Antidote

Rofolin 30 (Calcium Folinate 30)


Pharmacologic Category

Antidote; Chemotherapy Modulating Agent; Rescue Agent (Chemotherapy); Vitamin, Water Solubl

Dosing: Adult

Note: Because oral absorption is saturable at doses >25 mg, administering single oral doses >25 mg is not recommended (convert to parenteral therapy).

Colorectal cancer, advanced: IV: 200 mg/m2/day over at least 3 minutes for 5 days every 4 weeks for 2 cycles, then every 4 to 5 weeks (in combination with fluorouracil) or 20 mg/m2/day for 5 days every 4 weeks for 2 cycles, then every 4 to 5 weeks (in combination with fluorouracil). Note: Multiple leucovorin-containing regimens are available for the treatment of colorectal cancer. Refer to appropriate literature/guidelines for additional details.

Folic acid antagonist (eg, trimethoprim, pyrimethamine) overdose: Oral: 5 to 15 mg once daily

Folate-deficient megaloblastic anemia: IM, IV: ≤1 mg once daily

High-dose methotrexate-rescue: Initial: Oral, IM, IV: 15 mg (~10 mg/m2); start 24 hours after beginning methotrexate infusion; continue every 6 hours for 10 doses, until methotrexate level is <0.05 micromolar. Adjust dose as follows:

Normal methotrexate elimination (serum methotrexate level ~10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and <0.2 micromolar at 72 hours): Oral, IM, IV: 15 mg every 6 hours for 60 hours (10 doses) beginning 24 hours after the start of methotrexate infusion

Delayed late methotrexate elimination (serum methotrexate level remaining >0.2 micromolar at 72 hours and >0.05 micromolar at 96 hours after administration): Continue leucovorin calcium 15 mg (oral, IM or IV) every 6 hours until methotrexate level is <0.05 micromolar

Delayed early methotrexate elimination and/or acute renal injury (serum methotrexate level ≥50 micromolar at 24 hours, or ≥5 micromolar at 48 hours, or a doubling of serum creatinine level at 24 hours after methotrexate administration): IV: 150 mg every 3 hours until methotrexate level is <1 micromolar, then 15 mg every 3 hours until methotrexate level is <0.05 micromolar

High-dose methotrexate overexposure: Leucovorin nomogram dosing for high-dose methotrexate overexposure (off-label dosing; generalized dosing derived from reference nomogram figures, refer to each reference [Bleyer 1978; Bleyer 1981; Widemann 2006] or institution-specific nomogram for details):

At 24 hours:

For methotrexate levels of ≥100 micromolar at ~24 hours, leucovorin is initially dosed at 1,000 mg/m2 IV every 6 hours

For methotrexate levels of ≥10 to <100 micromolar at 24 hours, leucovorin is initially dosed at 100 mg/m2 IV every 3 or 6 hours

For methotrexate levels of ~1 to 10 micromolar at 24 hours, leucovorin is initially dosed at 10 mg/m2 IV or orally every 3 or 6 hours

At 48 hours:

For methotrexate levels of ≥100 micromolar at 48 hours, leucovorin is dosed at 1,000 mg/m2 IV every 6 hours

For methotrexate levels of ≥10 to <100 micromolar at 48 hours, leucovorin is dosed at 100 mg/m2 IV every 3 hours

For methotrexate levels of ~1 to 10 micromolar at 48 hours, leucovorin is dosed at 100 mg/m2 IV every 6 hours or 10 mg/m2 IV or orally to 100 mg/m2 IV every 3 hours

At 72 hours:

For methotrexate levels of ≥10 micromolar at 72 hours, leucovorin is dosed at 100 to 1,000 mg/m2 IV every 3 to 6 hours

For methotrexate levels of ~1 to 10 micromolar at 72 hours, leucovorin is dosed at 10 mg/m2 IV or orally to 100 mg/m2 IV every 3 hours

For methotrexate levels of ~0.1 to 1 micromolar at 72 hours, leucovorin is dosed at 10 mg/m2 IV or orally every 3 to 6 hours

If serum creatinine is increased more than 50% above baseline, increase the standard leucovorin dose to 100 mg/m2 IV every 3 hours, then adjust according to methotrexate levels above.

Follow methotrexate levels daily, leucovorin may be discontinued when methotrexate level is <0.1 micromolar

Methotrexate overdose (inadvertent) (begin as soon as possible after overdose): Oral, IM, IV: 10 mg/m2 every 6 hours until the methotrexate level is <0.01 micromolar. If serum creatinine is increased more than 50% above baseline 24 hours after methotrexate administration, if 24 hour methotrexate level is >5 micromolar, or if 48 hour methotrexate level is >0.9 micromolar, increase leucovorin dose to 100 mg/m2 IV every 3 hours until the methotrexate level is <0.01 micromolar.

Do not administer leucovorin intrathecally; the use of intrathecal leucovorin is not advised (Jardine 1996; Smith 2008).

Bladder cancer, neoadjuvant treatment (off-label use): IV, Oral: 15 mg every 6 hours for 4 doses on days 2 and 9, starting 24 hours after each methotrexate dose (in combination with methotrexate, vinblastine, and cisplatin) (Griffiths 2011).

