Bdfoie 4/Bdfoie 10 Adverse Reactions

Summary of the safety profile: The safety profile of Lenvatinib is based on data from 452 DTC patients and 496 HCC patients; allowing characterization only of common adverse drug reactions in DTC and HCC patients. The adverse reactions presented in this section are based on safety data of both DTC and HCC patients.
DTC: The most frequently reported adverse reactions (occurring in ≥30% of patients) are hypertension (68.6%), diarrhea (62.8%), decreased appetite (51.5%), decreased weight (49.1%), fatigue (45.8%), nausea (44.5%), proteinuria (36.9%), stomatitis (35.8%), vomiting (34.5%), dysphonia (34.1%), headache (34.1%), and palmar-plantar erythrodysesthesia syndrome (PPE) (32.7%). Hypertension and proteinuria tend to occur early during Lenvatinib treatment. The majority of Grade 3 to 4 adverse reactions occurred during the first 6 months of treatment except for diarrhea, which occurred throughout treatment, and weight loss, which tended to be cumulative over time.
The most important serious adverse reactions were renal failure and impairment (2.4%), arterial thromboembolisms (3.9%), cardiac failure (0.7%), intracranial tumour hemorrhage (0.7%), PRES/RPLS (0.2%), hepatic failure (0.2%), and arterial thromboembolisms (cerebrovascular accident (1.1%), transient ischemic attack (0.7%), and myocardial infarction (0.9%).
In 452 patients with RAI-refractory DTC, dose reduction and discontinuation were the actions taken for an adverse reaction in 63.1% and 19.5% of patients, respectively. Adverse reactions that most commonly led to dose reductions (in ≥5% of patients) were hypertension, proteinuria, diarrhea, fatigue, PPE, decreased weight, and decreased appetite. Adverse reactions that most commonly led to discontinuation of Lenvatinib were proteinuria, asthenia, hypertension, cerebrovascular accident, diarrhea, and pulmonary embolism.
HCC: The most frequently reported adverse reactions (occurring in ≥30% of patients) are hypertension (44.0%), diarrhea (38.1%), decreased appetite (34.9%), fatigue (30.6%), and decreased weight (30.4%).
The most important serious adverse reactions were hepatic failure (2.8%), hepatic encephalopathy (4.6%), esophageal varices hemorrhage (1.4%), cerebral hemorrhage (0.6%), arterial thromboembolic events (2.0%) including myocardial infarction (0.8%), cerebral infarction (0.4%) and cerebrovascular accident (0.4%) and renal failure/impairment events (1.4%). There was a higher incidence of decreased neutrophil count in patients with HCC (8.7% on Lenvatinib than in other non-HCC tumour types (1.4%)), which was not associated with infection, sepsis or bacterial peritonitis.
In 496 patients with HCC, dose modification (interruption or reduction) and discontinuation were the actions taken for an adverse reaction in 62.3% and 20.2% of patients, respectively. Adverse reactions that most commonly led to dose modifications (in ≥5% of patients) were decreased appetite, diarrhea, proteinuria, hypertension, fatigue, PPE and decreased platelet count. Adverse reactions that most commonly led to discontinuation of Lenvatinib were hepatic encephalopathy, fatigue, increased blood bilirubin, proteinuria and hepatic failure.
EC: The safety of lenvatinib in combination with pembrolizumab has been evaluated in 530 patients with advanced EC receiving 20 mg lenvatinib once daily and 200 mg pembrolizumab every 3 weeks. The most common (occurring in ≥20% of patients) adverse reactions were hypertension (63%), diarrhea (57%), hypothyroidism (56%), nausea (51%), decreased appetite (47%), vomiting (39%), fatigue (38%), decreased weight (35%), arthralgia (33%), proteinuria (29%), constipation (27%), headache (27%), urinary tract infection (27%), dysphonia (25%), abdominal pain (23%), asthenia (23%), palmar-plantar erythrodysesthesia syndrome (23%), stomatitis (23%), anemia (22%), and hypomagnesemia (20%). The most common (occurring in ≥5% of patients) severe (Grade ≥3) adverse reactions were hypertension (37.2%), decreased weight (9.1%), diarrhea (8.1%), increased lipase (7.7%), decreased appetite (6.4%), asthenia (6%), fatigue (6%), hypokalemia (5.7%), anemia (5.3%) and proteinuria (5.1%).
Discontinuation of lenvatinib occurred in 30.6% of patients, and discontinuation of both lenvatinib and pembrolizumab occurred in 15.3% of patients due to an adverse reaction. The most common (occurring in ≥1% of patients) adverse reactions leading to discontinuation of lenvatinib were hypertension (1.9%), diarrhea (1.3%), asthenia (1.3%), decreased appetite (1.3%), proteinuria (1.3%) and decreased weight (1.1%).
Dose interruption of lenvatinib due to an adverse reaction occurred in 63.2% of patients. Dose interruption of lenvatinib and pembrolizumab due to an adverse reaction occurred in 34.3% of patients. The most common (occurring in ≥5% of patients) adverse reactions leading to interruption of lenvatinib were hypertension (12.6%), diarrhea (11.5%), proteinuria (7.2%), vomiting (7%), fatigue (5.7%), and decreased appetite (5.7%).
Dose reduction of lenvatinib due to adverse reactions occurred in 67.0% of patients. The most common (occurring in ≥5% of patients) adverse reactions resulting in dose reduction of lenvatinib were hypertension (16.2%), diarrhea (12.5%), palmar-plantar erythrodysesthesia syndrome (9.1%), fatigue (8.7%), proteinuria (7.7%), decreased appetite (6.6%), nausea (5.5%), asthenia (5.1%), and decreased weight (5.1%).
Tabulated list of adverse reactions: Similar adverse reactions were observed in clinical trials in DTC and HCC.
Adverse reactions observed in clinical trials in DTC and HCC and reported from post-marketing use of Lenvatinib are listed in Table 6. The adverse reaction frequency category represents the most conservative estimate of frequency from the two individual populations.
Frequencies are defined as: Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Not known (cannot be estimated from the available data).
Within each frequency category, undesirable effects are presented in order of decreasing seriousness. (See Table 6.)

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