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Adjunct anti-epileptic drugs, Primary anti-epileptic drugs

Pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It does not bind directly to GABA_A, GABA_B or benzodiazepine receptors. Pregabalin binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of Pregabalin has not been fully elucidated, results in animal studies suggest that binding to the alpha2-delta subunit may be involved in Pregabalin's anti-nociceptive and antiseizure effects.

Neuropathic pain associated with diabetic peripheral neuropathy in adults (DPN): The maximum recommended dose of Pregabalin is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 ml/min. Dosing should begin at 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. Begin dosing of Pregabalin CR capsule at 165 mg once daily and increase to 330 mg once daily within 1 week based on individual patient response and tolerability. The maximum recommended dose of Pregabalin CR capsule is 330 mg once daily.

Postherpetic neuralgia in adults (PHN): The recommended dose of Pregabalin is 75 to 150 mg two times a day or 50 to 100 mg three times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 ml/min. Dosing should begin at 75 mg two times a day or 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 300 mg/day and who are able to tolerate Pregabalin, may be treated with up to 300 mg two times a day or 200 mg three times a day (600 mg/day).

Begin dosing of Pregabalin CR capsule at 165 mg once daily and increase to 330 mg once daily within 1 week based on individual patient response and tolerability. Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 330 mg once daily and who are able to tolerate Pregabalin CR capsule, may be treated with up to 660 mg once daily. In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, dosing above 330 mg/day should be reserved only for those patients who have on-going pain and are tolerating 330 mg daily. The maximum recommended dose of Pregabalin CR capsule is 660 mg once daily.

Management of fibromyalgia in adults: The recommended dose of Pregabalin is 300 to 450 mg/day. Dosing should begin at 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day).

Neuropathic pain associated with spinal cord injury in adults: The recommended dose range of Pregabalin is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient pain relief after 2 to 3 weeks of treatment with 150 mg two times a day and who tolerate Pregabalin may be treated with up to 300 mg two times a day.

Conversion from Pregabalin capsules to Pregabalin CR capsule tablet: When switching from Pregabalin capsules to Pregabalin CR capsule tablet on the day of the switch, instruct patients to take their morning dose of Pregabalin capsule as prescribed and initiate Pregabalin CR capsule therapy after an evening meal.

Pregabalin tablet total daily dose (dosed 2 or 3 times daily): Pregabalin CR capsule capsule dose (dosed once a day)

• 75 mg/daily: 82.5 mg/day
• 150 mg/daily: 165 mg/day
• 225 mg/daily: 247.5 mg/day
• 300 mg/daily: 330 mg/day
• 450 mg/daily: 495 mg/day
• 600 mg/daily: 660 mg/day

Route of administration: Pregabalin is taken in oral route. It can be taken with or without food. Pregabalin CR tablet should be administered after an evening meal. It should be swallowed whole and should not be split, crushed or chewed. If patients miss taking their dose of Pregabalin CR after an evening meal, then they should take their usual dose of Pregabalin CR prior to bedtime following a snack. If they miss taking the dose of Pregabalin CR prior to bedtime, then they should take their usual dose of Pregabalin CR following a morning meal. If they miss taking the dose of Pregabalin CR following the morning meal, then they should take their usual dose of Pregabalin CR at the usual time that evening following an evening meal. When discontinuing both Pregabalin and Pregabalin CR, it should be gradually tapered over a minimum of 1 week.

Most common side effects in adults are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and thinking abnormal (primarily difficulty with concentration/attention). Most common side effects in pediatric patients for the treatment of partial onset seizures are increased weight and increased appetite.

Pregabalin is contraindicated in patients with known hypersensitivity to Pregabalin or any of its components.

Angioedema (e.g., swelling of the throat, head and neck) can occur and may be associated with life threatening respiratory compromise requiring emergency treatment. Pregabalin should be discontinued immediately in these cases. Pregabalin should also be discontinued immediately if hypersensitivity reactions (e.g., hives, dyspnea and wheezing) occur. Antiepileptic drugs, including pregabalin, increase the risk of suicidal thoughts or behavior. Respiratory depression may occur with pregabalin when used with concomitant CNS depressants or in the setting of underlying respiratory impairment. Patients need to be monitored and dosage adjusted as appropriate. Pregabalin may cause dizziness and somnolence and impair patients ability to drive or operate machinery. Increased seizure frequency or other adverse reactions may occur if pregabalin is rapidly discontinued. Pregabalin should be withdrawn gradually over a minimum of 1 week. Pregabalin may cause peripheral edema. Caution should be exercised when coadministering pregabalin and thiazolidinedione antidiabetic agents.

Pregabalin is unlikely to be involved in significant pharmacokinetic drug interactions.

There are no adequate and well-controlled studies with pregabalin in pregnant women. Pregnant women should be advised of the potential risk to a fetus. Small amounts of pregabalin have been detected in the milk of lactating women. Because of the potential risk of tumorigenicity, breastfeeding is not recommended during treatment with pregabalin.

Use in children and adolescents: Safety and effectiveness in pediatric patients have not been established for the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, neuropathic pain associated with spinal cord injury and fibromyalgia. In case of adjunctive therapy for partial onset seizures, safety and effectiveness in pediatric patients below the age of 1 month have not been established. The safety and effectiveness of pregabalin extended-release tablet in pediatric patients have not been established.

In case of overdose with pregabalin, sign and symptoms are reduced consciousness, depression/anxiety, confusional state, agitation and restlessness. Seizures and heart block have also been reported. There is no specific antidote. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient.

Keep in a cool & dry place (below 30°C), protected from light & moisture. Keep out of the reach of children.

Citric Acid Monohydrate is indicated for the management of dry cough.

Cough suppressant

Citric Acid Monohydrate helps to reduce the dry cough and soothes the throat from any related discomfort and pain. Citric Acid is a demulcent which relieves irritation of the mucous membrane in the throat by forming a protective film. Citric Acid is absorbed after oral administration. It is found naturally in the body and is widely distributed.

1-5 years: 5 ml upto 4 times daily
6-12 years: 10 ml upto 4 times daily
>12 years & Adults: 20 ml upto 3-4 times daily

There are no known side effects from using this medicine when used as directed. If taken excessively above the stated dose, glycerol present in the medicine may cause headache, stomach upset and diarrhea.

It is contraindicated for the hypersensitivity to any of the ingredients of this medicine.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

No drug-drug interaction has been found.

There are no or limited amount of data from the use of Citric Acid Monohydrate in pregnant women. There is insufficient information on the excretion of Citric Acid Monohydrate & its metabolites in human milk.

Keep in a cool and dry place, away from light. Keep out of the reach of children.

Vitamin-C Preparations

vitamin C, the water-soluble vitamin, is readily absorbed from the gastrointestinal tract and is widely distributed in the body tissues. It is believed to be involved in biological oxidations and reductions used in cellular respiration. It is essential for the synthesis of collagen and intracellular material. Vitamin C deficiency develops when the dietary intake is inadequate and when increased demand is not fulfilled. Deficiency leads to the development of well defined syndrome known as scurvy, which is characterized by capillary fragility, bleeding (especially from small blood vessels and the gums), anaemia, cartilage and bone lesions and slow healing of wounds.

Oral administration-

• For the prevention of scurvy: 1 tablet daily
• For the treatment of scurvy: 1-2 tablets daily; but dose may be increased depending on the severity of the condition.
• For the reduction of risk of stroke in the elderly: 1-2 tablets daily.
• In other cases: 1 tablet daily or as directed by the physician.
• Maximum safe dose is 2000 mg daily in divided doses.

Parenteral administration-

• Vitamin C is usually administered orally. When oral administration is not feasible or when malabsorption is suspected, the drug may be administered IM, IV, or subcutaneously. When given parenterally, utilization of the vitamin reportedly is best after IM administration and that is the preferred parenteral route.
• For intravenous injection, dilution into a large volume parenteral such as Normal Saline, Water for Injection, or Glucose is recommended to minimize the adverse reactions associated with intravenous injection.
• The average protective dose of vitamin C for adults is 70 to 150 mg daily. In the presence of scurvy, doses of 300 mg to 1 g daily are recommended. However, as much as 6 g has been administered parenterally to normal adults without evidence of toxicity.
• To enhance wound healing, doses of 300 to 500 mg daily for a week or ten days both preoperatively and postoperatively are generally considered adequate, although considerably larger amounts have been recommended. In the treatment of burns, doses are governed by the extent of tissue injury. For severe burns, daily doses of 1 to 2 g are recommended. In other conditions in which the need for vitamin C is increased, three to five times the daily optimum allowances appear to be adequate.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

Vitamin C has little toxicity and only mega-doses of vitamin C may cause diarrhoea, abdominal bloating, iron over-absorption that is harmful in patients with thalassaemia, sideroblastic anemia, and haemochromatosis; hyperoxaluria, hyperuricosuria, and hemolysis in patients with glucose-6 phosphate dehydrogenase deficiency. A pregnant woman taking more than 5 gm/day may suffer fetal abortion.

