Lenvima

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some people taking lenvatinib have developed a perforation (a hole or tear) or a fistula (an abnormal passageway) within the stomach or intestines. Call your doctor if you have severe stomach pain, or if you feel like you are choking and gagging when you eat or drink.

Also call your doctor at once if you have:

• severe headache, vision problems, weakness, confusion, seizure (convulsions);
• easy bruising, unusual bleeding (nosebleeds, bleeding gums), heavy menstrual bleeding, or any other bleeding that will not stop;
• signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;
• heart problems--shortness of breath (even with mild exertion), swelling, rapid weight gain, chest pain or pressure, pain spreading to your jaw or shoulder;
• symptoms of a blood clot--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;
• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• low calcium levels--numbness or tingly feeling around your mouth, fast or slow heart rate, muscle tightness or contraction, overactive reflexes;
• kidney problems--little or no urinating, painful or difficult urination, pain in your lower back; or
• dangerously high blood pressure--pounding in your neck or ears, nosebleed, anxiety, severe chest pain, irregular heartbeats.

Common side effects may include:

• stomach pain, nausea, vomiting, diarrhea;
• loss of appetite, weight loss;
• muscle or joint pain;
• mouth sores;
• rash, blisters, oozing, or severe pain in the palms of your hands or the soles of your feet;
• headache, tiredness; or
• hoarse voice.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Lenvatinib can cause a serious heart problem, especially if you use certain medicines at the same time, including antibiotics, antidepressants, heart rhythm medicine, antipsychotic medicines, and medicines to treat cancer, malaria, HIV or AIDS. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with lenvatinib.

This list is not complete. Other drugs may interact with lenvatinib, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Lenvima is part of the drug class:

• Protein kinase inhibitors

Serious side effects have been reported with Lenvima including the following:

• High blood pressure. Your healthcare provider will monitor your blood pressure. If you develop high blood pressure, your doctor may prescribe medications to lower your blood pressure. Your doctor may decide to lower your Lenvima dose or stop Lenvima. 
• Heart problems. Call your healthcare provider right away if you get symptoms of heart problems, such as shortness of breath or swelling of your ankles.
• Blood clots. Call your healthcare provider right away if you experience any of the following symptoms:
  • severe pain or pressure in the chest
  • pain in your arms, back, neck or jaw
  • shortness of breath
  • numbness or weakness on one side of your body
  • sudden change in vision
  • severe headaches
  • difficulty speaking
• Liver problems. Your doctor will monitor your liver function before and during treatment with Lenvima. Call your healthcare provider right away if you experience any of the following symptoms:
  • your skin or the white part of your eyes turns yellow (jaundice)
  • dark urine
  • light-colored stools
• Kidney problems. Your doctor will monitor blood tests to check your kidneys. 
• Increased protein in the urine (proteinuria). If you develop protein in your urine, your healthcare provider may decrease your dose of Lenvima or stop your medication.
• Diarrhea. If you get diarrhea, ask your healthcare provider about what medications you can take to treat your diarrhea. Make sure to plenty of water to remain hydrated. Tell your healthcare provider or go to the emergency room, if you are unable to drink enough liquids and your diarrhea is not able to be controlled.
• Uncontrolled bleeding (hemorrhage). Call your healthcare provider right away if you experience any of the following symptoms:
  • severe and persistent nose bleeds
  • vomiting blood
  • red or black stools
  • coughing up blood or blood clots
  • heavy or new onset vaginal bleeding
• Irregular heartbeats (QT prolongation). Your healthcare provider will monitor you. 
• Low levels of blood calcium. Your healthcare provider will check your blood calcium levels during treatment. 
• Change in thyroid hormone levels. Your healthcare provider may have to adjust your thyroid medication. 
• Tear in stomach area (gastrointestinal perforation) or abnormal connection in stomach area (gastrointestinal fistula). Seek immediate attention if you experience severe stomach pain. 
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Call your healthcare provider right away if you experience severe headache, seizures, weakness, confusion, or blindness or change in vision. 

Do not take Lenvima if you are allergic to Lenvima or to any of its ingredients.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Lenvima, there are no specific foods that you must exclude from your diet when receiving this medication.

