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左卡尼汀口服溶液（Levocarnitine Oral Solution USP）

2014-11-24 13:12:14 作者：新特药房来源：互联网浏览次数：146 文字大小：【大】【中】【小】

简介： 部份中文左卡尼汀处方资料（仅供参考）药品英文名 Levocarnitine 药品别名左肉毒碱、左维生素B4、雷卡、东维力、L-Carnitine、Carnitor 药物剂型左卡尼汀注射剂：1g/5ml/支，0.5g/2.5ml/支；左卡尼汀 ...

关键字：左卡尼汀 Levocarnitine Oral Solution USP 适用于继发性卡尼汀缺乏症

部份中文左卡尼汀处方资料（仅供参考）
药品英文名
Levocarnitine
药品别名
左肉毒碱、左维生素B4、雷卡、东维力、L-Carnitine、Carnitor
药物剂型
左卡尼汀注射剂：1g/5ml/支，0.5g/2.5ml/支；
左卡尼汀口服溶液：1g/10ml；
左卡尼汀片剂：330mg/片。阴凉干燥处保存。
药理作用
本品是哺乳动物能量代谢中的必需物质，其主要功能是促进脂类代谢，可以使缺血、缺氧时堆积的脂酰辅酶A进入线粒体内，减少其对腺嘌呤核苷酸转位酶的抑制，使氧化磷酸化得以顺利进行。本品静注还可以纠正血液透析患者体内卡尼汀的缺乏，改善营养状态和因卡尼汀缺乏引起的一系列并发症。本品能加速正常心肌脂肪酸的氧化，为心肌ATP提供来源；降低乙酰辅酶A与游离辅酶A的比例，调节丙酮酸的氧化使葡萄糖氧化增加；减轻心脏缺血损伤程度，促进再灌注时心功能恢复，提高运动耐力。此外，本品还能增加NADH细胞色素C还原酶和细胞色素氧化酶的活性、参与某些药物的解毒作用，有效对抗蒽环类及其他抗肿瘤药物的心脏毒性。
药动学
一次口服0.5g，健康受试者血浆最大浓度为48.5μmol/L。按20mg/kg的剂量，在3min内缓慢静注后，血浆左卡尼汀符合二室模型，平均分布半衰期为0.585h，平均始末消除半衰期为17.4h，总的人体清除率平均为4.0L/h。左卡尼汀不与血浆蛋白结合，其排泄途径取决于给药途径，静注12h内从尿中回收大约70%，24h内大约80%。口服给药，尿中回收10%。
适应证
本品适用于继发性卡尼汀缺乏症。
1.主要用于慢性肾功能衰竭长期血液透析患者因卡尼汀缺乏产生的一系列并发症，临床表现如心肌病、骨骼肌病、心律失常、高脂血症以及低血压和透析中肌痉挛等。
2.可与促红细胞生成素并用治疗尿毒症贫血，并可参与冠状动脉粥样硬化性心脏病、心绞痛、心肌梗死、心肌炎、心功能不全、休克、缺血性脑血管病变、肝炎、肝硬化、糖尿病等疾病的辅助治疗。
3.其他：对小儿代谢性疾病、体重增长不良、疲劳肥胖等也有一定疗效。
禁忌证
对本品过敏者禁用。
注意事项
1.生殖毒性分级为B，尚不知本品是否经乳汁分泌，妊娠和哺乳期妇女慎用。本品口服溶液含有少量乙醇，对乙醇过敏的患者慎用。
2.在静脉给药前，建议先测定血浆卡尼汀水平，并建议每周和每月监测血生化、生命体征、血浆药物浓度和全身状况。
3.本品在0.9%NaCl或乳酸盐林格注射液中25℃放置，24h内稳定。
4.本品过量可引起腹泻。
不良反应
不良反应主要为一过性的恶心和呕吐，少见身体出现特殊气味、恶心和胃炎。口服或静注可引起癫痫发作，先前有癫痫发作的患者，可诱发癫痫或使癫痫加重。其他不良反应(发生率≥5%)主要如下：
1.全身系统胸痛、感冒症状、头痛、注射部位反应、疼痛等。
2.心血管系统心血管异常、高血压、低血压、心动过速等。
3.消化系统腹泻、消化不良、恶心、呕吐等。
4.内分泌系统甲状腺功能异常等。
5.血液淋巴系统贫血。
6.代谢系统高钙血症、高钾血症、血容量增多症。
7.神经系统头晕、失眠、压抑等。
8.呼吸系统咳嗽、咽喉炎、鼻炎。
9.皮肤瘙痒、皮症。
10.泌尿系统肾功能异常等。
用法用量
用于血液透析患者，每次透析结束时本品1.0g加入15ml生理氯化钠溶液静脉缓慢注射2～3min；用于治疗慢性充血性心力衰竭和心绞痛，本品3.0g加入5%葡萄糖注射液(糖尿病患者为生理氯化钠溶液)250ml，静滴，2～3h内滴完，每天1次，10天为一个疗程。口服时，成人每天1～3g，分2～3次服用，儿童初始剂量50mg/kg(最大剂量一天不超过3g)。
药物相应作用
接受丙戊酸的患者需增加左卡尼汀的用量。
Levocarnitine Oral Solution USP
1g/10mL
(118mL multidose)
For oral use only. Not for parenteral use.
DESCRIPTION
Levocarnitine is a carrier molecule in the transport of long-chain fatty acids across the inner mitochondrial membrane.
The chemical name of levocarnitine is 3-carboxy-2(R)-hydroxy-N,N,N-trimethyl-1-propanaminium, inner salt. Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol, and insoluble in acetone. The specific rotation of levocarnitine is between -29° and -32°. Its chemical structure is:
Molecular Formula: C7H15NO3
Molecular Weight: 161.20
Levocarnitine Oral Solution USP is intended solely for oral administration. Each 10 mL contains 1 gram of levocarnitine. Levocarnitine Oral Solution USP is available as 1 g/10 mL in bottles of 118 mL with the following inactive ingredients: Artificial Cherry Flavor, D,L-Malic Acid, Purified Water, Sucrose Syrup. Methylparaben NF and Propylparaben NF are added as preservatives. The pH is approximately 5.
