【药品名称】
商品名：卫萌
药物别名： 替尼泊甙，足叶噻吩甙，鬼臼甲叉甙，替尼泊苷,VM-26.
英文名： Teniposide或Vumon
英文缩写： VM-26或EPT或PGT或NSC-122891

【成分】
替尼泊苷 Teniposide

【药物分类】
抗肿瘤药

【制造商】
百时美施贵宝

【性状】
本药为中性亲脂性物质，几乎不溶于水，而溶于有机溶媒。本药含下列成分 ：N,N二甲基乙酰胺300 mg，苯甲醇150 mg，聚氧乙基蓖麻油2.5 g，无水乙醇42.7%，并用马来酸调节pH值在5左右。

【药理作用】
本药为鬼臼毒素的半合成衍生物，是周期特异性细胞毒药物，作用于细胞周期S2后期和G2期，通过阻止细胞的有丝分裂而起作用。本药也可引起DNA键的单股性和双股性断裂，其作用机理可能是抑制II型拓扑异构酶所致。

【药代动力学】
在一定的剂量范围内，本药的药代动力学参数呈线性，每日注射1次，连续用3日后，药物在体内不发生蓄积。成人和儿童对本药的代谢没有显著差异。静脉输注后，药物从中央室I相清除，即分布相半衰期约为1小时。本药在体内的高蛋白结合率(>99%)可能限制其在体内的分布。本药在脑脊液的浓度低于同时测定的血浆药物浓度。经肾脏的清除率仅占总清除率的10%左右。本药的清除半衰期为6-20小时。

【毒理研究】
本药与其它抗肿瘤药物合用，可引起急性非淋巴细胞性白血病。用药时应考虑到本药对人类是一个潜在的致癌因素。在各种细菌和哺乳动物遗传毒性实验中也发现本药的诱变性。动物实验已证实本药可以引起鼠细胞系的基因变异和人类细胞的DNA损伤。此外，在几种人类和鼠组织培养物中已证实发生了染色体畸变。动物实验也显示本药可减少猴和狗的精子生成，降低狗的睾丸和卵巢的重量。

【适应症】
本药通常与其它抗癌药物联合使用治疗 ：恶性淋巴瘤 ；何杰金氏病 ；急性或淋巴细胞性白血病之高危病例 ；颅内恶性肿瘤如胶质母细胞癌、空管膜瘤、星型细胞瘤、膀胱癌 ；神经母细胞瘤 ；儿童的其它实体瘤。

【用法用量】
单药治疗 每个疗程总剂量为300 mg/m2，在3-5日内给予，每3周或待骨髓象恢复后可重复下一个疗程。
联合治疗 与其它骨髓抑制药联合应用时，应适当降低本药的剂量，并应定期监测外周血象计数，必要时定期进行骨髓检查。唐氏综合征的病人对骨髓抑制性化学疗法的反应特别敏感，因此，对这些病人应考虑减少用量。

【不良反应】
血液学反应 ：本药治疗7-14日后可发生白细胞及血小板减少，通常2-3周内骨髓抑制可完全恢复。白细胞减少常较血小板减少常见且更严重。也可见贫血和免疫性溶血性贫血。
胃肠道反应 ：恶心、呕吐是主要的胃肠道毒性反应，但通常用止吐药物可以控制这些症状。也可见口炎、粘膜炎、厌食、腹泻、腹痛和肝功能异常。
秃发的发生率很高，特别见于多疗程的患者。
快速输注本药后可以发生暂时性低血压，已有报道显示病人可能由于心率失常和低血压而致突然死亡。
过敏反应 ：主要表现为寒战、发热、心动过速、支气管痉挛、呼吸困难以及低血压。这些反应可在第1次用药时就发生，更常见于脑肿瘤或神经细胞瘤的病人。出现这一反应的危险性可能与重复给药及药物在体内的蓄积有关。此外，潮红、出汗、荨麻疹、高血压及水肿等反应也有报道。
神经病变 ：硫酸长春新碱和本药相互作用而导致病人出现严重的神经病变，使用高于推荐剂量的本药也可引起中枢神经系统抑制。
其它不良反应有感染、肾功能不全、高血压、头痛、精神混乱和肌无力等。

【禁忌症】
对本药任一成分过敏者、严重白细胞减少或血小板减少者。

【警告】
本药可能导致严重的骨髓抑制、感染或出血。如发现骨髓受抑制应停止使用。曾有报道显示，初次使用或重复使用本药后偶见致死的严重过敏反应。

【注意事项】
有肝肾功能损害或肿瘤已侵犯骨髓的病人慎用。使用本药时，应定期监测白细胞和血小板计数。如白细胞计数低于2000/mm3或血小板低于75000/mm3，且并非由肿瘤本身所引起，应推迟使用，直至骨髓完全恢复正常。在开始输注本药之前，应特别注意留置导管处于正确的位置，以保证药物进入静脉，以免引起组织坏死和血栓性静脉炎。曾有报道显示输注本药时可出现低血压，所以在开始用药后30-60分钟内应注意监测，以免发生严重的副作用。

