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英文药名: Leucovorin (calcium folinate tablets)
中文药名: 亚叶酸钙片, 瘤可维
药品生产厂家: Wyeth Ayerst Pharmaceuticals
药品名称
中文通用名称：亚叶酸钙
英文通用名称：Calcium Folinate
其它名称：5-甲基四氢叶酸钙、安曲希、法益宁、甲酰四喋酸钙、甲酰四氢叶酸钙、甲叶钙、立可林、欧力、醛氢叶酸钙、确呋力、世明、同奥、亚乙酸、叶醛酸钙、Antrex、Calcii Folinas、Calciumfolinat、Calciumfolinat-Ebewe、CF、CF-Ca、Lederfoline、Leucovorin Calcium、Rescuvoli Wellcovorin、Wellcovorin
药理作用
1.药效学
本药为叶酸的活性形式，在体内不需叶酸还原酶的作用而直接显效，药理作用同叶酸。由于本药不会被二氢叶酸还原酶抑制剂所阻滞，临床上可用于抗叶酸药物，如大剂量甲氨蝶呤(MTX)治疗后的解救。
本药与氟尿嘧啶(5-Fu)联合疗法的作用机制为：5-Fu在体内活化为氟尿嘧啶脱氧核苷，并取代脱氧尿苷酸与胸苷酸合成酶及甲基四氢叶酸形成三联复合物，这一复合物比正常代谢状态下脱氧尿苷酸、胸苷酸合成酶、甲基四氢叶酸的三联复合物更稳定，不易解离，使胸苷酸合成酶失活，不能生成脱氧胸苷酸，从而抑制DNA生成，抑制癌细胞增殖。外源给予足量本药，经体内转变为甲基四氢叶酸，可进一步增加上述氟尿嘧啶脱氧核苷三联复合物的形成，增强5-Fu的作用。
2.药动学
本药口服易于吸收。血清还原叶酸达峰时间为：口服1.72±0.8小时，肌内注射0.71±0.09小时。无论何种给药途径，药物作用的持续时间均为3-6小时。肌内注射时血清还原叶酸半衰期为3.5小时。本药经肝脏和肠粘膜作用后代谢为5-甲基四氢叶酸，且口服代谢较肌内注射快而充分。80%-90%的代谢产物经肾脏排出，5%-8%随粪便排出。
适应症
1.主要用作叶酸拮抗剂(如甲氨蝶呤、乙胺嘧啶及甲氧苄啶等)的解毒剂，临床常用于预防大剂量甲氨蝶呤或用药过量所引起的严重毒性作用。
2.叶酸治疗口炎性腹泻、营养不良、妊娠期或婴儿期引起的巨幼细胞贫血疗效不佳时，也可选用本药。
3.与氟尿嘧啶合用，治疗晚期结肠、直肠癌，可延长患者生存期。
用法用量
成人
•常规剂量
•口服给药
1.甲氨蝶呤的"解救"治疗：一般剂量为每次5-15mg，每6-8小时1次，连用2日，使甲氨蝶呤血药浓度在5×10×E-8mol/L以下。
2.作为乙胺嘧啶或甲氧苄啶等药物的解毒剂：每日5-15mg，持续用药时间视中毒情况而定。
3.治疗巨幼细胞贫血：每日15mg。
4.与5－Fu合用于治疗晚期结肠、直肠癌：在5－Fu用药前半小时口服本药20-30mg/m2。
•肌内注射
1.甲氨蝶呤的"解救"治疗：一般剂量为每次9-15mg/m2，每6-8小时1次，连用2日，使甲氨蝶呤血药浓度在5×10×E-8mol/L以下。
2.作为乙胺嘧啶或甲氧苄啶等的解毒剂：每次9-15mg，持续用药时间视中毒情况而定。
3.治疗巨幼细胞贫血：每日1mg。
•静脉注射
与5－Fu合用于治疗晚期结肠、直肠癌：先用本药200mg/m2静脉注射(注射时间不少于3分钟)，接着用氟尿嘧啶300-400mg/m2注射，每日1次，连用5日为一疗程。根据毒性反应，每隔4-5周可重复1次，以延长患者生存期。
儿童
•常规剂量
可酌情参照成人用量。
任何疑问，请遵医嘱！
给药说明
1.本药应避免光线直接照射及与热源接触。
2.规定的剂量和给药时间均应严格遵守，不得随意更变。
3.因本药口服吸收的饱和剂量为每日25mg，如每日口服量在25mg以上，则宜改为肌内注射。
4.本药不宜与甲氨蝶呤同时用，以免影响后者抗叶酸作用。应一次大剂量使用甲氨蝶呤24-48小时后，再启用本药。应使甲氨蝶呤的血药浓度不低于其有效治疗浓度。
5.在对大剂量甲氨蝶呤的"解救"治疗中，如有酸性尿、脱水、胃肠道梗阻、胸腔积液、腹水或肾功能障碍等表现时，应注意调整剂量。
不良反应
本药的不良反应很少见，偶见荨麻疹、哮喘等过敏反应。
注意事项
1.禁忌症
(1)恶性贫血。
(2)维生素B12缺乏引起的巨幼细胞贫血(因合成血红蛋白过程中消耗维生素B12)。
2.慎用
尚不明确。
3.药物对妊娠的影响
尚不明确。
4.药物对哺乳的影响
尚不明确。
5.用药前后及用药时应当检查或监测
接受大剂量甲氨蝶呤而用本药"解救"者应进行下列各种实验室监测：
(1)治疗前应做肌酐廓清试验。
(2)每12-24小时应测定血浆或血清甲氨蝶呤的浓度，以调整本药用量和应用时间；当其浓度低于5×10×E-8mol/L时，可停止实验室监测。
(3)甲氨蝶呤治疗前及治疗后每24小时测定血清肌酐量，如用药24小时后血清肌酐量较治疗前升高50%，提示有严重肾毒性，要慎重处理。
(4)甲氨蝶呤用药前和用药后每6小时应监测尿液酸度，要求尿液pH值大于7，应用碳酸氢钠和水化治疗(在注射当天及注射后2日，每日补液量3000mL/m2)，以防止肾功能不全。
