Lenvatinib

Registered South African indications:

• Progressive, locally advanced or metastatic, radioactive iodine (RAI) refractory differentiated thyroid cancer (DTC)
• Advanced renal cell carcinoma (RCC) 
• Unresectable hepatocellular carcinoma (HCC)

Contraindications
South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Fistula(e), and/or at risk of developing fistula(e), such as after a major surgical procedure
• Severe and/or uncontrolled hypertension (BP≤150mmHg, diastolic BP≤95mmHg)
• Severe thrombocytopenia (<50x10³/µl) and/or active bleeding
• Due to undergo surgery or radiotherapy

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding

Cautions
South African manufacturer recommendations

• Pregnancy
• Women of childbearing potential and for ≥1 month after finishing treatment
• Breastfeeding
• Moderate (CrCl 30-59ml/min) to end-stage renal impairment (See additional prescribers points)
• Moderate to severe (Child-Pugh B or C) (for the indication of HCC)
• Severe hepatic impairment (Child-Pugh C) (for the indication of DTC and RCC)
• Greater hepatic tumour burden at baseline
• Dehydration and/or hypovolemia
• Cardiac failure within the previous 6 months
• Congenital long QT syndrome
• Congestive heart failure
• Bradydysrhythmias
• Progressive metastatic hepatic disease
• Arterial thromboembolic event within the previous 6 months
• Thrombocytopenia
• Pre-existing hypertension
• Prior surgery or radiotherapy
• Tumour regression or necrosis
• QT interval prolongation >500ms
• Electrolyte abnormalities
• Ethnic origin (See additional prescribers points) 
  -  Asian
• Undergoing major surgical procedure
• Presence of wounds
• Coadministration with agents known to prolong the QT interval, including Class Ia and III antiarrhythmics
• Coadministration with sorafenib or other anticancer treatments (See additional prescribers points)
• Coadministration with agents acting on the renin-angiotensin-aldosterone system
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Women of childbearing potential and for ≥1 month after finishing treatment
• Severe renal impairment 
• Moderate to severe hepatic impairment (Child-Pugh B or C) (for the indication of HCC)
• Severe hepatic impairment (Child-Pugh C) (for the indication of DTC and EC)
• Elderly 
• Greater hepatic tumour burden at baseline
• Pre-existing hypertension
• Congenital long QT syndrome
• Congestive heart failure
• Bradydysrhythmias
• Tumour regression or necrosis
• History of aneurysm
• Progressive metastatic hepatic metastases disease
• Dehydration and/or hypovolemia
• Prior surgery or radiotherapy
• Lung metastases
• Arterial thromboembolism within the previous 6 months
• QT interval prolongation >500ms
• Electrolyte abnormalities
• Invasive dental procedures
• Ethnic origin (See additional prescribers points) 
  -  Asian 
• Undergoing major surgical procedure
• Presence of wounds
• Eastern cooperative oncology group performance status (ECOG PS≥2)
• Coadministration with agents known to prolong the QT interval, including Class Ia and III antiarrhythmics
• Coadministration with or sequential use of sorafenib or other anticancer treatments (See additional prescribers points)
• Coadministration with or sequential use with antiresorptive therapy and/or other angiogenesis inhibitors (e.g. bevacizumab, TKI, mTOR inhibitors) (See additional prescribers points)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

 Lenvatinib treatment should be supervised by a healthcare provider experienced in the use of anticancer therapies

Used for the treatment of
Progressive, locally advanced or metastatic, radioactive iodine (RAI) refractory differentiated thyroid cancer (DTC)

• Oral (cap): 24mg (two 10mg caps and one 4mg cap), dly

Advanced renal cell carcinoma (Additional agent required) 
- Whose disease has progressed following one prior vascular endothelial growth factor targeted therapy

• Oral (cap): 18mg (one 10mg cap and two 4mg caps), dly

Unresectable hepatocellular carcinoma (HCC)

• Oral (cap):<60kg: 8mg (two 4mg caps), dly
• Oral (cap):≥60kg: 12mg (three 4mg caps), dly 

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Method of administration: See additional prescribing points 

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The daily dose is to be modified as needed according to the dose/toxicity management plan. Treatment should continue as long as there is clinical benefit or until unacceptable toxicity occurs

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Consult specialist for dosages and regimens (including dose modifications during the management of adverse reactions)

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International manufacturer recommendations