CLINICAL PHARMACOLOGY
Levocarnitine is a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy production.
Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma, RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to an underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with Levocarnitine Oral Solution USP. The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acylCoA esters.1-6
Secondary carnitine deficiency can be a consequence of inborn errors of metabolism. Levocarnitine Oral Solution USP may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect has been demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency.7,8 Autointoxication occurs in these patients due to the accumulation of acylCoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acylCoA compound to its free acid results in acidosis which can be life-threatening. Levocarnitine clears the acylCoA compound by formation of acylcarnitine, which is quickly excreted. Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 μmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma levocarnitine concentrations below age-related normal concentrations.
PHARMACOKINETICS
In a relative bioavailability study in 15 healthy adult male volunteers, Levocarnitine Tablets were found to be bio-equivalent to Levocarnitine Oral Solution USP. Following 4 days of dosing with 6 tablets of Levocarnitine 330 mg b.i.d. or 2 g of Levocarnitine oral solution b.i.d., the maximum plasma concentration (Cmax) was about 80 μmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours.
The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20 mg/kg of Levocarnitine were described by a two-compartment model. Following a single i.v. administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0-24h interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours.
The absolute bioavailability of levocarnitine from the two oral formulations of Levocarnitine, calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.9 ± 4.9% for Levocarnitine Oral Solution USP.
Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a mean of 4.00L/h.
Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human.9
METABOLISM AND EXCRETION
In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum concentration of [3H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hr after drug administration. Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered dose) and [3H]-γ-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than 1% of the administered dose.10
After attainment of steady state following 4 days of oral administration of Levocarnitine Oral Solution USP (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion).