药物相互作用
•药物-药物相互作用
1.与氟尿嘧啶合用，可加强后者的治疗作用。
2.与乙胺嘧啶或甲氧苄啶合用，可预防后者引起的继发性巨幼细胞贫血。
3.本药较大剂量与巴比妥、扑米酮或苯妥英钠合用，可影响后者的抗癫痫作用。
【原产地英文商品名】LEUCOVORIN-10mg/ml,50ml/Vial
【原产地英文药品名】LEUCOVORIN
【中文参考商品译名】
注：以下产品不同规格和不同规格，购买时请以电话咨询为准
·瘤可维-10毫克/毫升, 25毫升/瓶
·瘤可维-10毫克/毫升, 50毫升/瓶
·瘤可维-100毫克/瓶
·瘤可维-350毫克/瓶
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·瘤可维-10毫克/片, 12片/盒
·瘤可维-15毫克/片, 24片/盒
·瘤可维-25毫克/片, 25片/盒
·瘤可维-5毫克/片, 100片/瓶
【中文参考化合物名称】甲酰四氢叶酸
【生产厂家英文名】Lederle Laboratories
DESCRIPTION
Leucovorin Calcium Tablets contain either 5 mg or 25 mg leucovorin as the calcium salt of N-[4-[[(2-amino-5-formyl-1, 4, 5, 6, 7, 8-hexahydro-4-oxo-6-pteridinyl)-methyl]amino]benzoyl]-L-glutamic acid. This is equivalent to 5.40 mg or 27.01 mg of anhydrous leucovorin calcium. In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The 25mg tablet also contains D&C yellow no. 10 and FD&C blue no. 1.
Leucovorin is a water soluble form of reduced folate in the folate group; it is useful as an antidote to drugs which act as folic acid antagonists. These tablets are intended for oral administration only. The structural formula of leucovorin calcium is:
C20H21CaN7O7 Molecular Weight: 511.51
CLINICAL PHARMACOLOGY
Leucovorin is a racemic mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid. The biologically active compound of the mixture is the (-)-L-isomer, known as Citrovorum factor, or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. Following oral administration, leucovorin is rapidly absorbed and enters the general body pool of reduced folates. The increase in plasma and serum folate activity (determined microbiologically with Lactobacillus casei) seen after oral administration of leucovorin is predominantly due to 5-methyltetrahydrofolate.
Twenty normal men were given a single, oral 15 mg dose (7.5 mg/m2) of leucovorin calcium and serum folate concentrations were assayed with L. casei. Mean values observed (± one standard error) were:
-
-
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- Time to peak serum folate concentration: 1.72 ± 0.08 hours,
- Peak serum folate concentration achieved: 268 ± 18 ng/mL,
- Serum folate half-disappearance time: 3.5 hours.