Cofactor therapy in methanol toxicity (off-label use): IV: 1 mg/kg (maximum dose: 50 mg) over 30 to 60 minutes every 4 to 6 hours. Therapy should continue until methanol and formic acid have been completely eliminated (Barceloux 2002).

Esophageal cancer, advanced or metastatic (off-label use): IV: 400 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil and irinotecan [FOLFIRI]) until disease progression or unacceptable toxicity (Guimbaud 2014) or 200 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil and oxaliplatin) until disease progression or unacceptable toxicity (Al-Batran 2008).

Gastric cancer, advanced or metastatic (off-label use): IV: 400 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil and irinotecan [FOLFIRI]) until disease progression or unacceptable toxicity (Guimbaud 2014) or 200 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil and oxaliplatin) until disease progression or unacceptable toxicity (Al-Batran 2008).

Pancreatic cancer, metastatic (off-label use): IV: 400 mg/m2 over 2 hours once every 2 weeks (in combination with fluorouracil, oxaliplatin, and irinotecan [FOLFIRINOX]) for at least 6 months (Conroy 2011).

Pemetrexed toxicity (off-label dose): IV: 100 mg/m2 once, followed by 50 mg/m2 every 6 hours for 8 days (used in clinical trial for CTC grade 4 leukopenia ≥3 days; CTC grade 4 neutropenia ≥3 days; immediately for CTC grade 4 thrombocytopenia, bleeding associated with grade 3 thrombocytopenia, or grade 3 or 4 mucositis) (Alimta [prescribing information] 2017).

Prevention of pyrimethamine hematologic toxicity in HIV-infected patients (off-label use; HHS [OI adult 2015]): Oral:

Isosporiasis (Isospora belli):

Treatment: 10 to 25 mg once daily (in combination with pyrimethamine)

Chronic maintenance (secondary prophylaxis): 5 to 10 mg once daily (in combination with pyrimethamine)

Pneumocystis pneumonia (PCP): Prophylaxis (primary and secondary): 25 mg once weekly (in combination with pyrimethamine [with dapsone]) or 10 mg once daily (in combination with pyrimethamine [with atovaquone])

Toxoplasma gondii encephalitis:

Primary prophylaxis: 25 mg once weekly (in combination with pyrimethamine [with dapsone]) or 10 mg once daily (in combination with pyrimethamine [with atovaquone])

Treatment: 10 to 25 mg once daily (in combination with pyrimethamine [with either sulfadiazine, clindamycin, atovaquone, or azithromycin]). Note: May increase leucovorin to 50 to 100 mg/day in divided doses in cases of pyrimethamine toxicity (rash, nausea, bone marrow suppression).

Chronic maintenance (secondary prophylaxis): 10 to 25 mg once daily (in combination with pyrimethamine [with either sulfadiazine or clindamycin]) or 10 mg once daily (in combination with pyrimethamine [with atovaquone])

Dosing: Pediatric

(For additional information

see “Leucovorin: Pediatric drug information”

)

Note: Because oral absorption is saturable at doses >25 mg, administering single oral doses >25 mg is not recommended (convert to parenteral therapy).

Folic acid antagonist (eg, trimethoprim, pyrimethamine) overdose: Refer to adult dosing.

Folate-deficient megaloblastic anemia: Refer to adult dosing.

High-dose methotrexate-rescue: Refer to adult dosing.

Cofactor therapy in methanol toxicity (off-label use): Refer to adult dosing.

Prevention of pyrimethamine hematologic toxicity in HIV-exposed/-positive patients (off-label uses; CDC 2009):

Infants and Children >1 month of age: Note: Leucovorin should continue for 1 week after pyrimethamine is discontinued.

Toxoplasmosis (Toxoplasma gondii):

Primary prophylaxis: Oral: 5 mg once every 3 days (in combination with pyrimethamine [with either dapsone or atovaquone])

Secondary prophylaxis: Oral: 5 mg once every 3 days (in combination with pyrimethamine [with either sulfadiazine, atovaquone, or clindamycin])

Treatment (congenital): Oral or IM: 10 mg with every pyrimethamine dose (in combination with either sulfadiazine or clindamycin); treatment duration: 12 months

Treatment (acquired): Oral: Acute induction: 10 to 25 mg once daily (in combination with pyrimethamine [with either sulfadiazine, clindamycin, or atovaquone]) for ≥6 weeks

Adolescents: Refer to adult dosing

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Dosage Forms

30,200mg

Administration

Due to calcium content, do not administer IV solutions at a rate >160 mg/minute; not intended for intrathecal use.

Refer to individual protocols. Should be administered IM, IV push, or IV infusion (15 minutes to 2 hours). Leucovorin should not be administered concurrently with methotrexate. It is commonly initiated 24 hours after the start of methotrexate. Toxicity to normal tissues may be irreversible if leucovorin is not initiated by ~40 hours after the start of methotrexate.

As a rescue after folate antagonists: Administer by IV bolus, IM, or orally.

Do not administer orally in the presence of nausea or vomiting. Because oral absorption is saturable at doses above 25 mg, administering oral doses >25 mg is not recommended (convert to parenteral therapy).