Ingestion of megadose (more than 1000 mg daily) of vitamin C during pregnancy has resulted in scurvy in neonates. Vitamin C in mega-doses has been contraindicated for patients with hyperoxaluria. Vitamin C itself is a reactive substance in the redox system and can give rise to false positive reactions in certain analytical tests for glucose, uric acid, creatine and occult blood.

Potentially hazardous interactions: Ascorbic acid is incompatible in solution with aminophylline, bleomycin, erythromycin, lactobionate, nafcillin, nitrofurantoin sodium, conjugated oestrogen, sodium bicarbonate, sulphafurazole diethanolamine, chloramphenicol sodium succinate, chlorthiazide sodium and hydrocortisone sodium succinate.

Useful interactions: Ascorbic acid increases the apparent half-life of paracetamol and enhances iron absorption from the gastrointestinal tract.

The drug is safe in normal doses in pregnant women, but a daily intake of 5 gm or more is reported to have caused abortion. The drug may be taken safely during lactation.

Should be stored in a dry place below 30˚C.

Vitamin-C Preparations

vitamin C, the water-soluble vitamin, is readily absorbed from the gastrointestinal tract and is widely distributed in the body tissues. It is believed to be involved in biological oxidations and reductions used in cellular respiration. It is essential for the synthesis of collagen and intracellular material. Vitamin C deficiency develops when the dietary intake is inadequate and when increased demand is not fulfilled. Deficiency leads to the development of well defined syndrome known as scurvy, which is characterized by capillary fragility, bleeding (especially from small blood vessels and the gums), anaemia, cartilage and bone lesions and slow healing of wounds.

Oral administration-

• For the prevention of scurvy: 1 tablet daily
• For the treatment of scurvy: 1-2 tablets daily; but dose may be increased depending on the severity of the condition.
• For the reduction of risk of stroke in the elderly: 1-2 tablets daily.
• In other cases: 1 tablet daily or as directed by the physician.
• Maximum safe dose is 2000 mg daily in divided doses.

Parenteral administration-

• Vitamin C is usually administered orally. When oral administration is not feasible or when malabsorption is suspected, the drug may be administered IM, IV, or subcutaneously. When given parenterally, utilization of the vitamin reportedly is best after IM administration and that is the preferred parenteral route.
• For intravenous injection, dilution into a large volume parenteral such as Normal Saline, Water for Injection, or Glucose is recommended to minimize the adverse reactions associated with intravenous injection.
• The average protective dose of vitamin C for adults is 70 to 150 mg daily. In the presence of scurvy, doses of 300 mg to 1 g daily are recommended. However, as much as 6 g has been administered parenterally to normal adults without evidence of toxicity.
• To enhance wound healing, doses of 300 to 500 mg daily for a week or ten days both preoperatively and postoperatively are generally considered adequate, although considerably larger amounts have been recommended. In the treatment of burns, doses are governed by the extent of tissue injury. For severe burns, daily doses of 1 to 2 g are recommended. In other conditions in which the need for vitamin C is increased, three to five times the daily optimum allowances appear to be adequate.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

Vitamin C has little toxicity and only mega-doses of vitamin C may cause diarrhoea, abdominal bloating, iron over-absorption that is harmful in patients with thalassaemia, sideroblastic anemia, and haemochromatosis; hyperoxaluria, hyperuricosuria, and hemolysis in patients with glucose-6 phosphate dehydrogenase deficiency. A pregnant woman taking more than 5 gm/day may suffer fetal abortion.

Ingestion of megadose (more than 1000 mg daily) of vitamin C during pregnancy has resulted in scurvy in neonates. Vitamin C in mega-doses has been contraindicated for patients with hyperoxaluria. Vitamin C itself is a reactive substance in the redox system and can give rise to false positive reactions in certain analytical tests for glucose, uric acid, creatine and occult blood.

Potentially hazardous interactions: Ascorbic acid is incompatible in solution with aminophylline, bleomycin, erythromycin, lactobionate, nafcillin, nitrofurantoin sodium, conjugated oestrogen, sodium bicarbonate, sulphafurazole diethanolamine, chloramphenicol sodium succinate, chlorthiazide sodium and hydrocortisone sodium succinate.

Useful interactions: Ascorbic acid increases the apparent half-life of paracetamol and enhances iron absorption from the gastrointestinal tract.

The drug is safe in normal doses in pregnant women, but a daily intake of 5 gm or more is reported to have caused abortion. The drug may be taken safely during lactation.

Should be stored in a dry place below 30˚C.

Anthelmintic

Levamisole is the active laevo-isomer of tetramisole. It works by paralysing susceptible intestinal worms which are then excreted from the intestines. Levamisole also enhances cellular immune responses in humans.

The following doses of Levamisole are given as a single administration, preferably after a light meal.

• Age 1-4 year: 1 Tablets or 5 ml Syrup
• Age 5-15 year: 2 Tablets or 10 ml Syrup
• Age 16 year and over: 3 Tablets or 15 ml Syrup

In cases of severe hookworm infection it is suggested that a second standard dose be given one or seven days after the first, whichever timing is feasible.

Side-effects are infrequent. They are usually mild and transient and include nausea, vomiting, abdominal pain, giddiness(dizziness) and headache. An encephalopathylike syndrome has been reported to have occurred in a few patients two or three weeks after treatment.

There is no absolute contra-indication to the use of Levamisole

Effect on ability to drive or operate machinery: There is no evidence to suggest that Levamisole , used for anthelmintic purpose, will produce sedation. Mild and transient giddiness is an infrequent side-effect of treatment. No precautions are suggested concerning the ability to drive or operate machinery.

In case of concurrent microfilaraemia transient fever may occur.

May increase toxicity of phenytoin. Increases bioavailability of ivermectin; decreases bioavailability of albendazole. Alcohol causes disulfiram-like reaction.

Although studies in animals have shown that Levamisole produces no teratogenic effects, current medical practice requires that the benefits of any drug used during pregnancy should be weighed against the possible dangers.

Counter possible anticholinesterase activity with e.g. atropine. Control blood pressure and respiration . Do not use sedatives.

Tablet: Store in room temperature and protect from moisture.
Syrup: Store in room temperature and protect from light.

Letrozole is indicated for the first-line treatment of advanced/metastatic breast cancer (hormone receptor positive or receptor status unknown) in post-menopausal women.

Hormonal Chemotherapy

Mechanism of Action: Letrozole is a potent and highly specific nonsteroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the haem of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Letrozole exerts its antitumor effect by depriving estrogen-dependent breast cancer cells of their growth stimulus. In postmenopausal women, estrogens are derived mainly from the action of the aromatase enzyme, which coverts adrenal androgens primarily androstenedione and testosterone-to oestrone (E1) and oestradiol (E2). The suppression of estrogen biosynthesis in the peripheral tissues and the malignant tissues can be achieved by specifically inhibiting the aromatase enzyme.

In healthy postmenopausal women, single doses of 0.1, 0.5 and 2.5mg letrozole suppress serum oestrone and oestradiol by 75-78% and 78% from baseline respectively. Maximum suppression is achieved in 48-78 hours. In post-menopausal patients, with advanced breast cancer, daily doses of 0.1 to 5mg suppress plasma concentration of oestradiol, oestrone, and oestrone sulphate by 78-95% from baseline in all patients treated. Letrozole had no effect on plasma androgen concentrations (androstenedione and testosterone) among healthy postmenopausal women after single doses of 0.1, 0.5 and 2.5mg indicating that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Impairment of adrenal steroidogenesis has not been observed.

Pharmacokinetics: Letrozole is rapidly and completely absorbed from the gastrointestinal tract (absolute bioavailability 99.9%). Food slightly decreases the rate of absorption, but the extent of absorption remains unchanged. The minor effect of the absorption rate is not considered to be of clinical relevance and therefore letrozole may be taken after, with or before food. Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of letrozole but is relatively slow when compared to hepatic blood flow. The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this metabolite in vitro but their individual contributions to letrozole metabolism in vivo have not been established. The apparent terminal elimination half-life in plasma is about 2 days. After daily administration of 2.5mg of letrozole, steady-state levels are reached within 2 to 6 weeks.

The recommended dose of Letrozole is 2.5 mg once daily. Treatment with Letrozole should continue as long as tumor response is seen. The drug should be discontinued if tumor stops responding as judged by tumor progression. For elderly patients, no modification of the normal adult dosage regimen is necessary. No dosage adjustment is required for patients with mild to moderate hepatic impairment or renal impairment.

Adverse events associated with letrozole are generally mild to moderate and rarely severe enough to require discontinuation. Many can be attributed to either the underlying disease or the normal pharmacological consequence of oestrogen deprivation (hot flushes, hair thinning). The most frequently reported adverse events are musculoskeletal pain, arthralgia, headache, fatigue, nausea, dyspnoea, peripheral oedema, coughing, constipation, vomiting, chest pain, viral infection, diarrhoea, rash, abdominal pain, dyspepsia and anorexia. Dizziness, weight increase and pruritus are less commonly seen.

Letrozole is contraindicated in known or suspected hypersensitivity to letrozole, other aromatase inhibitors, or to any of their ingredients. It is contraindicated during pregnancy, lactation and in pre-menopausal women. It is also contraindicated in severe hepatic dysfunction.