Lenvatinib treatment should be initiated and supervised by a healthcare professional experienced in the use of anticancer therapies

Used for the treatment of
Differentiated thyroid cancer (DTC)
- As monotherapy for the treatment of progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine (RAI)

• Oral (cap): 24mg (two 10mg caps and one 4mg cap), dly

Hepatocellular carcinoma (HCC)
- As monotherapy for the treatment of advanced or unresectable hepatocellular carcinoma (HCC) with no prior systemic therapy

• Oral (cap):<60kg 8mg (two 4mg caps), dly
• Oral (cap):≥60kg: 12mg (three 4mg caps), dly 

Endometrial carcinoma (EC) (Additional agent required)
- In combination with pembrolizumab for the treatment of advanced or recurrent endometrial carcinoma (EC) with disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery or radiation

• Oral (cap): 20mg (two 10mg caps), dly

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Optimal medical management (i.e., treatment or therapy) for nausea, vomiting, and diarrhoea should be initiated prior to any lenvatinib therapy interruption or dose reduction; gastrointestinal toxicity should be actively treated in order to reduce the risk of development of renal impairment or failure

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If a dose is missed, and it cannot be taken within 12 hours, then that dose should be skipped and the next dose should be taken at the usual time of administration

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Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs

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Method of administration: See additional prescribing points

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Consult specialist for dosages and regimens (including dose modifications during the management of adverse reactions)

Not established for use in children below 18 years

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Lenvatinib should not be used in children younger than 2 years of age because of safety concerns identified in animal studies. The safety and efficacy of lenvatinib in children aged 2 to <18 years have not yet been established (International manufacturer recommendations)

Pregnancy
South African manufacturer recommendations

• Caution; not recommended 
• Lenvatinib should not be used during pregnancy
• There is limited information on the use of lenvatinib in pregnant women
• Lenvatinib was embryotoxic and teratogenic when administered to rats and rabbits during organogenesis at exposures below the clinical exposure (based on body surface area) at the maximum recommended human dose. Foetal anomalies included parietal oedema, cryptophthalmia, abnormal tail (rats), retroesophageal subclavian artery, fused ribs, and vertebral abnormalities (rabbits). These embryofoetal findings are probably related to the pharmacologic activity of lenvatinib as an antiangiogenic medicine
• Women of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment with lenvatinib and for at least one month after finishing treatment. It is currently unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method

International manufacturer recommendations

• Caution; not recommended
• There are no data on the use of lenvatinib in pregnant women. Lenvatinib was embryotoxic and teratogenic when administered to rats and rabbits 
• Lenvatinib should not be used during pregnancy unless clearly necessary and after careful consideration of the needs of the mother and the risk to the foetus
• Women of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment with lenvatinib and for at least one month after finishing treatment. It is currently unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method

Breastfeeding
South African manufacturer recommendations

• Caution; not recommended 
• Lenvatinib should not be used during breastfeeding. It is not known whether lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in rat milk and neonatal rats were more sensitive to the toxicity of lenvatinib compared to adults

International manufacturer recommendations

• Contraindicated 
• It is not known whether lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in rat milk. A risk to newborns or infants cannot be excluded and, therefore, lenvatinib is contraindicated during breastfeeding

Fertility
South African manufacturer recommendations

• Effects in humans are unknown. However, testicular and ovarian toxicity has been observed in rats, dogs, and monkeys. No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility. However, testicular and ovarian changes were observed in repeated-dose toxicity studies in animals at exposures 11-15 times (rat) or 0,6 to 7 times (monkey) the anticipated clinical exposure (based on AUC) at the maximum tolerated human dose. These findings were reversible at the end of a 4-week recovery period

International manufacturer recommendations

• Effects in humans are unknown. However, testicular and ovarian toxicity has been observed in rats, dogs, and monkeys

Renal Impairment
South African manufacturer recommendations

• Mild (CrCl 60-89ml/min): No dose adjustment recommended
• Moderate: (CrCl 30-59ml/min): Caution; no dose adjustment recommended 
• Severe (CrCl<30ml/min): Caution; dose adjustment recommended 
  DTC: Oral (cap): 14mg (one 10mg cap and one 14mg cap), dly 
  RCC: Oral (cap): 10mg (one 10mg cap), dly (additional agent required) 
  Further dose adjustments may be necessary based on the individual tolerability
• End-stage: Caution; not recommended 