Combination therapy with fluorouracil: Fluorouracil is usually given after, or at the midpoint, of the leucovorin infusion. Leucovorin is usually administered by IV bolus injection or short (10 to 120 minutes) IV infusion. Other administration schedules have been used; refer to individual protocols.

For the treatment of methanol toxicity, infuse over 30 to 60 minutes (Barceloux 2002)

Use

Colorectal cancer, advanced: Injection: Palliative treatment of advanced colorectal cancer to prolong survival (in combination with 5-fluorouracil).

Methotrexate toxicity:

Injection: Rescue agent after high-dose methotrexate treatment in osteosarcoma and to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.

Oral: Rescue agent to diminish toxicity and counteract effects of impaired methotrexate elimination and inadvertent overdoses of folic acid antagonists.

Megaloblastic anemia: Injection: Treatment of megaloblastic anemias due to folic acid deficiency (when oral therapy is not feasible).

Use: Off-Label

Adjunctive cofactor therapy in methanol toxicity; Bladder cancer (neoadjuvant treatment); Esophageal cancer (advanced or metastatic); Gastric cancer (advanced or metastatic); Pancreatic cancer (metastatic); Prevention of pyrimethamine hematologic toxicity in HIV-exposed/-positive patients (children); Prevention of pyrimethamine hematologic toxicity in HIV-infected patients (adolescents and adults)

Adverse Reactions

Frequency not defined. Toxicities (especially gastrointestinal toxicity) of fluorouracil are enhanced when used in combination with leucovorin.

Dermatologic: Erythema, pruritus, skin rash, urticaria

Hematologic & oncologic: Thrombocythemia

Hypersensitivity: Anaphylactoid reaction, hypersensitivity reaction

Respiratory: Wheezing

Contraindications

Pernicious anemia and other megaloblastic anemias secondary to vitamin B12-deficiency

Warnings/Precautions

Concerns related to adverse effects:

Hypersensitivity: Hypersensitivity, including allergic reactions, anaphylactoid reactions, and urticaria have been reported with ROFOLIN. Because ROFOLIN is typically administered in combination with other chemotherapy agents, it may be difficult to determine the causative agent for hypersensitivity reactions. In a series of 44 patients with hypersensitivity to ROFOLIN-containing regimens, hypersensitivity/infusion reaction to ROFOLIN was confirmed in 5 patients; reactions also occurred with subsequent rechallenge with LEVOleucovorin (Ureña-Tavera 2015).

Seizures: Seizures or syncope have been reported (rarely) in patients with cancer receiving ROFOLIN, usually in association with fluoropyrimidine administration, and most commonly in patients with CNS metastases or other predisposing factors; a causal relationship has not been established.

Disease-related concerns:

Anemias: ROFOLIN is inappropriate treatment for pernicious anemia and other megaloblastic anemias secondary to a lack of vitamin B12; a hematologic remission may occur while neurologic manifestations progress.

Renal impairment: ROFOLIN is excreted renally; the risk for toxicities may be increased in patients with renal impairment.

Concurrent drug therapy issues:

Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Fluorouracil: ROFOLIN may increase the toxicity of 5-fluorouracil; deaths from severe enterocolitis, diarrhea, and dehydration have been reported (in elderly patients); granulocytopenia and fever have also been reported.

Sulfamethoxazole-trimethoprim: Combination of leucovorin and sulfamethoxazole-trimethoprim for the acute treatment of PCP in patients with HIV infection has been reported to cause increased rates of treatment failure.

Dosage form specific issues:

Administration route: Parenteral administration may be preferred to oral if vomiting or malabsorption is likely. Because oral absorption is saturable at doses above 25 mg, administering oral doses greater than 25 mg is not recommended (convert to parenteral therapy).

Benzyl alcohol and derivatives: When doses >10 mg/m2 are required using the powder for injection, reconstitute using sterile water for injection, not a solution containing benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP [“Inactive” 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

Injection: Due to calcium content, do not administer IV solutions at a rate >160 mg/minute. Not intended for intrathecal use.

Other warnings and precautions:

Folic acid antagonist overdose: When used for the treatment of accidental folic acid antagonist overdose, administer as soon as possible.

Methotrexate overdose: When used for the treatment of a methotrexate overdose, administer IV ROFOLIN as soon as possible. Monitoring of the serum methotrexate concentration is essential to determine the optimal dose/duration of ROFOLIN; however, do not wait for the results of a methotrexate level before initiating ROFOLIN. It is important to adjust the ROFOLIN dose once a methotrexate level is known. The dose may need to be increased or administration prolonged in situations in which methotrexate excretion may be delayed (eg, ascites, pleural effusion, renal insufficiency, inadequate hydration). Never administer ROFOLIN intrathecally.

Methotrexate rescue therapy: Methotrexate serum concentrations should be monitored to determine dose and duration of ROFOLIN therapy. Dose may need increased or administration prolonged in situations where methotrexate excretion may be delayed (eg, ascites, pleural effusion, renal insufficiency, inadequate hydration). Never administer ROFOLIN intrathecally.

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