In breast cancer patients with moderate hepatic dysfunction, no dosage adjustment is necessary, but caution is recommended since letrozole elimination depends mainly on intrinsic metabolic clearance. Renal impairment (calculated creatinine clearance: 20 to 50 ml/min) did not affect steady-state plasma letrozole concentration at a dose of 2.5 mg or 5 mg. Hence, no dose adjustment is necessary for such renal function impairment. It is anticipated that letrozole could be removed from blood by dialysis since it is weakly bound to plasma proteins. The potential risks and benefits to such patients should be considered carefully before prescribing letrozole. In some cases, fatigue and dizziness have been observed with the use of letrozole. Patients should therefore, be advised that their physical and/or mental abilities required for operating machinery or driving a car may be impaired.

Clinical interaction studies with cimetidine and warfarin indicated that the co-administration of letrozole with these drugs does not result in clinically significant drug reactions, even through cimetidine is a known inhibitor of one of the cytochrome P450 isoenzymes capable of metabolising letrozole in vitro.

Oral administration of letrozole in pregnant rats resulted in teratogenicity and maternal toxicity at 0.03 mg/kg. Embryotoxicity and foetotoxicity were seen at doses >0.003 mg/kg and there was an increase in the incidence of foetal malformation among the animals treated. However, there are no adequate and well-controlled studies of letrozole in pregnant women and its use in these patients is not recommended. It is not known whether letrozole is excreted in human milk. Because many drugs are excreted in human milk, letrozole should not be administered to a nursing woman.

There is no clinical experience of overdosage. There is no specific antidote to letrozole. Since letrozole is not highly protein-bound, dialysis may be helpful. Emesis may be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs is appropriate.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFR ), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate 2 (FRS2 ) phosphorylation.

Absorption: The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with a high-fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.

Distribution: In vitro binding of Lenvatinib to human plasma proteins ranged from 98% to 99% at concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro.

Metabolism: The main metabolic pathways for Lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. Excretion: Ten days after a single administration of radiolabeled Lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

Elimination: The terminal elimination half-life of Lenvatinib was approximately 28 hours.

Important Dosage Information: The dose reduction is needed for certain patients with renal or hepatic impairment. Lenvatinib should be taken once daily, with or without food, at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Recommended Dosage for Differentiated Thyroid Cancer (DTC): The recommended dosage of Lenvatinib is 24 mg orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Renal Cell Carcinoma (RCC): The recommended dosage of Lenvatinib is 18 mg in combination with 5 mg Everolimus orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma (HCC): The recommended dosage of Lenvatinib is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Lenvatinib should be taken orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Endometrial Carcinoma: The recommended dosage of Lenvatinib is 20 mg orally once daily, in combination with Pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression.

Lenvatinib capsules can be swallowed whole or dissolved in a small glass of liquid. To dissolve in liquid, put capsules into 1 tablespoon of water or apple juice without breaking or crushing the capsules. Leave the capsules in the water or apple juice for at least 10 minutes. Stir for at least 3 minutes. After drinking the mixture, add 1 tablespoon of water or apple juice to the glass, swirl the contents a few times and swallow the water or apple juice.

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, wound healing complications.

It is contraindicated in patients with known hypersensitivity to Lenvatinib or to any component of the formulation.

Hypertension: Control blood pressure prior to initiating Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue Lenvatinib is based on severity.

Cardiac Dysfunction: Serious and fatal cardiac dysfunction can occur with Lenvatinib. Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Arterial Thromboembolic Events: Permanently discontinue Lenvatinib following an arterial thrombotic event. The safety of resuming Lenvatinib after an arterial thromboembolic event has not been established and Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity: Monitor liver function prior to initiating Lenvatinib, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Renal Failure or Impairment: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib for renal failure or impairment based on severity.

Proteinuria: Monitor for proteinuria prior to initiating Lenvatinib and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Diarrhea: Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Fistula Formation and Gastrointestinal Perforation: Permanently discontinue Lenvatinib in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula.

QT Interval Prolongation: Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at a reduced dose of Lenvatinib upon recovery based on severity.

Hypocalcemia: Hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction.

Reversible Posterior Leukoencephalopathy Syndrome: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events: Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue Lenvatinib based on the severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: Monitor thyroid function prior to initiating Lenvatinib and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications: Wound healing complications, including fistula formation and wound dehiscence, can occur with Lenvatinib. Withhold Lenvatinib for at least 6 days prior to scheduled surgery. Resume Lenvatinib after surgery based on clinical judgment of adequate wound healing. Permanently discontinue Lenvatinib in patients with wound healing complications.

Drugs That Prolong the QT Interval: Lenvatinib has been reported to prolong the QT/QTc interval. Avoid coadministration of Lenvatinib with medicinal products with a known potential to prolong the QT/QTc interval.

Use in Pregnancy: Based on the mechanism of action, Lenvatinib can cause embryo-fetal harm when administered to a pregnant female. Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment with Lenvatinib and for at least 30 days after the last dose.

Use in Lactation: It is not known whether Lenvatinib is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, women should be advised to discontinue breastfeeding during treatment with Lenvatinib and for at least 1 week after the last dose.

Dosage Modifications for Severe Renal Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is:

• Differentiated thyroid cancer: 14 mg orally once daily
• Renal cell carcinoma: 10 mg orally once daily
• Endometrial carcinoma: 10 mg orally once daily

Dosage Modifications for Severe Hepatic Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is:

• Differentiated thyroid cancer: 14 mg taken orally once daily
• Renal cell carcinoma: 10 mg taken orally once daily
• Endometrial carcinoma: 10 mg orally once daily Or as directed by the registered physician.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established.

Due to the high plasma protein binding, Lenvatinib is not expected to be dialyzable. Death due to multiorgan dysfunction occurred in a patient who received a single dose of Lenvatinib 120 mg orally.

Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.

Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFR ), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate 2 (FRS2 ) phosphorylation.

Absorption: The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with a high-fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.

Distribution: In vitro binding of Lenvatinib to human plasma proteins ranged from 98% to 99% at concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro.

Metabolism: The main metabolic pathways for Lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. Excretion: Ten days after a single administration of radiolabeled Lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

Elimination: The terminal elimination half-life of Lenvatinib was approximately 28 hours.

Important Dosage Information: The dose reduction is needed for certain patients with renal or hepatic impairment. Lenvatinib should be taken once daily, with or without food, at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Recommended Dosage for Differentiated Thyroid Cancer (DTC): The recommended dosage of Lenvatinib is 24 mg orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Renal Cell Carcinoma (RCC): The recommended dosage of Lenvatinib is 18 mg in combination with 5 mg Everolimus orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma (HCC): The recommended dosage of Lenvatinib is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Lenvatinib should be taken orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Endometrial Carcinoma: The recommended dosage of Lenvatinib is 20 mg orally once daily, in combination with Pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression.

Lenvatinib capsules can be swallowed whole or dissolved in a small glass of liquid. To dissolve in liquid, put capsules into 1 tablespoon of water or apple juice without breaking or crushing the capsules. Leave the capsules in the water or apple juice for at least 10 minutes. Stir for at least 3 minutes. After drinking the mixture, add 1 tablespoon of water or apple juice to the glass, swirl the contents a few times and swallow the water or apple juice.

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, wound healing complications.

It is contraindicated in patients with known hypersensitivity to Lenvatinib or to any component of the formulation.

Hypertension: Control blood pressure prior to initiating Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue Lenvatinib is based on severity.

Cardiac Dysfunction: Serious and fatal cardiac dysfunction can occur with Lenvatinib. Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Arterial Thromboembolic Events: Permanently discontinue Lenvatinib following an arterial thrombotic event. The safety of resuming Lenvatinib after an arterial thromboembolic event has not been established and Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity: Monitor liver function prior to initiating Lenvatinib, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Renal Failure or Impairment: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib for renal failure or impairment based on severity.

Proteinuria: Monitor for proteinuria prior to initiating Lenvatinib and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Diarrhea: Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Fistula Formation and Gastrointestinal Perforation: Permanently discontinue Lenvatinib in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula.

QT Interval Prolongation: Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at a reduced dose of Lenvatinib upon recovery based on severity.

Hypocalcemia: Hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction.

Reversible Posterior Leukoencephalopathy Syndrome: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events: Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue Lenvatinib based on the severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: Monitor thyroid function prior to initiating Lenvatinib and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications: Wound healing complications, including fistula formation and wound dehiscence, can occur with Lenvatinib. Withhold Lenvatinib for at least 6 days prior to scheduled surgery. Resume Lenvatinib after surgery based on clinical judgment of adequate wound healing. Permanently discontinue Lenvatinib in patients with wound healing complications.

Drugs That Prolong the QT Interval: Lenvatinib has been reported to prolong the QT/QTc interval. Avoid coadministration of Lenvatinib with medicinal products with a known potential to prolong the QT/QTc interval.

Use in Pregnancy: Based on the mechanism of action, Lenvatinib can cause embryo-fetal harm when administered to a pregnant female. Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment with Lenvatinib and for at least 30 days after the last dose.