General

Restricted Distribution Program

• Obtain lenvatinib mesylate only through designated specialty pharmacies.4

• Contact manufacturer at 855-347-2448 or consult the Lenvima website () for specific ordering and availability information.4

Administration

Oral Administration

Administer orally once daily without regard to meals.1 Take at the same time each day.1

If a dose of lenvatinib is missed, do not take the missed dose within 12 hours of the next dose.1

If lenvatinib is used immediately following sorafenib or other antineoplastic agents; potential risk for additive toxicities unless there is an adequate washout period between treatments.15 In clinical trials, the minimum washout period was 4 weeks.15

Dosage

Available as lenvatinib mesylate; dosage expressed in terms of lenvatinib.1

Adults

24 mg (two 10-mg capsules and one 4-mg capsule) once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Some adverse effects require temporary interruption and/or dosage reduction or discontinuance of therapy.1 If dosage reduction from 24 mg once daily is necessary, reduce dosage to 20 mg (two 10-mg capsules) once daily.1 If toxicity recurs on a dosage of 20 mg once daily, reduce dosage to 14 mg (one 10-mg capsule and one 4-mg capsule) once daily.1 If toxicity recurs on dosage of 14 mg once daily, reduce dosage to 10 mg (one 10-mg capsule) once daily.1 The manufacturer provides no specific recommendations for further dosage reductions.1

Dosage should be reduced in succession based on the previous dosage level (24 mg, 20 mg, or 14 mg once daily).1

Refers to the same or different adverse reaction requiring dosage adjustment.1

The manufacturer provides no specific recommendations for further dosage reductions.1

Safety of resuming lenvatinib following resolution of grade 4 adverse reactions not established.1

If grade 3 hypertension persists despite optimal antihypertensive therapy, withhold lenvatinib therapy.1 Once hypertension improves to ≤grade 2, may resume lenvatinib at a reduced dosage.1 If life-threatening hypertension occurs, discontinue lenvatinib.1 (See Hypertension under Cautions.)

If grade 3 cardiac dysfunction (i.e., decreased ventricular function, cardiac failure, or pulmonary edema) occurs, withhold lenvatinib therapy.1 Once the toxicity improves to ≤grade 1 or baseline, may resume lenvatinib at a reduced dosage or discontinue therapy, depending on severity and persistence of the cardiac dysfunction.1 If grade 4 cardiac dysfunction occurs, discontinue lenvatinib.1 (See Cardiac Dysfunction under Cautions.)

If ≥grade 3 QT-interval prolongation occurs, withhold lenvatinib therapy.1 Once the toxicity improves to ≤grade 1 or baseline, may resume lenvatinib at a reduced dosage.1 (See Prolongation of QT Interval under Cautions.)

If an arterial thromboembolic event occurs, discontinue lenvatinib.1 (See Arterial Thromboembolic Events under Cautions.)

If grade 3 hemorrhage occurs, withhold lenvatinib therapy.1 Once the hemorrhagic event improves to ≤grade 1 or to baseline, may resume lenvatinib at a reduced dosage or discontinue therapy, depending on severity and persistence of the hemorrhage.1 If grade 4 hemorrhage occurs, discontinue lenvatinib.1 (See Hemorrhage under Cautions.)

If grade 3 or 4 renal impairment or renal failure occurs, withhold lenvatinib therapy.1 Once the nephrotoxicity improves to ≤grade 1 or to baseline, may resume lenvatinib at a reduced dosage or discontinue therapy, depending on severity and persistence of the toxicity.1 (See Renal Failure and Impairment under Cautions.)

If grade 3 or 4 hepatotoxicity occurs, withhold lenvatinib therapy.1 Once the toxicity improves to ≤grade 1 or to baseline, may resume lenvatinib at a reduced dosage or discontinue therapy, depending on severity and persistence of the hepatotoxicity.1 (See Hepatic Toxicity under Cautions.)

Withhold lenvatinib therapy for proteinuria ≥2 g per 24 hours; may resume at a reduced dosage when proteinuria declines below this level.1

If nephrotic syndrome occurs, discontinue lenvatinib.1 (See Proteinuria under Cautions.)

If nausea, vomiting, or diarrhea occurs, medical management (e.g., use of antiemetic and/or antidiarrheal agents) is recommended prior to interruption of therapy or dosage reduction of lenvatinib.1

If GI perforation or a life-threatening fistula occurs, discontinue lenvatinib.1 (See GI Perforation and Fistula Formation under Cautions.)

If RPLS occurs, withhold lenvatinib therapy.1 Once the RPLS fully resolves, may resume lenvatinib at a reduced dosage or discontinue therapy, depending on severity and persistence of neurologic symptoms.1 (See RPLS under Cautions.)

