Folinic-Plus (leucovorin calcium/pyridoxal phosphate/mecobalamin)

Dosage of leucovorin calcium is expressed in terms of leucovorin.

Although pyridoxine was previously considered nontoxic even at high dosages, current evidence indicates that chronic administration of large dosages (e.g., 2 g daily) for the management of various conditions can cause severe adverse neurologic effects, and the risk to benefit of such dosages must be carefully weighed. (See Chronic Toxicity.)

Cyanocobalamin is administered by IM or deep subcutaneous injection. Cyanocobalamin also is administered orally and intranasally. Hydroxocobalamin is administered by IM injection or IV infusion. Oral therapy with vitamin B12 preparations is markedly inferior to parenteral therapy and should be used only for the treatment of dietary vitamin B12 deficiency in patients with normal GI absorption.

Pyridoxine hydrochloride is usually administered orally; however, the drug may be given by IM, IV, or subcutaneous injection when oral administration is not feasible. In infants with seizures, pyridoxine hydrochloride should be administered by IM or IV injection.

No dosing information is available for this tab.

No dosing information is available for this tab.

Safety of concomitant administration of other cyanide antidotes with hydroxocobalamin (Cyanokit(R)) has not been established. Caution is advised if another cyanide antidote is administered to patients receiving hydroxocobalamin.

Absorption of vitamin B12 from the GI tract may be decreased by aminoglycoside antibiotics, colchicine, extended-release potassium preparations, aminosalicylic acid and its salts, anticonvulsants (e.g., phenytoin, phenobarbital, primidone), cobalt irradiation of the small bowel, and by excessive alcohol intake lasting longer than 2 weeks. Neomycin-induced malabsorption of vitamin B12 may be increased by concurrent administration of colchicine.

Ascorbic acid may destroy substantial amounts of dietary vitamin B12 in vitro; this possibility should be considered when large doses of ascorbic acid are ingested within 1 hour of oral vitamin B12 administration.

Prednisone has been reported to increase the absorption of vitamin B12 and secretion of IF in a few patients with pernicious anemia, but not in patients with partial or total gastrectomy. The clinical importance of these findings is unknown.

Concurrent administration of chloramphenicol and vitamin B12 reportedly may antagonize the hematopoietic response to vitamin B12 in vitamin B12-deficient patients. The hematologic response to vitamin B12 in patients receiving both drugs should be carefully monitored and alternate anti-infectives should be considered.

Pyridoxine hydrochloride reverses the therapeutic effects of levodopa by accelerating peripheral metabolism of levodopa. Concomitant administration of carbidopa with levodopa prevents the reversal by pyridoxine of levodopa's effects. Pyridoxine hydrochloride should not be administered in dosages greater than 5 mg daily to patients receiving levodopa alone.

In one study, 200 mg of pyridoxine hydrochloride daily for 1 month resulted in a 50% decrease in serum concentrations of phenobarbital and phenytoin.

Although isoniazid interferes with pyridoxine metabolism, the American Academy of Pediatrics (AAP) states that children receiving isoniazid do not need pyridoxine supplements unless they have or are likely to have nutritional deficiencies. The AAP currently recommends that children and adolescents receiving meat- and milk-deficient diets, those with nutritional deficiencies (including symptomatic children with human immunodeficiency virus (HIV) infection), infants who are breast-feeding and their mothers, and pregnant women receive pyridoxine supplements.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Folic Acid/Pafolacianine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Folate, folic acid, and folate-containing supplements may reduce binding of pafolacianine to folate receptors expressed on ovarian cancer cells.

CLINICAL EFFECTS: Folate, folic acid, and folate-containing supplements could reduce the detection of malignant lesions with pafolacianine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid administration of folate, folic acid, or folate-containing supplements within 48 hours before administration of pafolacianine.

DISCUSSION: Folate, folic acid, and folate-containing supplements may reduce binding of pafolacianine to folate receptors expressed on cancer cells, which could result in reduced detection of malignant lesions with pafolacianine.

Folic Acid; Pyrimethamine/Hydantoins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown, but probably involves altered metabolism of the hydantoin.