Use in Lactation: It is not known whether Lenvatinib is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, women should be advised to discontinue breastfeeding during treatment with Lenvatinib and for at least 1 week after the last dose.

Dosage Modifications for Severe Renal Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is:

• Differentiated thyroid cancer: 14 mg orally once daily
• Renal cell carcinoma: 10 mg orally once daily
• Endometrial carcinoma: 10 mg orally once daily

Dosage Modifications for Severe Hepatic Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is:

• Differentiated thyroid cancer: 14 mg taken orally once daily
• Renal cell carcinoma: 10 mg taken orally once daily
• Endometrial carcinoma: 10 mg orally once daily Or as directed by the registered physician.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established.

Due to the high plasma protein binding, Lenvatinib is not expected to be dialyzable. Death due to multiorgan dysfunction occurred in a patient who received a single dose of Lenvatinib 120 mg orally.

Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.

Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFR ), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate 2 (FRS2 ) phosphorylation.

Absorption: The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with a high-fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.

Distribution: In vitro binding of Lenvatinib to human plasma proteins ranged from 98% to 99% at concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro.

Metabolism: The main metabolic pathways for Lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. Excretion: Ten days after a single administration of radiolabeled Lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

Elimination: The terminal elimination half-life of Lenvatinib was approximately 28 hours.

Important Dosage Information: The dose reduction is needed for certain patients with renal or hepatic impairment. Lenvatinib should be taken once daily, with or without food, at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Recommended Dosage for Differentiated Thyroid Cancer (DTC): The recommended dosage of Lenvatinib is 24 mg orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Renal Cell Carcinoma (RCC): The recommended dosage of Lenvatinib is 18 mg in combination with 5 mg Everolimus orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma (HCC): The recommended dosage of Lenvatinib is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Lenvatinib should be taken orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Endometrial Carcinoma: The recommended dosage of Lenvatinib is 20 mg orally once daily, in combination with Pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression.

Lenvatinib capsules can be swallowed whole or dissolved in a small glass of liquid. To dissolve in liquid, put capsules into 1 tablespoon of water or apple juice without breaking or crushing the capsules. Leave the capsules in the water or apple juice for at least 10 minutes. Stir for at least 3 minutes. After drinking the mixture, add 1 tablespoon of water or apple juice to the glass, swirl the contents a few times and swallow the water or apple juice.

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, wound healing complications.

It is contraindicated in patients with known hypersensitivity to Lenvatinib or to any component of the formulation.

Hypertension: Control blood pressure prior to initiating Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue Lenvatinib is based on severity.

Cardiac Dysfunction: Serious and fatal cardiac dysfunction can occur with Lenvatinib. Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Arterial Thromboembolic Events: Permanently discontinue Lenvatinib following an arterial thrombotic event. The safety of resuming Lenvatinib after an arterial thromboembolic event has not been established and Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity: Monitor liver function prior to initiating Lenvatinib, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Renal Failure or Impairment: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib for renal failure or impairment based on severity.

Proteinuria: Monitor for proteinuria prior to initiating Lenvatinib and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Diarrhea: Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Fistula Formation and Gastrointestinal Perforation: Permanently discontinue Lenvatinib in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula.

QT Interval Prolongation: Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at a reduced dose of Lenvatinib upon recovery based on severity.

Hypocalcemia: Hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction.

Reversible Posterior Leukoencephalopathy Syndrome: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events: Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue Lenvatinib based on the severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: Monitor thyroid function prior to initiating Lenvatinib and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications: Wound healing complications, including fistula formation and wound dehiscence, can occur with Lenvatinib. Withhold Lenvatinib for at least 6 days prior to scheduled surgery. Resume Lenvatinib after surgery based on clinical judgment of adequate wound healing. Permanently discontinue Lenvatinib in patients with wound healing complications.

Drugs That Prolong the QT Interval: Lenvatinib has been reported to prolong the QT/QTc interval. Avoid coadministration of Lenvatinib with medicinal products with a known potential to prolong the QT/QTc interval.

Use in Pregnancy: Based on the mechanism of action, Lenvatinib can cause embryo-fetal harm when administered to a pregnant female. Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment with Lenvatinib and for at least 30 days after the last dose.

Use in Lactation: It is not known whether Lenvatinib is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, women should be advised to discontinue breastfeeding during treatment with Lenvatinib and for at least 1 week after the last dose.

Dosage Modifications for Severe Renal Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is:

• Differentiated thyroid cancer: 14 mg orally once daily
• Renal cell carcinoma: 10 mg orally once daily
• Endometrial carcinoma: 10 mg orally once daily

Dosage Modifications for Severe Hepatic Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is:

• Differentiated thyroid cancer: 14 mg taken orally once daily
• Renal cell carcinoma: 10 mg taken orally once daily
• Endometrial carcinoma: 10 mg orally once daily Or as directed by the registered physician.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established.

Due to the high plasma protein binding, Lenvatinib is not expected to be dialyzable. Death due to multiorgan dysfunction occurred in a patient who received a single dose of Lenvatinib 120 mg orally.

Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.

Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFR ), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate 2 (FRS2 ) phosphorylation.

Absorption: The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with a high-fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.

Distribution: In vitro binding of Lenvatinib to human plasma proteins ranged from 98% to 99% at concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro.

Metabolism: The main metabolic pathways for Lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. Excretion: Ten days after a single administration of radiolabeled Lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

Elimination: The terminal elimination half-life of Lenvatinib was approximately 28 hours.

Important Dosage Information: The dose reduction is needed for certain patients with renal or hepatic impairment. Lenvatinib should be taken once daily, with or without food, at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Recommended Dosage for Differentiated Thyroid Cancer (DTC): The recommended dosage of Lenvatinib is 24 mg orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Renal Cell Carcinoma (RCC): The recommended dosage of Lenvatinib is 18 mg in combination with 5 mg Everolimus orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma (HCC): The recommended dosage of Lenvatinib is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Lenvatinib should be taken orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Endometrial Carcinoma: The recommended dosage of Lenvatinib is 20 mg orally once daily, in combination with Pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression.

Lenvatinib capsules can be swallowed whole or dissolved in a small glass of liquid. To dissolve in liquid, put capsules into 1 tablespoon of water or apple juice without breaking or crushing the capsules. Leave the capsules in the water or apple juice for at least 10 minutes. Stir for at least 3 minutes. After drinking the mixture, add 1 tablespoon of water or apple juice to the glass, swirl the contents a few times and swallow the water or apple juice.

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, wound healing complications.

It is contraindicated in patients with known hypersensitivity to Lenvatinib or to any component of the formulation.

Hypertension: Control blood pressure prior to initiating Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue Lenvatinib is based on severity.

Cardiac Dysfunction: Serious and fatal cardiac dysfunction can occur with Lenvatinib. Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Arterial Thromboembolic Events: Permanently discontinue Lenvatinib following an arterial thrombotic event. The safety of resuming Lenvatinib after an arterial thromboembolic event has not been established and Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity: Monitor liver function prior to initiating Lenvatinib, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Renal Failure or Impairment: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib for renal failure or impairment based on severity.

Proteinuria: Monitor for proteinuria prior to initiating Lenvatinib and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Diarrhea: Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Fistula Formation and Gastrointestinal Perforation: Permanently discontinue Lenvatinib in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula.

QT Interval Prolongation: Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at a reduced dose of Lenvatinib upon recovery based on severity.

Hypocalcemia: Hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction.

Reversible Posterior Leukoencephalopathy Syndrome: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events: Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue Lenvatinib based on the severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: Monitor thyroid function prior to initiating Lenvatinib and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications: Wound healing complications, including fistula formation and wound dehiscence, can occur with Lenvatinib. Withhold Lenvatinib for at least 6 days prior to scheduled surgery. Resume Lenvatinib after surgery based on clinical judgment of adequate wound healing. Permanently discontinue Lenvatinib in patients with wound healing complications.

Drugs That Prolong the QT Interval: Lenvatinib has been reported to prolong the QT/QTc interval. Avoid coadministration of Lenvatinib with medicinal products with a known potential to prolong the QT/QTc interval.

Use in Pregnancy: Based on the mechanism of action, Lenvatinib can cause embryo-fetal harm when administered to a pregnant female. Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment with Lenvatinib and for at least 30 days after the last dose.

Use in Lactation: It is not known whether Lenvatinib is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, women should be advised to discontinue breastfeeding during treatment with Lenvatinib and for at least 1 week after the last dose.

Dosage Modifications for Severe Renal Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is:

• Differentiated thyroid cancer: 14 mg orally once daily
• Renal cell carcinoma: 10 mg orally once daily
• Endometrial carcinoma: 10 mg orally once daily

Dosage Modifications for Severe Hepatic Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is:

• Differentiated thyroid cancer: 14 mg taken orally once daily
• Renal cell carcinoma: 10 mg taken orally once daily
• Endometrial carcinoma: 10 mg orally once daily Or as directed by the registered physician.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established.

Due to the high plasma protein binding, Lenvatinib is not expected to be dialyzable. Death due to multiorgan dysfunction occurred in a patient who received a single dose of Lenvatinib 120 mg orally.

Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.

Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFR ), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate 2 (FRS2 ) phosphorylation.

Absorption: The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with a high-fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.

Distribution: In vitro binding of Lenvatinib to human plasma proteins ranged from 98% to 99% at concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro.

Metabolism: The main metabolic pathways for Lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. Excretion: Ten days after a single administration of radiolabeled Lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

Elimination: The terminal elimination half-life of Lenvatinib was approximately 28 hours.

Important Dosage Information: The dose reduction is needed for certain patients with renal or hepatic impairment. Lenvatinib should be taken once daily, with or without food, at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Recommended Dosage for Differentiated Thyroid Cancer (DTC): The recommended dosage of Lenvatinib is 24 mg orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Renal Cell Carcinoma (RCC): The recommended dosage of Lenvatinib is 18 mg in combination with 5 mg Everolimus orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma (HCC): The recommended dosage of Lenvatinib is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Lenvatinib should be taken orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Endometrial Carcinoma: The recommended dosage of Lenvatinib is 20 mg orally once daily, in combination with Pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression.

Lenvatinib capsules can be swallowed whole or dissolved in a small glass of liquid. To dissolve in liquid, put capsules into 1 tablespoon of water or apple juice without breaking or crushing the capsules. Leave the capsules in the water or apple juice for at least 10 minutes. Stir for at least 3 minutes. After drinking the mixture, add 1 tablespoon of water or apple juice to the glass, swirl the contents a few times and swallow the water or apple juice.

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, wound healing complications.

It is contraindicated in patients with known hypersensitivity to Lenvatinib or to any component of the formulation.

Hypertension: Control blood pressure prior to initiating Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue Lenvatinib is based on severity.

Cardiac Dysfunction: Serious and fatal cardiac dysfunction can occur with Lenvatinib. Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Arterial Thromboembolic Events: Permanently discontinue Lenvatinib following an arterial thrombotic event. The safety of resuming Lenvatinib after an arterial thromboembolic event has not been established and Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity: Monitor liver function prior to initiating Lenvatinib, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Renal Failure or Impairment: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib for renal failure or impairment based on severity.

Proteinuria: Monitor for proteinuria prior to initiating Lenvatinib and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Diarrhea: Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Fistula Formation and Gastrointestinal Perforation: Permanently discontinue Lenvatinib in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula.

QT Interval Prolongation: Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at a reduced dose of Lenvatinib upon recovery based on severity.

Hypocalcemia: Hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction.

Reversible Posterior Leukoencephalopathy Syndrome: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events: Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue Lenvatinib based on the severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: Monitor thyroid function prior to initiating Lenvatinib and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications: Wound healing complications, including fistula formation and wound dehiscence, can occur with Lenvatinib. Withhold Lenvatinib for at least 6 days prior to scheduled surgery. Resume Lenvatinib after surgery based on clinical judgment of adequate wound healing. Permanently discontinue Lenvatinib in patients with wound healing complications.

Drugs That Prolong the QT Interval: Lenvatinib has been reported to prolong the QT/QTc interval. Avoid coadministration of Lenvatinib with medicinal products with a known potential to prolong the QT/QTc interval.

Use in Pregnancy: Based on the mechanism of action, Lenvatinib can cause embryo-fetal harm when administered to a pregnant female. Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment with Lenvatinib and for at least 30 days after the last dose.

Use in Lactation: It is not known whether Lenvatinib is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, women should be advised to discontinue breastfeeding during treatment with Lenvatinib and for at least 1 week after the last dose.

Dosage Modifications for Severe Renal Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is:

• Differentiated thyroid cancer: 14 mg orally once daily
• Renal cell carcinoma: 10 mg orally once daily
• Endometrial carcinoma: 10 mg orally once daily

Dosage Modifications for Severe Hepatic Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is:

• Differentiated thyroid cancer: 14 mg taken orally once daily
• Renal cell carcinoma: 10 mg taken orally once daily
• Endometrial carcinoma: 10 mg orally once daily Or as directed by the registered physician.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established.

Due to the high plasma protein binding, Lenvatinib is not expected to be dialyzable. Death due to multiorgan dysfunction occurred in a patient who received a single dose of Lenvatinib 120 mg orally.

Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.

Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFR ), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate 2 (FRS2 ) phosphorylation.

Absorption: The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with a high-fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.

Distribution: In vitro binding of Lenvatinib to human plasma proteins ranged from 98% to 99% at concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro.

Metabolism: The main metabolic pathways for Lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. Excretion: Ten days after a single administration of radiolabeled Lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

Elimination: The terminal elimination half-life of Lenvatinib was approximately 28 hours.

Important Dosage Information: The dose reduction is needed for certain patients with renal or hepatic impairment. Lenvatinib should be taken once daily, with or without food, at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Recommended Dosage for Differentiated Thyroid Cancer (DTC): The recommended dosage of Lenvatinib is 24 mg orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Renal Cell Carcinoma (RCC): The recommended dosage of Lenvatinib is 18 mg in combination with 5 mg Everolimus orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma (HCC): The recommended dosage of Lenvatinib is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Lenvatinib should be taken orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Endometrial Carcinoma: The recommended dosage of Lenvatinib is 20 mg orally once daily, in combination with Pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression.

Lenvatinib capsules can be swallowed whole or dissolved in a small glass of liquid. To dissolve in liquid, put capsules into 1 tablespoon of water or apple juice without breaking or crushing the capsules. Leave the capsules in the water or apple juice for at least 10 minutes. Stir for at least 3 minutes. After drinking the mixture, add 1 tablespoon of water or apple juice to the glass, swirl the contents a few times and swallow the water or apple juice.

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, wound healing complications.

It is contraindicated in patients with known hypersensitivity to Lenvatinib or to any component of the formulation.

Hypertension: Control blood pressure prior to initiating Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue Lenvatinib is based on severity.

Cardiac Dysfunction: Serious and fatal cardiac dysfunction can occur with Lenvatinib. Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Arterial Thromboembolic Events: Permanently discontinue Lenvatinib following an arterial thrombotic event. The safety of resuming Lenvatinib after an arterial thromboembolic event has not been established and Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity: Monitor liver function prior to initiating Lenvatinib, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Renal Failure or Impairment: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib for renal failure or impairment based on severity.

Proteinuria: Monitor for proteinuria prior to initiating Lenvatinib and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Diarrhea: Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Fistula Formation and Gastrointestinal Perforation: Permanently discontinue Lenvatinib in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula.

QT Interval Prolongation: Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at a reduced dose of Lenvatinib upon recovery based on severity.

Hypocalcemia: Hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction.

Reversible Posterior Leukoencephalopathy Syndrome: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events: Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue Lenvatinib based on the severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: Monitor thyroid function prior to initiating Lenvatinib and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications: Wound healing complications, including fistula formation and wound dehiscence, can occur with Lenvatinib. Withhold Lenvatinib for at least 6 days prior to scheduled surgery. Resume Lenvatinib after surgery based on clinical judgment of adequate wound healing. Permanently discontinue Lenvatinib in patients with wound healing complications.

Drugs That Prolong the QT Interval: Lenvatinib has been reported to prolong the QT/QTc interval. Avoid coadministration of Lenvatinib with medicinal products with a known potential to prolong the QT/QTc interval.

Use in Pregnancy: Based on the mechanism of action, Lenvatinib can cause embryo-fetal harm when administered to a pregnant female. Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment with Lenvatinib and for at least 30 days after the last dose.

Use in Lactation: It is not known whether Lenvatinib is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, women should be advised to discontinue breastfeeding during treatment with Lenvatinib and for at least 1 week after the last dose.

Dosage Modifications for Severe Renal Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is:

• Differentiated thyroid cancer: 14 mg orally once daily
• Renal cell carcinoma: 10 mg orally once daily
• Endometrial carcinoma: 10 mg orally once daily

Dosage Modifications for Severe Hepatic Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is:

• Differentiated thyroid cancer: 14 mg taken orally once daily
• Renal cell carcinoma: 10 mg taken orally once daily
• Endometrial carcinoma: 10 mg orally once daily Or as directed by the registered physician.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established.

Due to the high plasma protein binding, Lenvatinib is not expected to be dialyzable. Death due to multiorgan dysfunction occurred in a patient who received a single dose of Lenvatinib 120 mg orally.

Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.

Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFR ), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate 2 (FRS2 ) phosphorylation.

Absorption: The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with a high-fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.

Distribution: In vitro binding of Lenvatinib to human plasma proteins ranged from 98% to 99% at concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro.

Metabolism: The main metabolic pathways for Lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. Excretion: Ten days after a single administration of radiolabeled Lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

Elimination: The terminal elimination half-life of Lenvatinib was approximately 28 hours.

Important Dosage Information: The dose reduction is needed for certain patients with renal or hepatic impairment. Lenvatinib should be taken once daily, with or without food, at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Recommended Dosage for Differentiated Thyroid Cancer (DTC): The recommended dosage of Lenvatinib is 24 mg orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Renal Cell Carcinoma (RCC): The recommended dosage of Lenvatinib is 18 mg in combination with 5 mg Everolimus orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma (HCC): The recommended dosage of Lenvatinib is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Lenvatinib should be taken orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Endometrial Carcinoma: The recommended dosage of Lenvatinib is 20 mg orally once daily, in combination with Pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression.

