1:1:1) to LENVIMA 18 mg orally once daily with everolimus 5 mg orally once daily (n=51), LENVIMA 24 mg orally once daily (n=52), or everolimus 10 mg orally once daily (n=50) [see Pharmacology: Pharmacodynamics: Clinical Studies: Renal Cell Carcinoma under Actions]. This data also includes patients on the dose escalation portion of the study who received LENVIMA with everolimus (n=11). The median treatment duration was 8.1 months for LENVIMA with everolimus. Among 62 patients who received LENVIMA with everolimus, the median age was 61 years, 71% were men, and 98% were White.
The most common adverse reactions observed in the LENVIMA with everolimus-treated group (≥30%) were, in order of decreasing frequency, diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, hemorrhagic events, and proteinuria. The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%).
Adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA with everolimus. The most common adverse reactions (≥5%) resulting in dose reductions in the LENVIMA with everolimus-treated group were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%).
Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the LENVIMA with everolimus-treated group.
Table 9 presents the adverse reactions in >15% of patients in the LENVIMA with everolimus arm. Study 205 was not designed to demonstrate a statistically significant difference in adverse reaction rates for LENVIMA in combination with everolimus, as compared to everolimus for any specific adverse reaction listed in Table 9. (See Table 9.)

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In Table 10, Grade 3-4 laboratory abnormalities occurring in ≥3% of patients in the LENVIMA with everolimus arm are presented. (See Table 10.)

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Hepatocellular Carcinoma: The safety of LENVIMA was evaluated in REFLECT, which randomized (1:1) patients with unresectable hepatocellular carcinoma (HCC) to LENVIMA (n=476) or sorafenib (n=475) [see Pharmacology: Pharmacodynamics: Clinical Studies: Hepatocellular Carcinoma under Actions]. The dose of LENVIMA was 12 mg orally once daily for patients with a baseline body weight of ≥60 kg and 8 mg orally once daily for patients with a baseline body weight of <60 kg. The dose of sorafenib was 400 mg orally twice daily. Duration of treatment was ≥6 months in 49% and 32% of patients in the LENVIMA and sorafenib groups, respectively. Among the 476 patients who received LENVIMA in REFLECT, the median age was 63 years, 85% were men, 28% were White and 70% were Asian.
The most common adverse reactions observed in the LENVIMA-treated patients (≥20%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea.
The most common serious adverse reactions (≥2%) in LENVIMA-treated patients were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%).
Adverse reactions led to dose reduction or interruption in 62% of patients receiving LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%).
Treatment discontinuation due to adverse reactions occurred in 20% of patients in the LENVIMA-treated group. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).
Table 11 summarizes the adverse reactions that occurred in ≥10% of patients receiving LENVIMA in REFLECT. REFLECT was not designed to demonstrate a statistically significant reduction in adverse reaction rates for LENVIMA, as compared to sorafenib, for any specified adverse reaction listed in Table 11. (See Table 11.)

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In Table 12, Grade 3-4 laboratory abnormalities occurring in ≥2% of patients in the LENVIMA arm in REFLECT (HCC) are presented. (See Table 12.)

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Endometrial Carcinoma: The safety of LENVIMA (20 mg orally once daily) in combination with pembrolizumab (200 mg intravenously every 3 weeks) was evaluated in Study 111, a single-arm, multicenter, open-label trial in 94 patients with endometrial carcinoma whose tumors had progressed following one line of systemic therapy and were not MSI-H or dMMR [see Pharmacology: Pharmacodynamics: Clinical Studies: Endometrial Carcinoma (EC) under Actions]. The median duration of study treatment was 7 months (range: 0.03 to 37.8 months). Pembrolizumab was continued for a maximum of 24 months; however, treatment with LENVIMA could be continued beyond 24 months.
Fatal adverse reactions occurred in 3% of patients treated with LENVIMA and pembrolizumab, including gastrointestinal perforation, RPLS with intraventricular hemorrhage, and intracranial hemorrhage.
Serious adverse reactions occurred in 52% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in ≥3% of patients were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%).
Permanent discontinuation due to adverse reaction (Grade 1-4) occurred in 21% of patients who received LENVIMA and pembrolizumab. The most common adverse reactions (>2%) resulting in discontinuation of LENVIMA were gastrointestinal perforation or fistula (2%), muscular weakness (2%), and pancreatitis (2%).
Adverse reactions led to dose reduction or interruption in 88% of patients receiving LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were fatigue (32%), hypertension (26%), diarrhea (18%), nausea (13%), palmar-plantar erythrodysesthesia (13%), vomiting (13%), decreased appetite (12%), musculoskeletal pain (11%), stomatitis (9%), abdominal pain (7%), hemorrhages (7%), renal impairment (6%), decreased weight (6%), rash (5%), headache (5%), increased lipase (5%), and proteinuria (5%).
Table 13 presents the adverse reactions in ≥20% of patients with LENVIMA in combination with pembrolizumab. (See Table 13.)

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Table 14 presents, laboratory abnormalities in ≥20% (All Grades) or ≥3% (Grades 3-4) of patients with LENVIMA in combination with pembrolizumab. (See Table 14.)

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Postmarketing Experience: The following adverse reactions have been identified during post approval use of LENVIMA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal: pancreatitis, increased amylase.
General: impaired wound healing.
Hepatobiliary: cholecystitis.
Renal and Urinary: nephrotic syndrome.
Vascular: arterial (including aortic) aneurysms, dissections, and rupture.
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