International manufacturer recommendations

• Mild or moderate: No dose adjustment recommended 
• Severe: Caution; dose adjustment recommended 
  DTC: Oral (cap): 14mg (one 10mg cap and one 14mg cap), dly
  Further dose adjustments may be necessary based on individual tolerability
  HCC: The available data do not allow for a dosing recommendation
  EC: Oral (cap): 10mg (one 10mg cap), dly
  Further dose adjustments may be necessary based on individual tolerability
• End-stage: Caution; not recommended 

Hepatic Impairment
South African manufacturer recommendations

DTC and RCC

• Mild to moderate (Child-Pugh A or B): No dose adjustment recommended 
• Severe (Child-Pugh C): Caution; dose adjustment recommended 
  DTC: Oral (cap): 14mg (one 10mg cap and one 14mg cap) , dly
  RCC: Oral (cap): 10mg (one 10mg cap), dly (additional agent required)
  Further dose adjustments may be necessary on the basis of individual tolerability

HCC

• Mild (Child-Pugh A): No dose adjustment recommended 
• Moderate (Child-Pugh B): Caution; no dose adjustment recommended 
  The available data do not allow for a dosing recommendation for patients with HCC and moderate hepatic impairment
• Severe: (Child-Pugh C): Caution; not recommended
  Lenvatinib has not been studied in patients with HCC and severe hepatic impairment (Child-Pugh C) and therefore the use of lenvatinib in these patients is not recommended

International manufacturer recommendations

DTC and EC

• Mild to moderate (Child-Pugh A or B): No dose adjustment recommended  
• Severe (Child-Pugh C): Caution; dose adjustment recommended 
  DTC: Oral (cap): 14mg (one 10mg cap and one 14mg cap), dly
  Further dose adjustments may be necessary on the basis of individual tolerability
  EC: Oral (cap): 10mg (one 10mg cap), dly (additional agent required)
  Further dose adjustments may be necessary on the basis of individual tolerability 

HCC

• Mild (Child-Pugh A): No dose adjustment recommended 
• Moderate (Child-Pugh B): Caution; no dose adjustment recommended 
  The available very limited data are not sufficient to allow for a dosing recommendation. Close monitoring of overall safety is recommended in these patients
• Severe (Child-Pugh C): Caution; not recommended
  Lenvatinib has not been studied in patients with severe hepatic impairment (Child-Pugh C) and is not recommended for use in these patients

Elderly
South African manufacturer recommendations

• No dose adjustment recommended 
  Limited data are available on the use in patients aged ≥75 years

International manufacturer recommendations

• Caution; no dose adjustment recommended 
  DTC: Patients of age ≥75 years were more likely to experience Grade 3 or 4 hypertension, proteinuria, decreased appetite, and dehydration
  HCC: Patients of age ≥75 years were more likely to experience hypertension, proteinuria, decreased appetite, asthenia, dehydration, dizziness, malaise, peripheral oedema, pruritus and hepatic encephalopathy. Hepatic encephalopathy occurred at more than twice the incidence in patients aged ≥75 years (17.2%) than in those <75 years (7.1%). Hepatic encephalopathy tended to be associated with adverse disease characteristics at baseline or with the use of concomitant medicinal products. Arterial thromboembolic events also occurred at an increased incidence in this age group
  EC: Patients of age ≥75 years were more likely to experience urinary tract infections and Grade ≥3 hypertension (≥10% increase compared to patients of age <65 years

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Dizziness
• Headache
• Dysgeusia
• Cerebrovascular accident
• Posterior reversible encephalopathy syndrome
• Monoparesis
• Transient ischaemic attack
• Fatigue

Cardiovascular Disorders 

• Myocardial infarction
  - Acute myocardial infarction
• Cardiac failure
• Prolonged QT electrocardiogram
• Decreased ejection fraction
• Haemorrhage
  DTC
  - Epistaxis
  - Haemoptysis
  - Haematuria
  - Contusion
  - Haematochezia
  - Gingival bleeding
  - Petechial
  - Pulmonary haemorrhage
  - Rectal haemorrhage
  - Blood urine present
  - Haematoma 
  - Vaginal haemorrhage
  HCC
  - Epistaxis
  - Haematuria
  - Gingival bleeding
  - Haemoptysis
  - Oesophageal varices haemorrhage
  - Haemorrhoidal haemorrhage
  - Mouth haemorrhage
  - Rectal haemorrhage 
  - Upper gastrointestinal haemorrhage
  EC
  - Vaginal haemorrhage
• Hypertension
  - Hypertensive crisis
  - Increased diastolic blood pressure
  - Orthostatic hypertension
  - Increased blood pressure
• Hypotension
• Aneurysms and artery dissections