Lenvatinib capsules can be swallowed whole or dissolved in a small glass of liquid. To dissolve in liquid, put capsules into 1 tablespoon of water or apple juice without breaking or crushing the capsules. Leave the capsules in the water or apple juice for at least 10 minutes. Stir for at least 3 minutes. After drinking the mixture, add 1 tablespoon of water or apple juice to the glass, swirl the contents a few times and swallow the water or apple juice.

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, wound healing complications.

It is contraindicated in patients with known hypersensitivity to Lenvatinib or to any component of the formulation.

Hypertension: Control blood pressure prior to initiating Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue Lenvatinib is based on severity.

Cardiac Dysfunction: Serious and fatal cardiac dysfunction can occur with Lenvatinib. Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Arterial Thromboembolic Events: Permanently discontinue Lenvatinib following an arterial thrombotic event. The safety of resuming Lenvatinib after an arterial thromboembolic event has not been established and Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity: Monitor liver function prior to initiating Lenvatinib, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Renal Failure or Impairment: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib for renal failure or impairment based on severity.

Proteinuria: Monitor for proteinuria prior to initiating Lenvatinib and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Diarrhea: Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Fistula Formation and Gastrointestinal Perforation: Permanently discontinue Lenvatinib in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula.

QT Interval Prolongation: Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at a reduced dose of Lenvatinib upon recovery based on severity.

Hypocalcemia: Hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction.

Reversible Posterior Leukoencephalopathy Syndrome: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events: Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue Lenvatinib based on the severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: Monitor thyroid function prior to initiating Lenvatinib and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications: Wound healing complications, including fistula formation and wound dehiscence, can occur with Lenvatinib. Withhold Lenvatinib for at least 6 days prior to scheduled surgery. Resume Lenvatinib after surgery based on clinical judgment of adequate wound healing. Permanently discontinue Lenvatinib in patients with wound healing complications.

Drugs That Prolong the QT Interval: Lenvatinib has been reported to prolong the QT/QTc interval. Avoid coadministration of Lenvatinib with medicinal products with a known potential to prolong the QT/QTc interval.

Use in Pregnancy: Based on the mechanism of action, Lenvatinib can cause embryo-fetal harm when administered to a pregnant female. Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment with Lenvatinib and for at least 30 days after the last dose.

Use in Lactation: It is not known whether Lenvatinib is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, women should be advised to discontinue breastfeeding during treatment with Lenvatinib and for at least 1 week after the last dose.

Dosage Modifications for Severe Renal Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is:

• Differentiated thyroid cancer: 14 mg orally once daily
• Renal cell carcinoma: 10 mg orally once daily
• Endometrial carcinoma: 10 mg orally once daily

Dosage Modifications for Severe Hepatic Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is:

• Differentiated thyroid cancer: 14 mg taken orally once daily
• Renal cell carcinoma: 10 mg taken orally once daily
• Endometrial carcinoma: 10 mg orally once daily Or as directed by the registered physician.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established.

Due to the high plasma protein binding, Lenvatinib is not expected to be dialyzable. Death due to multiorgan dysfunction occurred in a patient who received a single dose of Lenvatinib 120 mg orally.

Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.

Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFR ), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate 2 (FRS2 ) phosphorylation.

Absorption: The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with a high-fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.

Distribution: In vitro binding of Lenvatinib to human plasma proteins ranged from 98% to 99% at concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro.

Metabolism: The main metabolic pathways for Lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. Excretion: Ten days after a single administration of radiolabeled Lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

Elimination: The terminal elimination half-life of Lenvatinib was approximately 28 hours.

Important Dosage Information: The dose reduction is needed for certain patients with renal or hepatic impairment. Lenvatinib should be taken once daily, with or without food, at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Recommended Dosage for Differentiated Thyroid Cancer (DTC): The recommended dosage of Lenvatinib is 24 mg orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Renal Cell Carcinoma (RCC): The recommended dosage of Lenvatinib is 18 mg in combination with 5 mg Everolimus orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma (HCC): The recommended dosage of Lenvatinib is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Lenvatinib should be taken orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Endometrial Carcinoma: The recommended dosage of Lenvatinib is 20 mg orally once daily, in combination with Pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression.

Lenvatinib capsules can be swallowed whole or dissolved in a small glass of liquid. To dissolve in liquid, put capsules into 1 tablespoon of water or apple juice without breaking or crushing the capsules. Leave the capsules in the water or apple juice for at least 10 minutes. Stir for at least 3 minutes. After drinking the mixture, add 1 tablespoon of water or apple juice to the glass, swirl the contents a few times and swallow the water or apple juice.

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, wound healing complications.

It is contraindicated in patients with known hypersensitivity to Lenvatinib or to any component of the formulation.

Hypertension: Control blood pressure prior to initiating Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue Lenvatinib is based on severity.

Cardiac Dysfunction: Serious and fatal cardiac dysfunction can occur with Lenvatinib. Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Arterial Thromboembolic Events: Permanently discontinue Lenvatinib following an arterial thrombotic event. The safety of resuming Lenvatinib after an arterial thromboembolic event has not been established and Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity: Monitor liver function prior to initiating Lenvatinib, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Renal Failure or Impairment: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib for renal failure or impairment based on severity.

Proteinuria: Monitor for proteinuria prior to initiating Lenvatinib and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Diarrhea: Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Fistula Formation and Gastrointestinal Perforation: Permanently discontinue Lenvatinib in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula.

QT Interval Prolongation: Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at a reduced dose of Lenvatinib upon recovery based on severity.

Hypocalcemia: Hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction.

Reversible Posterior Leukoencephalopathy Syndrome: Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events: Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue Lenvatinib based on the severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: Monitor thyroid function prior to initiating Lenvatinib and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications: Wound healing complications, including fistula formation and wound dehiscence, can occur with Lenvatinib. Withhold Lenvatinib for at least 6 days prior to scheduled surgery. Resume Lenvatinib after surgery based on clinical judgment of adequate wound healing. Permanently discontinue Lenvatinib in patients with wound healing complications.

Drugs That Prolong the QT Interval: Lenvatinib has been reported to prolong the QT/QTc interval. Avoid coadministration of Lenvatinib with medicinal products with a known potential to prolong the QT/QTc interval.

Use in Pregnancy: Based on the mechanism of action, Lenvatinib can cause embryo-fetal harm when administered to a pregnant female. Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to use effective contraception during treatment with Lenvatinib and for at least 30 days after the last dose.

Use in Lactation: It is not known whether Lenvatinib is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, women should be advised to discontinue breastfeeding during treatment with Lenvatinib and for at least 1 week after the last dose.

Dosage Modifications for Severe Renal Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is:

• Differentiated thyroid cancer: 14 mg orally once daily
• Renal cell carcinoma: 10 mg orally once daily
• Endometrial carcinoma: 10 mg orally once daily

Dosage Modifications for Severe Hepatic Impairment: The recommended dosage of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is:

• Differentiated thyroid cancer: 14 mg taken orally once daily
• Renal cell carcinoma: 10 mg taken orally once daily
• Endometrial carcinoma: 10 mg orally once daily Or as directed by the registered physician.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established.

Due to the high plasma protein binding, Lenvatinib is not expected to be dialyzable. Death due to multiorgan dysfunction occurred in a patient who received a single dose of Lenvatinib 120 mg orally.

Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.

4-Quinolone preparations

Levofloxacin is a synthetic, broad-spectrum, third generation fluoroquinolone antibiotic. Chemically, Levofloxacin is a chiral fluorinated carboxyquinolone. Levofloxacin exerts antibacterial action by inhibiting bacterial topoisomerase IV and DNA gyrase, the enzymes required for DNA replication, transcription repair and recombination. It has in vitro activity against a wide range of gm-ve and gm+ve microorganisms.

The usual dose of Levofloxacin Tablets is 250 mg or 500 mg or 750 mg administered orally every 24 hours. Levofloxacin tablets can be administered without regard to food. Levofloxacin oral solution should be taken 1 hour before, or  2 hours after eating.

Levofloxacin injection should only be administered by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration. The usual dose of Levofloxacin injection is 250 mg or 500 mg administered by slow infusion over 60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 24 hours. Since the Levofloxacin injections are for single-use only, any unused portion should be discarded. Additives or other medications should not be added to Levofloxacin Injection or infused simultaneously through the same intravenous line.