Oral tablets yielded areas under serum folate concentration-time curves (AUCs) that were 12% greater than equal amounts of leucovorin given intramuscularly and equal to the same amounts given intravenously.
Oral absorption of leucovorin is saturable at doses above 25 mg. The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg and 37% for 100 mg.
INDICATIONS AND USAGE
Leucovorin calcium tablets are indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.
CONTRAINDICATIONS
Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B12. A hematologic remission may occur while neurological manifestations continue to progress.
WARNINGS
In the treatment of accidental overdosage of folic acid antagonists, leucovorin should be administered as promptly as possible. As the time interval between antifolate administration (e.g., methotrexate) and leucovorin rescue increases, leucovorin’s effectiveness in counteracting hematologic toxicity decreases.
Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.
Delayed methotrexate excretion may be caused by a third space fluid accumulation (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of leucovorin or prolonged administration may be indicated. Doses higher than those recommended for oral use must be given intravenously.
Leucovorin may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.1 Concomitant granulocytopenia and fever were present in some but not all of the patients.
The concomitant use of leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and mortality in a placebo controlled study.
PRECAUTIONS
General
Parenteral administration is preferable to oral dosing if there is a possibility that the patient may vomit or not absorb the leucovorin. Leucovorin has no effect on other established toxicities of methotrexate, such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.
Drug Interactions
Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children.
Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin enter CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.
Leucovorin may enhance the toxicity of fluorouracil (see WARNINGS).
Pregnancy
Teratogenic Effects:
Pregnancy Category C.
Animal reproduction studies have not been conducted with leucovorin. It is also not known whether leucovorin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Leucovorin should be given to a pregnant woman only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when leucovorin is administered to a nursing mother.
Pediatric Use
See Drug Interactions subsection.
ADVERSE REACTIONS
Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following the administration of both oral and parenteral leucovorin.
OVERDOSAGE
Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists.
DOSAGE AND ADMINISTRATION
Leucovorin calcium tablets are intended for oral administration. Because absorption is saturable, oral administration of doses greater than 25 mg is not recommended.
Impaired Methotrexate Elimination or Inadvertent Overdosage
Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion (see WARNINGS). Leucovorin 15 mg (10 mg/m2) should be administered IM, IV, or PO every 6 hours until serum methotrexate level is less than 10 -8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally.
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 leucovorin should be increased to 150 mg (100 mg/m2) IV every 3 hours until the methotrexate level is less than 10 -8 M. Doses greater then 25 mg should be given parenterally (see CLINICAL PHARMACOLOGY).
Hydration (3L/d) and urinary alkalinization with sodium bicarbonate should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.
The recommended dose of leucovorin to counteract hematologic toxicity from folic acid antagonists with less affinity for mammalian dihydrofolate reductase than methotrexate (i.e., trimethoprim, pyrimethamine) is substantially less and 5 to 15 mg of leucovorin per day has been recommended by some investigators.
Patients who experience delayed early methotrexate elimination are likely to develop reversible non-oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until 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. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 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.
HOW SUPPLIED
Leucovorin Calcium Tablets, USP are available as:
| 5 mg: |
White, round, unscored, biconvex tablets. Debossed with stylized b on one side and 484 on the other side. |
| Available in bottles of: |
| 20 |
NDC 0555-0484-18 |
| 30 |
NDC 0555-0484-01 |
| 100 |
NDC 0555-0484-02 |
| 1000 |
NDC 0555-0484-05 |
| 25 mg: |
Pale green, round, unscored, biconvex tablets. Debossed with stylized b on one side and 485 on the other side. |
| Available in bottles of: |
| 25 |
NDC 0555-0485-27 |
| 500 |
NDC 0555-0485-04 |
Protect from light and moisture.
Dispense with a child-resistant closure in a tight, light-resistant container.
Store at controlled room temperature 15°-25°C (59°-77°F)[See USP].
REFERENCES
- Grem JL, Shoemaker DD, Petrelli NJ, Douglas HO Jr: Severe and fatal toxic effects observed in treatment with high- and low-dose leucovorin plus 5-Fluorouracil for colorectal carcinoma. Cancer Treat Rep 1987;71:1122.
- Link MP, Goorin AM, Miser AW et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986: 314:1600-1606.
MANUFACTURED BY
BARR LABORATORIES, INC.
POMONA, NY 10970
Revised OCTOBER 2002 | 