Special Populations

Hepatic Impairment

Severe hepatic impairment (Child-Pugh class C): Reduce dosage to 14 mg (one 10-mg capsule and one 4-mg capsule) once daily.1 13

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment required.1 13

Renal Impairment

Severe renal impairment (Clcr <30 mL/minute): Reduce dosage to 14 mg (one 10-mg capsule and one 4-mg capsule) once daily.1

Mild or moderate renal impairment (Clcr 30–89 mL/minute): No dosage adjustment required.1

End-stage renal disease: Not studied; no specific dosage recommendations.1

Geriatric Patients

No specific dosage recommendations.1

In the U.S.

• Lenvima

Available Dosage Forms:

• Capsule

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Tyrosine Kinase Inhibitor

Medicines used to treat cancer are very strong and can have many side effects. Before taking this medicine, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

This medicine comes with a patient information insert. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Swallow the capsule whole, or you may dissolve the capsules in a small glass of liquid. Measure 1 tablespoon of water or apple juice and place the capsules into the liquid without breaking or crushing them. Allow the capsules to dissolve in the liquid for at least 10 minutes. Stir for at least 3 minutes and drink the mixture. Add an additional 1 tablespoon of apple juice or water to the glass and swallow it immediately.

Take this medicine the same way every day. This means take it at the same time and take it consistently, either with or without food.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For the treatment of thyroid cancer:
    • Adults—24 milligrams (mg) (two 10 mg capsules and one 4 mg capsule) per day as a single dose. Your doctor may adjust your dose if needed.
    • Children—Use and dose must be determined by your doctor.
  • For the treatment of advanced kidney cancer (taken with everolimus):
    • Adults—18 milligrams (mg) (one 10 mg capsule and two 4 mg capsules) per day as a single dose. Your doctor may adjust your dose if needed.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Do not take this medicine if it has been more than 12 hours since you missed your last dose.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

If you will be taking this medicine for a long time, it is very important that your doctor check you at regular visits for any problems or unwanted effects. Blood and urine tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant during treatment and for at least 2 weeks after you stop taking this medicine. If you think you have become pregnant while using the medicine, tell your doctor right away.

Your doctor will check your blood pressure on a regular basis while you are taking this medicine. You might need to monitor your blood pressure at home. Tell your doctor right away if you have a severe headache, lightheadedness, or changes in your vision.

This medicine may increase your risk of having blood clots, heart attack, or stroke. Check with your doctor right away if you have chest pain or discomfort, nausea, numbness or weakness in your arm or leg, or on one side of your body, pain or discomfort in your arms, jaw, back, or neck, shortness of breath, sweating, or vomiting.

Make sure any doctor or dentist who treats you knows that you are using this medicine. You may need to stop using this medicine before having surgery.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.

This medicine may cause diarrhea, and in some cases it can be severe. Do not take any medicine to treat diarrhea without first checking with your doctor. If you have any questions about this or if mild diarrhea continues or gets worse, check with your doctor.

Check with your doctor right away if you have decreased frequency or amount of urine, bloody urine, increased thirst, swelling of the face, fingers, or lower legs, trouble breathing, or weight gain. These could be symptoms of serious kidney problems.

Check with your doctor right away if you have severe stomach pain, or gagging, coughing or choking when you eat or drink. These could be symptoms of a perforation (tear) or fistula (hole) in the bowel.

Contact your doctor right away if you have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you or anyone in your family has ever had a heart rhythm problem such as QT prolongation.

Check with your doctor right away if you have a headache, seizures, confusion, blurred vision or other visual problems. These may be symptoms of a rare and serious brain condition called reversible posterior leukoencephalopathy syndrome (RPLS).

This medicine may increase your chance of bleeding. Tell your doctor right away if you cough up blood or have bleeding gums, difficulty with breathing or swallowing, dizziness, increased menstrual flow or vaginal bleeding, nosebleeds, prolonged bleeding from cuts, red or dark brown urine, or red or black, tarry stools. Stay away from rough sports or other situations where you could be bruised, cut, or injured. Brush and floss your teeth gently. Be careful when using sharp objects, including razors and fingernail clippers.

Talk with your doctor before using this medicine if you plan to have children. Some men and women who use this medicine have become infertile (unable to have children).

