FDA

Levoleucovorin Calcium

Approved 14 Sept 2018IntravenousSolution

The FDA lists this product in 19 strengths and forms.

Indications

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

Levoleucovor injection is a folate analog indicated for: · Rescue after high-dose methotrexate therapy in osteosarcoma. · Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. · Use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.( 1 ) Limitations of Use Levoleucovorin injection is not approved for pernicious anemia and megaloblastic anemias.

Improper use may cause a hematologic remission while neurologic manifestations continue to progress. ( 1.1)

1.1 Limitations of Use · Levoleucovorin injection is not approved for pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B 12 .Improper use may cause a hematologic remission while neurologic manifestations continue to progress.

Contraindications

Levoleucovorin injection is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. Levoleucovorin is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. (4 )

Warnings and precautions

Due to Ca ++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute. ( 5.1 ) Levoleucovorin injection enhances the toxicity of fluorouracil. ( 5 . 2 , 7 ) Concomitant use of d,l-leucovorin with trimethoprim sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study. ( 5.3 ) 5 .1 Rate of Administration Because of the Ca ++ content of the levoleucovorin solution, no more than 16 mL (160 mg of levoleucovorin) should be injected intravenously per minute.

At a glance

Brand name: Levoleucovorin Calcium
Route: Intravenous
Dosage form: Solution
Applicant: Gland
Status: Prescription
FDA approval: 14 Sept 2018
Application: ANDA210892-002
RxCUI: 979509

Indications

Improper use may cause a hematologic remission while neurologic manifestations continue to progress. ( 1.1)

Warnings and precautions

Adverse reactions

Allergic reactions were reported in patients receiving Levoleucovorin injection. ( 6.3 ) Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving Levoleucovorin injection as rescue after high-dose methotrexate therapy. ( 6.1 ) The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving Levoleucovorin injection in combination with 5-FU were diarrhea, nausea and stomatitis.

( 6.2) To report SUSPECTED ADVERSE REACTIONS, contact Dr.Reddys’ Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical 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/m 2 followed by Levoleucovorin injection rescue for osteosarcoma in 16 patients age 6 to 21.

Most patients received levoleucovorin injection 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 Body System/ Adverse Reactions Number (%) of Patients with Adverse Reactions (N =16) Number (%) of Courses with Adverse Reactions (N = 58) All Grade 3+ All Grade 3+ Gastrointestinal Stomatitis 6 (37.5) 1 (6.3) 10 (17.2) 1 (1.7) Vomiting 6 (37.5) 0 14 (24.1) 0 Nausea 3 (18.8) 0 3 (5.2) 0 Diarrhea 1 (6.3) 0 1 (1.7) 0 Dyspepsia 1 (6.3) 0 1 (1.7) 0 Typhlitis 1 (6.3) 1 (6.3) 1 (1.7) 1 (1.7) Respiratory Dyspnea 1 (6.3) 0 1 (1.7) 0 Skin and Appendages Dermatitis 1 (6.3) 0 1 (1.7) 0 Other Confusion 1 (6.3) 0 1 (1.7) 0 Neuropathy 1 (6.3) 0 1 (1.7) 0 Renal function abnormal 1 (6.3) 0 3 (5.2) 0 Taste perversion 1 (6.3) 0 1 (1.7) 0 Total number of patients 9 (56.3) 2 (12.5) Total number of courses 25 (43.1) 2 (3.4) 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 levoleucovorin injection rescue because patients were receiving other myelosuppressive chemotherapy.

6.2Clinical 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/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or with 5-FU 370 mg/m 2 intravenously and d,l-leucovorin 200 mg/m 2 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 Adverse Reaction Levoleucovorin injection /5FU n=318 d,l -Leucovorin/5FU n=307 Adverse Event N (%) Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Gastrointestinal Stomatitis 229 (72%) 37 (12%) 221 (72%) 44 (14%) Diarrhea 222 (70%) 61 (19%) 201 (65%) 51 (17%) Nausea 197 (62%) 25 (8%) 186 (61%) 26 (8%) Vomiting 128 (40%) 17 (5%) 114 (37%) 18 (6%) Abdominal Pain 1 45 (14%) 10 (3%) 57 (19%) 10 (3%) General Disorders Asthenia/Fatigue/Malaise 91 (29%) 15 (5%) 99 (32%) 34 (11%) Metabolism and Nutrition Anorexia/Decreased Appetite 76 (24%) 13 (4%) 77 (25%) 5 (2%) Skin Disorders Dermatitis 91 (29%) 3 (1%) 86 (28%) 4 (1%) Alopecia 83 (26%) 1 (0.3%) 87 (28%) 3 (1%) 1 Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness

6.3Postmarketing 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 injection 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).

Levoleucovorin Calcium

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Levoleucovorin Calcium

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.3Potential

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Category C.

Adverse reactions

6.1Clinical Studies in High-Dose Methotrexate Therapy

6.2Clinical Studies in Combination with 5-FU in Colorectal Cancer

6.3Postmarketing Experience

Composition

Strengths and forms

Official product information