CLINICAL EFFECTS: May observe decreased effectiveness of hydantoin, resulting in loss of seizure control.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If both drugs are administered, monitor both the hydantoin plasma levels as well as the seizure control of the patient. Adjust the dose of hydantoin accordingly.

DISCUSSION: The effects of an interaction are not expected to occur in the majority of patients. Discontinuation of folic acid has caused phenytoin levels to increase in patients who experienced a decrease in phenytoin levels when folic acid was started. Monitor these patients for hydantoin toxicity. Signs and symptoms of hydantoin toxicity include ataxia, nystagmus and involuntary movements.

Leucovorin/Fluorouracil & Fluorouracil Prodrugs

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Leucovorin has been shown to enhance both the therapeutic and toxic effects of fluoropyrimidines, such as 5-fluorouracil (5-FU).(1)

CLINICAL EFFECTS: Leucovorin, when used concurrently with 5-FU, has been shown to increase side effects of 5-FU.(1)

PREDISPOSING FACTORS: Patients who are intermediate or poor dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no DPYD function. Since DPYD is the rate-limiting enzyme involved in fluoropyrimidine metabolism, these patients may be more susceptible to the effects of this interaction.(3)

PATIENT MANAGEMENT: When leucovorin is added to 5-FU therapy, the dose of 5-FU must be reduced from that of the normally administered dose. Patients should be closely monitored for appearance and severity of side effects to determine whether it is appropriate to alter the dose of 5-FU.(1)

DISCUSSION: A retrospective study reviewed all patients over the age of 18 years treated with combination fluorouracil and leucovorin either as adjuvant or palliative treatment. A total of 122 patients (60% male) were included in the study. Ninety-four patients received fluorouracil (425 mg/m2, IV) and leucovorin (20 mg/m2, IV) daily for five days and repeated every four weeks. Twenty-eight patients received fluorouracil (400 mg/m2, IV) and leucovorin (80 mg/m2, IV) once per week for six weeks of an eight week course. All patients were treated for up to six months. Forty-eight patients (39%) experienced toxicity including fatigue (21%), mucositis (17%), diarrhea (11%), and nausea (11%).(2) A study involving 35 patients evaluated a combination of cisplatin (20 mg/m2) on Day 1 through Day 3, leucovorin (200 mg/m2) on Day 1 through Day 5, and 5-fluorouracil (500 mg/m2) on Day 1 through Day 5. If patients tolerated the low dose of 5-fluorouracil, the dose was increased to a maximum of 750 mg/m2/day during the remaining courses. Grade I mucositis occurred in three patients, Grade II in 16 patients, and Grade III in 13 patients. The dose of 5-fluorouracil was decreased in patients with Grade II and Grade III mucositis, which helped to decrease symptoms.(3) A randomized trial in advanced colorectal carcinoma patients compared fluorouracil (500 mg/m2 on Days 1-5) every four weeks with escalation as tolerated with high-dose leucovorin (500mg/m2) with fluorouracil (600 mg/m2) given weekly for six weeks with a two-week rest period and with low-dose leucovorin (25 mg/m2) with fluorouracil (600 mg/m2) given weekly for six weeks with a two-week rest period. Severe or worse diarrhea was reported in 25% and 13% of patients receiving high-dose leucovorin and low-dose leucovorin with fluorouracil, respectively. Nine elderly patients experienced fatal toxicity during the initial treatment cycle with combination therapy.(4) A study in five patients with metastatic colorectal carcinoma examined the effects of high dose leucovorin (500 mg/m2) on fluorouracil pharmacokinetics. Subjects received a single dose of fluorouracil (600 mg/m2) with leucovorin and, one week later, without leucovorin. With concurrent leucovorin, the time of distribution of fluorouracil increased 44% (p<0.0005) and fluorouracil volume of distribution increased 84% (p<0.03). There were no changes in fluorouracil plasma clearance or AUC. Although fluorouracil anabolite levels were lower at two minutes and five minutes post-dose when administered following leucovorin, levels were similar thereafter.(5)

Leucovorin/Trimethoprim-Sulfamethoxazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Leucovorin may protect Pneumocystis jirovecii from the effects of trimethoprim-sulfamethoxazole by providing a source of folate.(1,2)