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

The following adverse reactions are discussed elsewhere in the label:

• Hypertension [see Warnings and Precautions (5.1)]
  
• Cardiac Dysfunction [see Warnings and Precautions (5.2)]
  
• Arterial Thromboembolic Events [see Warnings and Precautions (5.3)]
  
• Hepatotoxicity [see Warnings and Precautions (5.4)]
  
• Proteinuria [see Warnings and Precautions (5.5)]
  
• Diarrhea [see Warnings and Precautions (5.6)]
  
• Renal Failure and Impairment [see Warnings and Precautions (5.7)]
  
• Gastrointestinal Perforation and Fistula Formation [see Warnings and Precautions (5.8)]
  
• QT Interval Prolongation [see Warnings and Precautions (5.9)]
  
• Hypocalcemia [see Warnings and Precautions (5.10)]
  
• Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.11)]
  
• Hemorrhagic Events [see Warnings and Precautions (5.12)]
  
• Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction [see Warnings and Precautions (5.13)]

6.1             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 the Warnings and Precautions section reflect exposure to Lenvima as a single agent in 261 DTC patients (Study 1) and Lenvima + everolimus in 62 RCC patients (Study 2). Safety data obtained in 1160 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 [see Warnings and Precautions (5.4, 5.10, 5.11)]. In the entire single agent population, the median age was 60 years (range 21-89 years), the dose range was 0.2 mg to 32 mg, and the median duration of exposure was 5.5 months.  

Differentiated Thyroid Cancer

The safety data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) to Lenvima (n=261) or placebo (n=131) [see Clinical Studies (14.1)].  The median treatment duration was 16.1 months for Lenvima and 3.9 months for placebo.  Among 261 patients who received Lenvima in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity.

In Study 1, the most common adverse reactions observed in Lenvima-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, 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 and 5% of patients receiving placebo; 18% of patients discontinued Lenvima and 5% discontinued placebo 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 4 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in Lenvima-treated patients than patients receiving placebo in the double-blind phase of the DTC study.  

a Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure
b Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation
c Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness, epigastric discomfort, and gastrointestinal pain
d Includes oral pain, glossodynia, and oropharyngeal pain
e Includes asthenia, fatigue, and malaise
f Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia
g Includes macular rash, maculo-papular rash, generalized rash, and rash
h Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infection

A clinically important adverse reaction occurring more frequently in Lenvima-treated patients than patients receiving placebo, but with an incidence of less than 5% was pulmonary embolism (3%, including fatal reports vs 2%, respectively).

In addition the following laboratory abnormalities (all Grades) occurred in greater than 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 data described below are derived from Study 2 which randomized (1:1:1) patients with unresectable advanced or metastatic renal cell carcinoma (RCC) to Lenvima 18 mg + everolimus 5 mg (n=51), Lenvima 24 mg (n=52), or everolimus 10 mg (n=50) once daily [see Clinical Studies (14.2)].  This data also includes patients on the dose escalation portion of the study who received Lenvima 18 mg + everolimus 5 mg (n=11). The median treatment duration was 8.1 months for Lenvima + everolimus and 4.1 months for everolimus. Among 62 patients who received Lenvima + everolimus in Study 2, the median age was 61 years, 71% were men, and 98% were White.

The most common adverse reactions observed in the Lenvima + 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, weight decreased, 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 + everolimus and 54% in patients receiving everolimus.  The most common adverse reactions (≥ 5%) resulting in dose reductions in the Lenvima + 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 + everolimus-treated group and 12% of patients in the everolimus-treated group.

Table 6 presents the adverse reactions in > 15% of patients in the Lenvima + Everolimus arm.

a       Includes abdominal discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain
b       Includes gingival pain, glossodynia, and oropharyngeal pain
c       Includes aphthous stomatitis, gingival inflammation, glossitis, and mouth ulceration
d       Includes asthenia, fatigue, lethargy and malaise
e       Includes arthralgia, back pain, extremity pain, musculoskeletal pain, and myalgia
f       Includes blood creatinine increased, blood urea increased, creatinine renal clearance decreased, nephropathy toxic, renal failure, renal failure acute, and renal impairment  
g       Includes erythema, erythematous rash, genital rash, macular rash, maculo-papular rash, , papular rash, pruritic rash, pustular rash, and septic rash
h       Includes hemorrhagic diarrhea, epistaxis, gastric hemorrhage, hemarthrosis, hematoma, hematuria, hemoptysis, lip hemorrhage, renal hematoma, and scrotal hematocele 