Adults:

• Acute sinusitis: 500 mg once daily for 10-14 days, or 750 mg once daily for 5 days
• Exacerbation of chronic bronchitis: 500 mg once daily for 7 days, or 750 mg once daily for 3 days (Uncomplicated), 750 mg once daily for 5 days (Complicated)
• Community-acquired pneumonia: 500 mg once daily for 7-14 days, or 750 mg once daily for 5 days
• Uncomplicated urinary-tract infections: 250 mg once daily for 3 days
• Complicated urinary-tract infections and acute pyelonephritis: 250 mg once daily for 7-10 days
• Uncomplicated skin and soft-tissue infections: 500 mg once daily for 7-10 days.
• Complicated skin and soft-tissue infections: 750 mg once daily for 7-14 days.
• Enteric fever: 500 mg once daily for 7-14 days.
• Diarrhea, cholera, shigellosis & enteritis: Mild to moderate case: 500 mg (single dose). Moderate to sever case: 500 mg once daily for 3 days

Children:

• Children 6 months to <5 years: 10 mg/kg every 12 hours.
• Children >5 years: 10 mg/kg every 24 hours

In each case, sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.

Instructions for the Use of Levofloxacin Infusion-

• Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution.
• Do not use if the solution is cloudy or a precipitate is present.
• Do not use flexible containers in series connections.
• Close flow control clamp of administration set.
• Remove cover from port at bottom of container.
• Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.
• Suspend container from hanger.
• Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Levoxin Injection.
• Open flow control clamp to expel air from set. Close clamp.
• Regulate rate of administration with flow control clamp.

Levofloxacin is generally well tolerated. However, a few side-effects can usually be seen. There is a risk of retinal detachment. Other side-effects include: nausea, vomiting, diarrhea, abdominal pain, flatulence and rare occurrence of phototoxicity (0.1%). Side-effects that may be seen very rarely include tremors, depression, anxiety, confusion etc.

Levofloxacin is contraindicated in patients with a history of hypersensitivity to levofloxacin, quinolone antimicrobial agents, or any other components of this product.

The following measures should be taken during administration of Levofloxacin:

• Levofloxacin Injection should only be administered by slow intravenous infusion over a period of 60 or 90 minutes depending on the dosage.
• While administrating Levofloxacin, adequate amount of water should be taken to avoid concentrated form of urine.
• Dose adjustment should be exercised during Levofloxacin administration in presence of renal insufficiency.

No quinolone should be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line. Antacids, Iron and Adsorbents reduce absorption of Levofloxacin. NSAID may increase the risk of CNS stimulation. Warfarin may increase the risk of bleeding.

Levofloxacin is not recommended for use during pregnancy or nursing, as the effects on the unborn child or nursing infant are unknown.

Levofloxacin exhibits a low potential for acute toxicity. However, in the events of an acute overdosage, the stomach should be emptied. The patients should be kept under observation and appropriate hydration should be maintained.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

4-Quinolone preparations

Levofloxacin is a synthetic, broad-spectrum, third generation fluoroquinolone antibiotic. Chemically, Levofloxacin is a chiral fluorinated carboxyquinolone. Levofloxacin exerts antibacterial action by inhibiting bacterial topoisomerase IV and DNA gyrase, the enzymes required for DNA replication, transcription repair and recombination. It has in vitro activity against a wide range of gm-ve and gm+ve microorganisms.

The usual dose of Levofloxacin Tablets is 250 mg or 500 mg or 750 mg administered orally every 24 hours. Levofloxacin tablets can be administered without regard to food. Levofloxacin oral solution should be taken 1 hour before, or  2 hours after eating.

Levofloxacin injection should only be administered by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration. The usual dose of Levofloxacin injection is 250 mg or 500 mg administered by slow infusion over 60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 24 hours. Since the Levofloxacin injections are for single-use only, any unused portion should be discarded. Additives or other medications should not be added to Levofloxacin Injection or infused simultaneously through the same intravenous line.

Adults:

• Acute sinusitis: 500 mg once daily for 10-14 days, or 750 mg once daily for 5 days
• Exacerbation of chronic bronchitis: 500 mg once daily for 7 days, or 750 mg once daily for 3 days (Uncomplicated), 750 mg once daily for 5 days (Complicated)
• Community-acquired pneumonia: 500 mg once daily for 7-14 days, or 750 mg once daily for 5 days
• Uncomplicated urinary-tract infections: 250 mg once daily for 3 days
• Complicated urinary-tract infections and acute pyelonephritis: 250 mg once daily for 7-10 days
• Uncomplicated skin and soft-tissue infections: 500 mg once daily for 7-10 days.
• Complicated skin and soft-tissue infections: 750 mg once daily for 7-14 days.
• Enteric fever: 500 mg once daily for 7-14 days.
• Diarrhea, cholera, shigellosis & enteritis: Mild to moderate case: 500 mg (single dose). Moderate to sever case: 500 mg once daily for 3 days

Children:

• Children 6 months to <5 years: 10 mg/kg every 12 hours.
• Children >5 years: 10 mg/kg every 24 hours

In each case, sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.

Instructions for the Use of Levofloxacin Infusion-

• Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution.
• Do not use if the solution is cloudy or a precipitate is present.
• Do not use flexible containers in series connections.
• Close flow control clamp of administration set.
• Remove cover from port at bottom of container.
• Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.
• Suspend container from hanger.
• Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Levoxin Injection.
• Open flow control clamp to expel air from set. Close clamp.
• Regulate rate of administration with flow control clamp.

Levofloxacin is generally well tolerated. However, a few side-effects can usually be seen. There is a risk of retinal detachment. Other side-effects include: nausea, vomiting, diarrhea, abdominal pain, flatulence and rare occurrence of phototoxicity (0.1%). Side-effects that may be seen very rarely include tremors, depression, anxiety, confusion etc.

Levofloxacin is contraindicated in patients with a history of hypersensitivity to levofloxacin, quinolone antimicrobial agents, or any other components of this product.

The following measures should be taken during administration of Levofloxacin:

• Levofloxacin Injection should only be administered by slow intravenous infusion over a period of 60 or 90 minutes depending on the dosage.
• While administrating Levofloxacin, adequate amount of water should be taken to avoid concentrated form of urine.
• Dose adjustment should be exercised during Levofloxacin administration in presence of renal insufficiency.

No quinolone should be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line. Antacids, Iron and Adsorbents reduce absorption of Levofloxacin. NSAID may increase the risk of CNS stimulation. Warfarin may increase the risk of bleeding.

Levofloxacin is not recommended for use during pregnancy or nursing, as the effects on the unborn child or nursing infant are unknown.

Levofloxacin exhibits a low potential for acute toxicity. However, in the events of an acute overdosage, the stomach should be emptied. The patients should be kept under observation and appropriate hydration should be maintained.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

4-Quinolone preparations

Levofloxacin eye drops is a sterile topical ophthalmic solution. It is a synthetic, broad spectrum, third generation fluoroquinolone bactericidal antibiotic, which active against a broad spectrum of Gram-positive & Gram-negative ocular pathogens. It functions by inhibiting bacterial topoisomerase IV and DNA gyrase enzymes required for DNA replication, transcription, repair and recombination.

0.5% eye drop: Adults and children 1 year of age and older:

• Days 1 and 2: Instill 1-2 drops in the affected eye(s) every 2 hours while awake, up to 8 times per day.
• Days 3 through 7: Instill 1-2 drops in the affected eye(s) every 4 hours while awake, up to 4 times per day.

1.5% eye drop: Adults and children 6 years of age and older:

• Days 1 through 3: Instill one to two drops in the affected eye(s) every 30 minutes to 2 hours while awake and approximately 4 and 6 hours after retiring.
• Day 4 through treatment completion: Instill one to two drops in the affected eye(s) every 1 to 4 hours while awake.

Children <1 year: Safety and effectiveness of Levofloxacin below 1 year of age have not been established.

Side effects occurred only approximately 1-3% of patients that may include transient blurred vision, fever, foreign body sensation, headache, transient ocular burning, ocular pain or discomfort, pharyngitis and photophobia. In less than 1% of patients included allergic reactions, lid edema, ocular dryness and ocular itching.

It is contraindicated in patients with a history of hypersensitivity to Levofloxacin, to other quinolones or to any of the components of this medication

Prolonged use may result in the overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy.

Specific drug interaction studies have not been conducted with levofloxacin eye drops. But the systemic administration of some quinolones has been shown to elevate plasma concentrations of theophylline, interfere with the metabolism of caffeine and enhance the effects of the oral anticoagulant warfarin and its derivatives.

Pregnancy Category C. Levofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Levofloxacin has not been measured in human milk. Caution should be exercised when Levofloxacin eye drops is administered to a nursing mother.

Eye drops should be protected from light, store in a cool (15°-25° C) and dry place & keep out of reach of children.

4-Quinolone preparations

Levofloxacin is a synthetic, broad-spectrum, third generation fluoroquinolone antibiotic. Chemically, Levofloxacin is a chiral fluorinated carboxyquinolone. Levofloxacin exerts antibacterial action by inhibiting bacterial topoisomerase IV and DNA gyrase, the enzymes required for DNA replication, transcription repair and recombination. It has in vitro activity against a wide range of gm-ve and gm+ve microorganisms.

The usual dose of Levofloxacin Tablets is 250 mg or 500 mg or 750 mg administered orally every 24 hours. Levofloxacin tablets can be administered without regard to food. Levofloxacin oral solution should be taken 1 hour before, or  2 hours after eating.