Respiratory Disorders 

• Dysphonia
• Pulmonary embolism
• Pneumothorax

Gastrointestinal Disorders 

• Diarrhoea
• Gastrointestinal and abdominal pains
  - Abdominal discomfort
  - Abdominal pain
  - Lower abdominal pain
  - Upper abdominal pain
  - Abdominal tenderness
  - Epigastric discomfort
  - Gastrointestinal pain
• Nausea and vomiting
• Oral inflammation
  - Aphthous stomatitis
  - Aphthous ulcer
  - Gingival erosion
  - Gingival ulceration
  - Oral mucosal blistering
  - Stomatitis
  - Glossitis
  - Mouth ulceration
  - Mucosal inflammation
• Oral pain
  - Glossodynia
  - Gingival pain
  - Oropharyngeal discomfort
  - Oropharyngeal pain
  - Tongue discomfort
• Constipation
• Dyspepsia
• Dry mouth
• Increased lipase
• Increased amylase
• Anal fistula
• Flatulence
• Pancreatitis
  - Acute pancreatitis

Hepatobiliary Disorders

• Increased blood bilirubin
  - Hyperbilirubinaemia
  - Jaundice
  - Increased conjugated bilirubin
• Increased alanine aminotransferase
• Increased aspartate aminotransferase
• Increased blood alkaline phosphatase
• Increased gamma-glutamyltransferase
• Hepatic failure
  - Acute hepatic failure
  - Chronic hepatic failure
• Hepatic encephalopathy
  - Hepatic coma 
  - Metabolic encephalopathy 
  - Encephalopathy
• Abnormal hepatic function
• Cholecystitis
• Hepatocellular damage/hepatitis
  - Drug-induced liver injury
  - Hepatic steatosis
  - Cholestatic liver injury

Genitourinary Disorders

• Urinary tract infection
• Proteinuria
• Increased blood creatinine
• Renal failure
  - Acute prerenal failure
  - Acute renal failure acute
  - Acute kidney injury
  - Renal tubular necrosis
• Renal impairment
• Increased blood urea
• Nephrotic syndrome

Endocrine and Metabolic Disorders 

• Hypothyroidism
• Increased blood thyroid-stimulating hormone
• Hypocalcaemia
• Hypokalaemia
• Hypercholesterolaemia
  - Increased blood cholesterol
• Hypomagnesaemia
  - Decreased blood magnesium
• Decreased weight
• Decreased appetite
• Dehydration

Musculoskeletal Disorders 

• Back pain
• Arthralgia
• Myalgia
• Pain in extremity
• Musculoskeletal pain
• Osteonecrosis of the jaw

Skin and Subcutaneous Tissue Disorders 

• Palmar-plantar erythrodysaesthesia syndrome
• Rash
• Alopecia
• Hyperkeratosis

Immune, Blood and Lymphatic System Disorders 

• Peripheral oedema
• Perineal abscess
• Thrombocytopenia
  - Decreased platelet count
• Lymphopenia
  - Decreased lymphocyte count
• Leukopenia
  - Decreased white blood cell count
• Neutropenia
  - Decreased neutrophil count
• Splenic infarction
• Hypoalbuminaemia
  - Decreased blood albumin

Others

• Impaired healing
• Non-gastrointestinal fistula (fistula occurring outside of the stomach and intestines)
  - Tracheal fistula
  - Tracheo-oesophageal fistula
  - Oesophageal fistula
  - Female genital tract fistula
  - Cutaneous fistula

• Oral contraceptives (See additional prescribing points)

• Hepatic function (at baseline, every 2 weeks for 2 months and then at least monthly)
• Renal function
  - Proteinuria (baseline and periodically during treatment. Urine dipstick; if 2+ then 24-hour urine protein is required)
• Electrolytes (baseline and periodically)
  - Serum calcium (at least monthly)
• Thyroid function (baseline and monthly or as clinically indicated)
  - TSH levels
• Blood pressure  (after 1 week, then every 2 weeks for 2 months and then at least monthly)
• Dental exam (before and periodically during treatment)
• Hepatitis B virus (HBV) screening (before beginning or at the beginning of systemic anticancer therapy)
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Specific cases may require

