Levoleucovorin

Name: Levoleucovorin

Overdose

No data are available for overdosage with levoleucovorin.

What should i discuss with my healthcare provider before i receive levoleucovorin (fusilev)?

You should not receive this medication if you are allergic to levoleucovorin or to folic acid or folinic acid.

If possible, before you receive levoleucovorin, tell your doctor or caregivers if you have:

  • kidney disease;
  • liver disease; or
  • if you are dehydrated.

FDA pregnancy category C. It is not known whether levoleucovorin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether levoleucovorin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using levoleucovorin.

In an emergency situation, it may not be possible before you are treated with levoleucovorin to tell your caregivers if you are pregnant or breast feeding. Make sure any doctor caring for your pregnancy or your baby knows you have received this medication.

What is the most important information I should know about levoleucovorin?

You should not be treated with this medicine if you are allergic to levoleucovorin or to folic acid or folinic acid.

What should I discuss with my healthcare provider before I receive levoleucovorin?

You should not be treated with this medicine if you are allergic to levoleucovorin, folic acid, or folinic acid.

If possible, before you receive levoleucovorin, tell your doctor or caregivers if you have:

  • kidney disease;

  • liver disease; or

  • if you are dehydrated.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether levoleucovorin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using levoleucovorin.

In an emergency situation it may not be possible to tell your caregivers if you are pregnant or breast-feeding. Make sure any doctor caring for your pregnancy or your baby knows you have received this medicine.

What should I avoid while receiving levoleucovorin?

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

Levoleucovorin side effects

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

Tell your doctor or caregivers at once if you have:

  • blisters or ulcers in your mouth, red or swollen gums, trouble swallowing;

  • severe ongoing nausea, vomiting, or diarrhea;

  • a light-headed feeling, like you might pass out;

  • seizure (convulsions);

  • dehydration symptoms--feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin; or

  • kidney problems--little or no urination; painful or difficult urination; swelling in your feet or ankles.

Common side effects may include:

  • nausea, vomiting;

  • diarrhea; or

  • mouth sores.

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

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Mouth irritation or mouth sores.
  • Fever.
  • Very bad belly pain or bloody loose stools.
  • Shortness of breath.
  • Feeling confused.
  • A burning, numbness, or tingling feeling that is not normal.
  • Not able to pass urine or change in how much urine is passed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No studies have been conducted to evaluate the potential of Levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility.

Animal Toxicology And/Or Pharmacology

The acute intravenous LD50 values in adult mice and rats were 575 mg/kg (1725 mg/m2) and 378 mg/kg (2268 mg/m2), respectively. Signs of sedation, tremors, reduced motor activity, prostration, labored breathing and/or convulsion were observed in these studies. Anticipated human dose for each administration is approximately 5 mg/m2 for high-dose methotrexate therapy which represents a 3-log safety margin.

How Supplied/Storage and Handling

Levoleucovorin Injection, 175 mg, contains 17.5 mL sterile solution in a single-dose vial. Each mL contains Levoleucovorin calcium mixed hydrates equivalent to 10 mg Levoleucovorin, 8.3 mg sodium chloride and sodium hydroxide for pH adjustment to pH 8.1 (6.5 to 8.5).

175 mg/17.5 mL (10 mg/mL) solution:                       NDC 70121-1572-1

Store in refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light. Store in carton until contents are used.

Manufactured by:

Amneal Pharmaceuticals Pvt. Ltd. Parenteral Unit

Plot No. 15, PHARMEZ Special Economic Zone,

Sarkhej-Bavla N.H. No. 8A,

Vil.: Matoda, Tal.: Sanand,

Ahmedabad, Gujarat 382213, INDIA

Distributed by:

Amneal Biosciences LLC

Bridgewater, NJ 08807

Rev. 06-2017-00

Dosing Pediatric

Note: Levoleucovorin, when substituted in place of leucovorin calcium (the racemic form), is dosed at one-half the usual dose of leucovorin calcium:

High-dose methotrexate rescue: Children and Adolescents: Refer to adult dosing.

Folic acid antagonist overdose: Children and Adolescents: Refer to adult dosing.

Impaired methotrexate elimination: Children and Adolescents: Refer to adult dosing.

Adverse Reactions

Adverse reactions reported with levoleucovorin either as a part of combination chemotherapy or following chemotherapy.

>10%:

Central nervous system: Fatigue (≤29%), malaise (≤29%)

Dermatologic: Dermatitis (6% to 29%), alopecia (≤26%)

Gastrointestinal: Stomatitis (38% to 72%; grades 3/4: 6% to 12%), diarrhea (6% to 70%; grades 3/4: ≤19%), nausea (19% to 62%), vomiting (38% to 40%), anorexia (≤24%), decreased appetite (≤24%), abdominal pain (≤14%)

Neuromuscular & skeletal: Weakness (≤29%)

1% to 10%:

Central nervous system: Confusion (6%), neuropathy (6%)

Gastrointestinal: Dysgeusia (6%), dyspepsia (6%), typhlitis (6%)

Renal: Renal insufficiency (6%)

Respiratory: Dyspnea (6%)

<1% (Limited to important or life-threatening): Disruption of body temperature regulation, hypersensitivity reaction, pruritus, rigors, skin rash

Important information

You should not be treated with this medication if you are allergic to levoleucovorin or to folic acid or folinic acid.