INDICATIONS AND USAGE
Levocarnitine Oral Solution USP is indicated in the treatment of primary systemic carnitine deficiency. In the reported cases, the clinical presentation consisted of recurrent episodes of Reye-like encephalopathy, hypoketotic hypoglycemia, and/or cardiomyopathy. Associated symptoms included hypotonia, muscle weakness and failure to thrive. A diagnosis of primary carnitine deficiency requires that serum, red cell and/or tissue carnitine levels be low and that the patient does not have a primary defect in fatty acid or organic acid oxidation (see Clinical Pharmacology). In some patients, particularly those presenting with cardiomyopathy, carnitine supplementation rapidly alleviated signs and symptoms. Treatment should include, in addition to carnitine, supportive and other therapy as indicated by the condition of the patient.
Levocarnitine Oral Solution USP is also indicated for acute and chronic treatment of patients with an inborn error of metabolism which results in a secondary carnitine deficiency.
CONTRAINDICATIONS
None known
WARNINGS
None.
PRECAUTIONS
General
Levocarnitine Oral Solution USP is for oral/internal use only.
Not for parenteral use.
Gastrointestinal reactions may result from a too rapid consumption of carnitine. Levocarnitine Oral Solution USP may be consumed alone, or dissolved in drinks or other liquid foods to reduce taste fatigue. It should be consumed slowly and doses should be spaced evenly throughout the day to maximize tolerance.
The safety and efficacy of oral levocarnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally excreted in the urine.
Carcinogenesis, mutagenesis, impairment of fertility
Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombe indicate that levocarnitine is not mutagenic. No long-term animal studies have been performed to evaluate the carcinogenic potential of levocarnitine.
Pregnancy
Pregnancy Category B.
Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to Levocarnitine Oral Solution USP. There are, however, no adequate and well controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Levocarnitine supplementation in nursing mothers has not been specifically studied.
Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment.
Pediatric Use
See Dosage and Administration.
ADVERSE REACTIONS
Various mild gastrointestinal complaints have been reported during the long-term administration of oral L- or D,L-carnitine; these include transient nausea and vomiting, abdominal cramps, and diarrhea. Mild myasthenia has been described only in uremic patients receiving D,L-carnitine. Gastrointestinal adverse reactions with Levocarnitine Oral Solution USP dissolved in liquids might be avoided by a slow consumption of the solution or by a greater dilution. Decreasing the dosage often diminishes or eliminates drug-related patient body odor or gastrointestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration, and after any dosage increases.
Seizures have been reported to occur in patients with or without pre-existing seizure activity receiving either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure frequency and/or severity has been reported.
OVERDOSAGE
There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea.
DOSAGE AND ADMINISTRATION
Levocarnitine Oral Solution USP.
For oral use only. Not for parenteral use.
Adults: The recommended dosage of levocarnitine is 1 to 3 g/day for a 50 kg subject, which is equivalent to 10 to 30 mL/day of Levocarnitine Oral Solution USP. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 1 g/day, (10 mL/day), and be increased slowly while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.
Infants and children: The recommended dosage of levocarnitine is 50 to 100 mg/kg/day which is equivalent to 0.5 mL/kg/day Levocarnitine Oral Solution USP. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 50 mg/kg/day, and be increased slowly to a maximum of 3 g/day (30 mL/day) while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.
Levocarnitine Oral Solution USP may be consumed alone or dissolved in drink or other liquid food. Doses should be spaced evenly throughout the day (every three or four hours) preferably during or following meals and should be consumed slowly in order to maximize tolerance.
HOW SUPPLIED
Levocarnitine Oral Solution USP is supplied in 118 mL (4 FL. OZ.) multiple-dose plastic containers. The multiple-dose containers are packaged 24 per case (NDC 64980-503-12). Store at 20° to 25°C (68° to 77°F); excursion permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].