• Electrocardiogram (in patients with congenital long QT syndrome, heart failure, bradyarrhythmias, or in those on concomitant medications known to prolong the QT interval)
• Pregnancy test (before treatment initiation in patients who can become pregnant)

Additional observations

• Signs and symptoms of
  - Cardiac dysfunction
  - Arterial thrombosis
  - Reversible posterior leukoencephalopathy syndrome (confirm with magnetic resonance imaging)
  - Fistula formation
  - Gastrointestinal perforation
  - Bleeding/hemorrhagic events
  - Diarrhoea
  - Dehydration
  - Wound healing complications
• Signs of hepatic failure
  - Hepatic encephalopathy (patients with hepatocellular carcinoma)
• Adherence

Method of administration

• Lenvatinib should be taken at about the same time each day, with or without food
• The capsules should be swallowed whole with water. If unable to swallow the capsule whole place the capsule, without breaking or crushing, in a glass of approximately 25ml of water or apple juice
• The capsules must be left to disintegrate in the liquid for at least 10 minutes and then gently stirred for at least 3 minutes to dissolve the capsule's shells. The suspension is to be swallowed. After drinking, the same amount of water or apple juice (25ml) must be added to the glass and swirled a few times. The additional liquid must be swallowed. Do not mix more than one medicine in the glass at the same time
• The person preparing the suspension should ensure their hands are thoroughly washed on completion of preparation and taking of the medication. If a patient misses a dose, and it cannot be taken within 12 hours, then that dose should be skipped and the next dose should be taken at the usual time of administration

Renal impairment (South African manufacturer recommendations)

• Patients with baseline renal function <60 ml/minute experienced more adverse events, including fatal and serious adverse events of Grade 3 or 4, than those with normal renal function and were more likely to require a treatment interruption, dose reduction or discontinuation of treatment. The recommended starting dose is lower for patients with renal impairment and it is also recommended these patients be monitored closely during treatment. There is no clinical trial experience of patients with severe renal impairment

Ethnic origin

• Limited data are available for patients of ethnic origin other than Caucasian or Asian. Lenvatinib should be used with caution in such patients, given the reduced tolerability of lenvatinib in Asian patients (South African manufacturer recommendations)
• No adjustment of starting dose is required on the basis of race. Limited data are available on use in patients from ethnic origins other than Caucasian or Asian (International manufacturer recommendations)

Oral contraceptives

• It is currently unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method

QT interval prolongation

• Lenvatinib should be withheld in the event of development of QT interval prolongation >500ms. Lenvatinib should be resumed at a reduced dose when QTc prolongation is resolved to <480ms or baseline

Coadministration with sorafenib or other anticancer treatments

• There are no data on the use of lenvatinib immediately following sorafenib or other anticancer treatments and there may be a potential risk for additive toxicities unless there is an adequate washout period between treatments. The minimal washout period in clinical trials was of 4 weeks

Coadministration or prior  treatment with antiresorptive bone therapy, and/or other angiogenesis inhibitors (International manufacturer recommendations)

• Some cases of osteonecrosis of the jaw (ONJ) were reported in patients who had received prior or concomitant treatment with antiresorptive bone therapy, and/or other angiogenesis inhibitors, e.g., bevacizumab, tyrosine kinase inhibitors (TKI), mammalian target of rapamycin (mTOR) inhibitors. Caution should therefore be exercised when lenvatinib is used either simultaneously or sequentially with antiresorptive therapy and/or other angiogenesis inhibitors

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor (PDGF) receptor PDGFRα, KIT, and RET. In addition, lenvatinib had selective, direct antiproliferative activity in hepatocellular cell lines dependent on activated FGFR signalling, which is attributed to the inhibition of FGFR signalling by lenvatinib. In syngeneic mouse tumour models, lenvatinib decreased tumour-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumour activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone. Although not studied directly with lenvatinib, the mechanism of action (MOA) for hypertension is postulated to be mediated by the inhibition of VEGFR2 in vascular endothelial cells. Similarly, although not studied directly, the MOA for proteinuria is postulated to be mediated by downregulation of VEGFR1 and VEGFR2 in the podocytes of the glomerulus. The mechanism of action for hypothyroidism is not fully elucidated.

Capsule 4mg

• Lenvima (Equity Pharmaceuticals) originator

Capsule 10mg

• Lenvima (Equity Pharmaceuticals) originator