6.2             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 Disorders: pancreatitis, amylase increased

Hepatobiliary Disorders: cholecystitis

Lenvima, a kinase inhibitor, is the mesylate salt of lenvatinib. Its chemical name is 4-[3-chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate. The molecular formula is C21H19ClN4O4 • CH4O3S, and the molecular weight of the mesylate salt is 522.96. The chemical structure of lenvatinib mesylate is:

Lenvatinib mesylate is a white to pale reddish yellow powder. It is slightly soluble in water and practically insoluble in ethanol (dehydrated). The dissociation constant (pKa value) of lenvatinib mesylate is 5.05 at 25°C. The partition coefficient (log P value) is 3.30.

Each 4 mg or 10 mg capsule of lenvatinib is equivalent to 4.90 mg or 12.25 mg of lenvatinib mesylate. Following are inactive ingredients: Calcium Carbonate, USP; Mannitol, USP; Microcrystalline Cellulose, NF; Hydroxypropyl Cellulose, NF; Hydroxypropyl Cellulose (type H), NF; and Talc, USP. The hypromellose capsule shell contains titanium dioxide, ferric oxide yellow, and ferric oxide red. The printing ink contains shellac, black iron oxide, potassium hydroxide, and propylene glycol.

13.1             Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with lenvatinib. Lenvatinib mesylate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Lenvatinib was not clastogenic in the in vitro mouse lymphoma thymidine kinase assay or the in vivo rat micronucleus assay.

No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility; however, results from general toxicology studies in rats, monkeys, and dogs suggest there is a potential for lenvatinib to impair fertility. Male dogs exhibited testicular hypocellularity of the seminiferous epithelium and desquamated seminiferous epithelial cells in the epididymides at lenvatinib exposures approximately 0.02 to 0.09 times the clinical exposure by AUC at the recommended human dose. Follicular atresia of the ovaries was observed in monkeys and rats at exposures 0.2 to 0.8 times and 10 to 44 times the clinical exposure by AUC at the 24 mg clinical dose, respectively. In addition, in monkeys, a decreased incidence of menstruation was reported at lenvatinib exposures lower than those in humans at the 24 mg clinical dose.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypertension:

Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated [see Warnings and Precautions (5.1)].

Cardiac Dysfunction:

Advise patients that Lenvima can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction such as shortness of breath or swelling of ankles [see Warnings and Precautions (5.2)].

Arterial Thrombotic Events:

Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke [see Warnings and Precautions (5.3)].

Hepatotoxicity:

Advise patients that they will need to undergo laboratory tests to monitor for liver function and to report any new symptoms indicating hepatic toxicity or failure [see Warnings and Precautions (5.4)].

Diarrhea:

Advise patients when to start standard anti-diarrheal therapy and to maintain adequate hydration. Advise patients to contact their healthcare provider if they are unable to maintain adequate hydration [see Warnings and Precautions (5.6)].

Proteinuria and Renal Failure/Impairment:

Advise patients that they will need to undergo regular laboratory tests to monitor for kidney function and protein in the urine [see Warnings and Precautions (5.5, 5.7)].

Gastrointestinal perforation or fistula formation:

Advise patients that Lenvima can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain [see Warnings and Precautions (5.8)].

QTc Interval Prolongation

Advise patients who are at risk for QTc prolongation that they will need to undergo regular ECGs. Advise all patients that they will need to undergo laboratory tests to monitor electrolytes [see Warnings and Precautions (5.9)].

Hemorrhagic Events:

Advise patients that Lenvima can increase the risk for bleeding and to contact their healthcare provider for bleeding or symptoms of severe bleeding [see Warnings and Precautions (5.12)].

Embryofetal Toxicity:

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.14), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with Lenvima and for at least 2 weeks following completion of therapy [see Use in Specific Populations (8.3)]. 

Lactation:

Advise nursing women to discontinue breastfeeding during treatment with Lenvima [see Use in Specific Populations (8.2)].

Distributed by:
Eisai Inc.
Woodcliff Lake, NJ 07677

Lenvima® is a registered trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc.

© 2017 Eisai Inc.