CLINICAL EFFECTS: Concurrent use of leucovorin in patients undergoing prophylaxis against or being treated for Pneumocystis jiroveci pneumonia (formerly called Pneumocystic carinii) with trimethoprim-sulfamethoxazole has been associated with treatment failure and increased mortality.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of leucovorin and trimethoprim-sulfamethoxazole should be avoided in patients undergoing prophylaxis against or being treated for Pneumocystis jiroveci (formerly carinii) pneumonia.(1-4) The Australian manufacturer of leucovorin states simultaneous administration of folinic acid and folic acid antagonists (e.g. trimethoprim-sulfamethoxazole, pyrimethamine) is contraindicated because the folinic acid can completely negate the effect of the folic acid antagonist.(5) Leucovorin is an effective treatment for trimethoprim-sulfamethoxazole induced bone marrow suppression.(3)

DISCUSSION: In a prospective, double-blind study in 92 AIDS patients with Pneumocystis jiroveci (formerly carinii) pneumonia, concurrent use of leucovorin with trimethoprim-sulfamethoxazole resulted in an increase in treatment failure (15% versus 0) and death (11% versus 0). Leucovorin was also associated with a shorter time to therapeutic failure. Patients receiving leucovorin did have a lower incidence of neutropenia; however, there was no difference in the time to occurrence of neutropenia.(4) In a study in 12 AIDS/ARC patients, leucovorin had no effect on trimethoprim-sulfamethoxazole induced cytopenia.(6) In a study in HIV patients with no history of Pneumocystis jiroveci pneumonia, administration of leucovorin had no effect on patient tolerance to trimethoprim-sulfamethoxazole.(7) In a case report, two renal transplant patients with Pneumocystis jiroveci pneumonia failed to respond to treatment with trimethoprim-sulfamethoxazole until concurrent leucovorin was discontinued.(1) In a case report, an AIDS patient developed Pneumocystis jiroveci pneumonia despite a regimen of concurrent trimethoprim-sulfamethoxazole and leucovorin.(2)

Pyridoxine/Levodopa

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Pyridoxine increases levodopa metabolism, decreasing the amount of levodopa available to the central nervous system.

CLINICAL EFFECTS: The pharmacologic effects of levodopa may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid pyridoxine in patients receiving levodopa alone; however, the interaction can be minimized by giving levodopa with a peripheral decarboxylase inhibitor (e.g. carbidopa, benserazide). Treatment with combination carbidopa-levodopa may contribute to reduced vitamin B6 levels. Higher doses of carbidopa-levodopa may increase the risk of vitamin B6 deficiency. Seizures associated with vitamin B6 deficiency have been reported in the postmarketing setting. In patients taking combination therapy with carbidopa/levodopa, evaluate vitamin B6 levels periodically while on treatment or if symptoms associated with vitamin B6 deficiency are identified. Supplement with vitamin B6 as necessary.

DISCUSSION: In patients with Parkinson's disease, as little as 10 mg of pyridoxine may reverse the clinical benefits as well as the adverse effects of levodopa. Coadministration of levodopa with either carbidopa or benserazide has minimized the effects of this interaction.

There is no enhanced messaging for this drug.

• Leber's hereditary optic atrophy

There are no severe contraindications for this drug.

• Atrophic gastritis
• Hypokalemia

There is no enhanced messaging for this drug.

There are no severe adverse reactions for this drug.

Less Frequent

• Diarrhea
• Pruritus of skin

No enhanced messaging available.

No enhanced messaging available.

Animal reproduction studies have not been performed with leucovorin. It is also not known whether leucovorin can cause fetal harm when administered to pregnant women. Leucovorin should be used during pregnancy only when clearly needed.

Adequate and well-controlled studies have not been conducted in pregnant women. However, vitamin B12 requirements are increased in pregnant women. Parenteral preparations should be used during pregnancy only when the potential benefits justify the potential risks to the fetus.

Since it is not known if leucovorin is distributed into milk, the drug should be used with caution in nursing women.

Vitamin B12 is distributed into human milk. Vitamin B12 requirements are increased in lactating women.

Hydroxocobalamin may be administered to lactating women with suspected or known cyanocobalamin poisoning. There is no data available to determine when breastfeeding may be restarted following administration of IV hydroxocobalamin.

No enhanced messaging available.