Tell your doctor if you are taking sulfa drugs, seizure medication, a cancer medication called fluorouracil (5FU), or a multivitamin or mineral supplement than contains folic acid.

In an emergency situation, it may not be possible before you are treated to tell your caregivers about all of your medical conditions or if you are pregnant or breast-feeding. However, make sure any doctor caring for you afterward knows that you have received levoleucovorin.

Tell your doctor or caregivers at once if you have fever, chills, white patches or sores inside your mouth or on your lips, severe or ongoing diarrhea, confusion, urination problems, or if you feel very thirsty or hot, if you are unable to urinate, and you have heavy sweating or hot and dry skin.

What should I avoid while receiving levoleucovorin?

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

Levoleucovorin dosing information

Usual Adult Dose for Methotrexate Rescue:

Levoleucovorin Rescue After High Dose Methotrexate Therapy:

Dose: 7.5 mg (approximately 5 mg/m2) IV every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. (The recommendations for levoleucovorin rescue are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours.)

Serum creatinine and methotrexate levels should be determined at least once daily. Levoleucovorin administration, hydration, and urinary alkalinization (pH of 7.0 or greater) Dosage should be adjusted or rescue extended based on the following guidelines:

Guidelines - Dosage and Administration
Clinical Situation 1) Normal Methotrexate Elimination
Laboratory Findings: Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.
Levoleucovorin Dosage and Duration: 7.5 mg IV every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).

Clinical Situation 2) Delayed Late Methotrexate Elimination
Laboratory Findings: Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.
Levoleucovorin Dosage and Duration: Continue 7.5 mg IV every 6 hours, until methotrexate level is less than 0.05 micromolar.

Clinical Situation 3) Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury
Laboratory Findings: Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, or; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).
Levoleucovorin Dosage and Duration: 75 mg IV every 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg IV every 3 hours until methotrexate level is less than 0.05 micromolar.

Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate levoleucovorin therapy, these patients require continuing hydration, urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, levoleucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

Delayed methotrexate excretion may be caused by accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses or prolonged administration may be indicated.

Although levoleucovorin may ameliorate the hematologic toxicity associated with high dose methotrexate, this medicine has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.

Usual Adult Dose for Methotrexate Overdosage:

Dosing Recommendations for Inadvertent Methotrexate Overdosage

Dose: 7.5 mg (approximately 5 mg/m2) should be administered IV every 6 hours until the serum methotrexate level is less than 10^-8 M.

Levoleucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. As the time interval between antifolate administration (e.g., methotrexate) and levoleucovorin rescue increases, levoleucovorin effectiveness in counteracting toxicity may decrease.

Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10^-6 M or the 48 hour level is greater than 9 x 10^-7 M, the dose of levoleucovorin should be increased to 50 mg/m2 IV every 3 hours until the methotrexate level is less than 10^-8 M. Hydration (3 L/day) and urinary alkalinization with NaHCO3 should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

Usual Adult Dose for Colorectal Cancer:

For use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer:
Regimen 1: 100 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m2 by intravenous injection.
Regimen 2: 10 mg/m2 by intravenous injection followed by 5-FU at 425 mg/m2 by intravenous injection.

Treatment is repeated daily for five days. This five day treatment course may be repeated at 4 week (28 day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

In subsequent treatment courses, the dosage of 5-FU should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-FU should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity. For patients who experienced no toxicity in the prior treatment course, 5-FU dosage may be increased by 10%. Levoleucovorin dosages are not adjusted for toxicity.

Usual Adult Dose for Methotrexate Rescue

Levoleucovorin Rescue After High Dose Methotrexate Therapy:

Dose: 7.5 mg (approximately 5 mg/m2) IV every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. (The recommendations for levoleucovorin rescue are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours.)

Serum creatinine and methotrexate levels should be determined at least once daily. Levoleucovorin administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 0.05 micromolar. The levoleucovorin dose should be adjusted or rescue extended based on the following guidelines:

Guidelines for Levoleucovorin Dosage and Administration
Clinical Situation 1) Normal Methotrexate Elimination
Laboratory Findings: Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.
Levoleucovorin Dosage and Duration: 7.5 mg IV every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).

Clinical Situation 2) Delayed Late Methotrexate Elimination
Laboratory Findings: Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.
Levoleucovorin Dosage and Duration: Continue 7.5 mg IV every 6 hours, until methotrexate level is less than 0.05 micromolar.

Clinical Situation 3) Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury
Laboratory Findings: Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, or; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).
Levoleucovorin Dosage and Duration: 75 mg IV every 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg IV every 3 hours until methotrexate level is less than 0.05 micromolar.

Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate levoleucovorin therapy, these patients require continuing hydration, urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, levoleucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

Delayed methotrexate excretion may be caused by accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of levoleucovorin or prolonged administration may be indicated.

Although levoleucovorin may ameliorate the hematologic toxicity associated with high dose methotrexate, levoleucovorin has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.

Liver Dose Adjustments

Data not available

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