PRINCIPAL DISPLAY PANEL

NDC 62856-708-05
Lenvima
(lenvatinib) capsules
8 mg daily dose

PRINCIPAL DISPLAY PANEL

NDC 62856-710-30
Lenvima
(lenvatinib) capsules
10 mg daily dose
30 day supply
10 mg daily- dose carton containing 6 cards

PRINCIPAL DISPLAY PANEL

NDC 62856-714-30
Lenvima
(lenvatinib) capsules
14 mg daily dose
30 day supply
14 mg daily- dose carton containing 6 cards

PRINCIPAL DISPLAY PANEL

NDC 62856-718-30
Lenvima
(lenvatinib) capsules
18 mg daily dose

PRINCIPAL DISPLAY PANEL

NDC 62856-720-30
Lenvima
(lenvatinib) capsules
20 mg daily dose
30 day supply
20 mg daily- dose carton containing 6 cards

PRINCIPAL DISPLAY PANEL

NDC 62856-724-30
Lenvima
(lenvatinib) capsules
24 mg daily dose
30 day supply
24 mg daily- dose carton containing 6 cards

Get emergency medical help if you have signs of an allergic reaction to Lenvima: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some people taking Lenvima have developed a perforation (a hole or tear) or a fistula (an abnormal passageway) within the stomach or intestines. Call your doctor if you have severe stomach pain, or if you feel like you are choking and gagging when you eat or drink.

Also call your doctor at once if you have:

• severe diarrhea;

• severe headache, vision problems, weakness, confusion, seizure (convulsions);

• easy bruising, unusual bleeding (nosebleeds, bleeding gums), heavy menstrual bleeding, or any other bleeding that will not stop;

• signs of stomach bleeding - bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

• heart problems - shortness of breath (even with mild exertion), swelling in your ankles, chest pain or pressure, pain spreading to your jaw or shoulder;

• symptoms of a blood clot - sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

• liver problems - nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• low calcium levels - numbness or tingly feeling around your mouth, fast or slow heart rate, muscle tightness or contraction, overactive reflexes;

• kidney problems - little or no urinating, painful or difficult urination, pain in your lower back; or

• dangerously high blood pressure - pounding in your neck or ears, nosebleed, anxiety, severe chest pain, irregular heartbeats.

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common Lenvima side effects may include:

• stomach pain, nausea, vomiting, diarrhea;

• loss of appetite, weight loss;

• muscle or joint pain;

• mouth sores;

• rash, redness, itching, or peeling on the palms of your hands or the soles of your feet;

• headache, tiredness; or

• cough, hoarse voice.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Lenvima can cause a serious heart problem, especially if you use certain medicines at the same time, including antibiotics, antidepressants, heart rhythm medicine, antipsychotic medicines, and medicines to treat cancer, malaria, HIV or AIDS. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with Lenvima.

This list is not complete. Other drugs may interact with lenvatinib, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Applies to lenvatinib: capsule oral, oral capsule

Along with its needed effects, lenvatinib (the active ingredient contained in Lenvima) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking lenvatinib:

• Bladder pain
• bloating or swelling of the face, arms, hands, lower legs, or feet
• changes in vision
• chest pain or discomfort
• confusion
• coughing up blood
• decreased frequency or amount of urine
• difficulty with breathing or swallowing
• dilated neck veins
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• extreme fatigue
• fainting
• increase in heart rate
• increased menstrual flow or vaginal bleeding
• lower back or side pain
• muscle cramps in the hands, arms, feet, legs, or face
• nervousness
• nosebleeds
• numbness and tingling around the mouth, fingertips, or feet
• paralysis
• rapid or irregular breathing
• rapid weight gain
• red or black, tarry stools
• red or dark brown urine
• redness, swelling, or pain of the skin
• severe headache
• slow or fast heartbeat
• swelling of the face, fingers, feet, or lower legs
• tingling of the hands or feet
• tremor
• ulceration of the skin
• unusual tiredness or weakness
• unusual bleeding or bruising
• vomiting
• wrinkled skin

• Abdominal or stomach pain or tenderness
• clay colored stools
• dark urine
• difficulty with speaking
• fever
• heartburn or indigestion
• inability to move the arms, legs, or facial muscles
• pain or discomfort in the arms, jaw, back, or neck
• severe abdominal or stomach pain, cramping, or burning
• vomiting of material that looks like coffee grounds
• yellow eyes or skin

Some side effects of lenvatinib may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Belching
• change or loss of taste
• decreased appetite
• dry mouth
• hair loss or thinning of the hair
• headache
• hoarseness
• itching or skin rash
• muscle pain or stiffness
• nausea
• pain in the joints
• sore throat
• swelling or inflammation of the mouth
• trouble sleeping
• voice changes