Levofloxacin injection should only be administered by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration. The usual dose of Levofloxacin injection is 250 mg or 500 mg administered by slow infusion over 60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 24 hours. Since the Levofloxacin injections are for single-use only, any unused portion should be discarded. Additives or other medications should not be added to Levofloxacin Injection or infused simultaneously through the same intravenous line.

Adults:

• Acute sinusitis: 500 mg once daily for 10-14 days, or 750 mg once daily for 5 days
• Exacerbation of chronic bronchitis: 500 mg once daily for 7 days, or 750 mg once daily for 3 days (Uncomplicated), 750 mg once daily for 5 days (Complicated)
• Community-acquired pneumonia: 500 mg once daily for 7-14 days, or 750 mg once daily for 5 days
• Uncomplicated urinary-tract infections: 250 mg once daily for 3 days
• Complicated urinary-tract infections and acute pyelonephritis: 250 mg once daily for 7-10 days
• Uncomplicated skin and soft-tissue infections: 500 mg once daily for 7-10 days.
• Complicated skin and soft-tissue infections: 750 mg once daily for 7-14 days.
• Enteric fever: 500 mg once daily for 7-14 days.
• Diarrhea, cholera, shigellosis & enteritis: Mild to moderate case: 500 mg (single dose). Moderate to sever case: 500 mg once daily for 3 days

Children:

• Children 6 months to <5 years: 10 mg/kg every 12 hours.
• Children >5 years: 10 mg/kg every 24 hours

In each case, sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.

Instructions for the Use of Levofloxacin Infusion-

• Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution.
• Do not use if the solution is cloudy or a precipitate is present.
• Do not use flexible containers in series connections.
• Close flow control clamp of administration set.
• Remove cover from port at bottom of container.
• Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.
• Suspend container from hanger.
• Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Levoxin Injection.
• Open flow control clamp to expel air from set. Close clamp.
• Regulate rate of administration with flow control clamp.

Levofloxacin is generally well tolerated. However, a few side-effects can usually be seen. There is a risk of retinal detachment. Other side-effects include: nausea, vomiting, diarrhea, abdominal pain, flatulence and rare occurrence of phototoxicity (0.1%). Side-effects that may be seen very rarely include tremors, depression, anxiety, confusion etc.

Levofloxacin is contraindicated in patients with a history of hypersensitivity to levofloxacin, quinolone antimicrobial agents, or any other components of this product.

The following measures should be taken during administration of Levofloxacin:

• Levofloxacin Injection should only be administered by slow intravenous infusion over a period of 60 or 90 minutes depending on the dosage.
• While administrating Levofloxacin, adequate amount of water should be taken to avoid concentrated form of urine.
• Dose adjustment should be exercised during Levofloxacin administration in presence of renal insufficiency.

No quinolone should be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line. Antacids, Iron and Adsorbents reduce absorption of Levofloxacin. NSAID may increase the risk of CNS stimulation. Warfarin may increase the risk of bleeding.

Levofloxacin is not recommended for use during pregnancy or nursing, as the effects on the unborn child or nursing infant are unknown.

Levofloxacin exhibits a low potential for acute toxicity. However, in the events of an acute overdosage, the stomach should be emptied. The patients should be kept under observation and appropriate hydration should be maintained.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

4-Quinolone preparations

Levofloxacin is a synthetic, broad-spectrum, third generation fluoroquinolone antibiotic. Chemically, Levofloxacin is a chiral fluorinated carboxyquinolone. Levofloxacin exerts antibacterial action by inhibiting bacterial topoisomerase IV and DNA gyrase, the enzymes required for DNA replication, transcription repair and recombination. It has in vitro activity against a wide range of gm-ve and gm+ve microorganisms.

The usual dose of Levofloxacin Tablets is 250 mg or 500 mg or 750 mg administered orally every 24 hours. Levofloxacin tablets can be administered without regard to food. Levofloxacin oral solution should be taken 1 hour before, or  2 hours after eating.

Levofloxacin injection should only be administered by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration. The usual dose of Levofloxacin injection is 250 mg or 500 mg administered by slow infusion over 60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 24 hours. Since the Levofloxacin injections are for single-use only, any unused portion should be discarded. Additives or other medications should not be added to Levofloxacin Injection or infused simultaneously through the same intravenous line.

Adults:

• Acute sinusitis: 500 mg once daily for 10-14 days, or 750 mg once daily for 5 days
• Exacerbation of chronic bronchitis: 500 mg once daily for 7 days, or 750 mg once daily for 3 days (Uncomplicated), 750 mg once daily for 5 days (Complicated)
• Community-acquired pneumonia: 500 mg once daily for 7-14 days, or 750 mg once daily for 5 days
• Uncomplicated urinary-tract infections: 250 mg once daily for 3 days
• Complicated urinary-tract infections and acute pyelonephritis: 250 mg once daily for 7-10 days
• Uncomplicated skin and soft-tissue infections: 500 mg once daily for 7-10 days.
• Complicated skin and soft-tissue infections: 750 mg once daily for 7-14 days.
• Enteric fever: 500 mg once daily for 7-14 days.
• Diarrhea, cholera, shigellosis & enteritis: Mild to moderate case: 500 mg (single dose). Moderate to sever case: 500 mg once daily for 3 days

Children:

• Children 6 months to <5 years: 10 mg/kg every 12 hours.
• Children >5 years: 10 mg/kg every 24 hours

In each case, sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.

Instructions for the Use of Levofloxacin Infusion-

• Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution.
• Do not use if the solution is cloudy or a precipitate is present.
• Do not use flexible containers in series connections.
• Close flow control clamp of administration set.
• Remove cover from port at bottom of container.
• Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.
• Suspend container from hanger.
• Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Levoxin Injection.
• Open flow control clamp to expel air from set. Close clamp.
• Regulate rate of administration with flow control clamp.

Levofloxacin is generally well tolerated. However, a few side-effects can usually be seen. There is a risk of retinal detachment. Other side-effects include: nausea, vomiting, diarrhea, abdominal pain, flatulence and rare occurrence of phototoxicity (0.1%). Side-effects that may be seen very rarely include tremors, depression, anxiety, confusion etc.

Levofloxacin is contraindicated in patients with a history of hypersensitivity to levofloxacin, quinolone antimicrobial agents, or any other components of this product.

The following measures should be taken during administration of Levofloxacin:

• Levofloxacin Injection should only be administered by slow intravenous infusion over a period of 60 or 90 minutes depending on the dosage.
• While administrating Levofloxacin, adequate amount of water should be taken to avoid concentrated form of urine.
• Dose adjustment should be exercised during Levofloxacin administration in presence of renal insufficiency.

No quinolone should be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line. Antacids, Iron and Adsorbents reduce absorption of Levofloxacin. NSAID may increase the risk of CNS stimulation. Warfarin may increase the risk of bleeding.

Levofloxacin is not recommended for use during pregnancy or nursing, as the effects on the unborn child or nursing infant are unknown.

Levofloxacin exhibits a low potential for acute toxicity. However, in the events of an acute overdosage, the stomach should be emptied. The patients should be kept under observation and appropriate hydration should be maintained.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Dextromethorphan is indicated in Chronic dry cough or unproductive cough; Acute dry cough which is interfering with normal function or sleep.

Cough suppressant

Dextromethorphan suppresses the cough reflex by a direct action on the cough center in the medulla of the brain. Dextromethorphan shows high affinity binding to several regions of the brain, including the medullary cough center. This compound is an NMDA receptor antagonist and acts as a non-competitive channel blocker. It is one of the widely used antitussives, and is also used to study the involvement of glutamate receptors in neurotoxicity.

Adults and Children over 12 years: 15 to 30 mg three to four times per day. However, 60 mg doses up to four times per day have been used without increased side effects.
Children between 6 and 12 years: 5-15 mg up to four times per day.
Children between 2 and 6 years: 2.5-5 mg up to four times per day.

Adverse effects with Dextromethorphan are rare, but nausea and dizziness sometimes occur. The drug produces no analgesia or addiction and little or no CNS depression. Excitation, confusion and respiratory depression may occur after overdosage.

Hypersensitivity to Dextromethorphan or any other component.

Do not use Dextromethorphan to control a cough that is associated with smoking, asthma, or emphysema, or a cough that is productive (produces sputum or phlegm).

The following medicines should be taken carefully while concomitantly use with Dextromethorphan: Amiodarone, Fluoexetine, Quinidine, CNS depressants and Monoamine oxidase (MAO) inhibitors.

Pregnancy: Adequate and well-controlled studies in human have not been done. However, Dextromethorphan has not been reported to cause birth defects.

Lactation: It is not known whether dextromethorphan passes into breast milk. However, Dextromethorphan has not been reported to cause problems in nursing babies.

Symptoms: In mild overdose, tachycardia, hypertension, vomiting, mydriasis, diaphoresis, nystagmus, euphoria, loss of motor coordination, and giggling; in moderate intoxication, in addition to those listed above, hallucinations and a plodding ataxic gait; in severely intoxication, agitation or somnolence.

Management: treatment is symptomatic and supportive. Naloxone may be useful in reversing toxicity.

Store at 15-30° C