Fusilev

Levoleucovorin is the levo isomeric form of racemic d,l-leucovorin, present as the calcium salt. Levoleucovorin is the pharmacologically active isomer of leucovorin [(6-S)-leucovorin].

Fusilev for Injection and Fusilev Injection contain levoleucovorin calcium, which is one of several active, chemically reduced derivatives of folic acid. It is useful as antidote to the inhibition of dihydrofolate reductase by methotrexate. This compound has the chemical designation calcium (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6pteridinyl)methyl] amino]benzoyl}-L-glutamate pentahydrate. The molecular weight is 601.6 and the structural formula is:

Its molecular formula is: C20H21CaN7O7• 5H2O.

Fusilev for Injection is supplied as a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol per 50 mg vial. Sodium hydroxide and/or hydrocholoric acid are used to adjust the pH during manufacture. It is intended for intravenous administration after reconstitution with 5.3 mL of sterile 0.9% Sodium Chloride Injection, USP [See DOSAGE AND ADMINISTRATION]

Fusilev Injection is supplied as a sterile solution of either 175 mg levoleucovorin in 17.5 mL or 250 mg levoleucovorin in 25 mL. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. Sodium hydroxide is used for pH adjustment to pH 8.0 (6.5 to 8.5).

• Spectrum Pharmaceuticals, Inc.

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.

Clinical Studies in High-Dose Methotrexate Therapy

Since clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following table presents the frequency of adverse reactions which occurred during the administration of 58 courses of high-dose methotrexate 12 grams/m² followed by Fusilev rescue for osteosarcoma in 16 patients age 6-21. Most patients received Fusilev 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate.

Table 2 : Adverse Reactions with High-Dose Methotrexate Therapy

The incidence of adverse reactions may be underestimated because not all patients were fully evaluable for toxicity for all cycles in the clinical trials. Leukopenia and thrombocytopenia were observed, but could not be attributed to high-dose methotrexate with Fusilev rescue because patients were receiving other myelosuppressive chemotherapy.

Clinical Studies in Combination with 5-FU in Colorectal Cancer

A randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with advanced colorectal cancer failed to show superiority of a regimen of 5-FU + levoleucovorin to 5-FU + d,l-leucovorin in overall survival. Patients were randomized to 5-FU 370 mg/m² intravenously and levoleucovorin 100 mg/m² intravenously, both daily for 5 days, or with 5-FU 370 mg/m² intravenously and d,l-leucovorin 200 mg/m² intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity. The following table presents the most frequent adverse reactions which occurred in patients in the 2 treatment arms.

Table 3 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm

Postmarketing Experience

Since adverse reactions from spontaneous reports are provided voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Spontaneously reported adverse reactions collected by the WHO Collaborating Center for International Drug Monitoring in Uppsala Sweden have yielded seven cases where levoleucovorin was administered with a regimen of methotrexate. The events were dyspnea, pruritus, rash, temperature change and rigors. For 217 adverse reactions (108 reports) where levoleucovorin was a suspected or interacting medication, there were 40 occurrences of “possible allergic reactions.”

In an analysis where calcium levoleucovorin was reported as the primary suspect drug and fluorouracil (FU) was reported as a concomitant medication, possible allergic reactions were reported among 47 cases (67 events).

Read the entire FDA prescribing information for Fusilev (levoleucovorin)

Levoleucovorin is used to treat or prevent toxic effects of methotrexate in people who have received methotrexate to treat bone cancer.

Levoleucovorin is also used to treat or prevent toxic effects of methotrexate in people whose bodies do not eliminate methotrexate properly after the drug is metabolized. Levoleucovorin may also be used to treat toxic effects of an accidental methotrexate overdose.

Levoleucovorin is also used in combination chemotherapy with fluorouracil to treat colorectal cancer that has spread to other parts of the body. Levoleucovorin treats only the symptoms of colorectal cancer but does not treat the cancer itself.

Levoleucovorin should not be used to treat anemia that is caused by a lack of vitamin B12.

Levoleucovorin may also be used for purposes not listed in this medication guide.

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

• Tell all of your health care providers that you take Fusilev. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• If this medicine is used with fluorouracil, side effects from fluorouracil may happen more often. Deaths from very bad bowel problems, diarrhea, and dehydration have happened in older people getting Fusilev with fluorouracil. Talk with the doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Fusilev, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Fusilev. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Fusilev.

Review Date: October 4, 2017

• Fusilev® is a folate analog.
• Fusilev rescue is indicated after high-dose methotrexate therapy in osteosarcoma.
• Fusilev is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.
• Fusilev is indicated for use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.

Limitations of Use

• Fusilev is not approved for pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B12. Improper use may cause a hematologic remission while neurologic manifestations continue to progress.

Fusilev is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid.

Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects. However, both folic and folinic acids share some common metabolic pathways. Caution should be taken when taking folinic acid in combination with anticonvulsant drugs.

Preliminary human studies have shown that small quantities of systemically administered leucovorin enter the CSF, primarily as its major metabolite, 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration.

Fusilev increases the toxicity of 5-fluorouracil [see Warnings and Precautions (5.2)].

More frequent side effects include: diarrhea. See below for a comprehensive list of adverse effects.

There are no data on the excretion of levoleucovorin into human milk. Because many drugs are excreted in human milk, caution is recommended when levoleucovorin is administered to a nursing mother.