【孕妇及哺乳期妇女用药】
孕妇使用本药可对胎儿造成损害。在动物实验中，给予妊娠大鼠本药后可出现胚胎毒性和致畸性。本药是否从人乳中排泄尚不明了，故应慎用于妊娠及哺乳妇女。

【儿童用药】
本品含有苯甲醇。曾报道，当使用含大量苯甲醇冲洗液洗低体重早产儿时，发生以喘息性呼吸、核黄疸症、代谢性酸中毒、神经退行性变、血液异常为特征表现的综合征，并可能引起死亡。

【药物相互作用】
苯巴比妥和苯妥英等对肝代谢起诱导作用的药物可增加本药的清除，导致药物在体内的作用时间缩短。因此，接受这类抗惊厥药治疗的病人应增加本药的用量。甲苯磺丁脲、水杨酸钠和磺胺甲噻二唑在体外可以置换与血浆蛋白结合的鬼臼噻吩甙。由于本药的蛋白结合率极高，少量降低与蛋白结合的药物即可导致游离药物的显著增高，进而增强药物的毒性。

【药物过量】
症状 过量用药和先前用过止吐药的病人可发生急性中枢神经抑制和低血压。治疗 尚未发现有效的解毒药，应给予对症支持治疗。

【用药须知】
为了避免本药从聚氯乙烯容器中抽提出塑化剂DEHP，应使用不含DEHP的大容量灭菌容器，如玻璃或聚烯烃容器制备本药的溶液。同样，给病人输注药液时亦应使用不含DEHP的器具。使用本药前可将一安瓿用50、125、250或500 mL的5%葡萄糖或0.9%的氯化钠注射液稀释，然后将已稀释的溶液进行静脉输注，输注时间不少于30分钟。为减少发生低血压的可能性，本药不应静脉推注或快速静脉输注。浓度为1 mg/mL的溶液，贮存于室温或普通日光灯下时的稳定性较差，因此需在制备后4小时以内使用以减少沉淀发生的可能性。同样，通过各种输液器具长时间输注本药时，也可发生沉淀反应。因此，在给病人输液时，需检查药液及整个输液系统。肝素溶液可引起本药产生沉淀，因此在给病人输液之前或之后，必须用5%葡萄糖或0.9%氯化钠注射液彻底冲洗注射针/管等用具。配制时应轻轻搅动溶液，剧烈搅动可引起沉淀。本药不应与其它药物混合使用。如药液溅上皮肤粘膜，应立即用肥皂和清水彻底清洗。

【贮藏/有效期】
25°C以下储存。

【原产地英文商品名】VUMON
【原产地英文药品名】TENIPOSIDE, VM-26
【原产地英文化合物名称】替尼泊苷
【中文参考商品译名】10毫克/毫升/支, 5支/盒
【中文参考商品译名】威猛
【中文参考化合物名称】鬼臼噻吩甙
【生产厂家英文名】Bristol-Myers Squibb

VUMON - teniposide injection, solution 
E.R. Squibb & Sons, L.L.C.

VUMON®
(teniposide injection)

WARNING VUMON (teniposide injection) is a cytotoxic drug which should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate treatment facilities are readily available. Severe myelosuppression with resulting infection or bleeding may occur. Hypersensitivity reactions, including anaphylaxis-like symptoms, may occur with initial dosing or at repeated exposure to VUMON. Epinephrine, with or without corticosteroids and antihistamines, has been employed to alleviate hypersensitivity reaction symptoms.

DESCRIPTION

VUMON® (teniposide injection) (also commonly known as VM-26), is supplied as a sterile nonpyrogenic solution in a nonaqueous medium intended for dilution with a suitable parenteral vehicle prior to intravenous infusion. VUMON is available in 50 mg (5 mL) ampules. Each mL contains 10 mg teniposide, 30 mg benzyl alcohol, 60 mg N,N-dimethylacetamide, 500 mg purified Cremophor® EL (polyoxyethylated castor oil)*, and 42.7% (v/v) dehydrated alcohol. The pH of the clear solution is adjusted to approximately 5 with maleic acid.

*Cremophor® EL is the registered trademark of BASF Aktiengesellschaft.
 Cremophor® EL is further purified by a Bristol-Myers Squibb Company proprietary process before use.

Teniposide is a semisynthetic derivative of podophyllotoxin. The chemical name for teniposide is 4′-demethylepipodophyllotoxin 9-[4,6-O-(R)-2-thenylidene-β-D-glucopyranoside]. Teniposide differs from etoposide, another podophyllotoxin derivative, by the substitution of a thenylidene group on the glucopyranoside ring.

Teniposide has the following structural formula:

Teniposide is a white to off-white crystalline powder with the empirical formula C32H32O13S and a molecular weight of 656.66. It is a lipophilic compound with a partition coefficient value (octanol/water) of approximately 100. Teniposide is insoluble in water and ether. It is slightly soluble in methanol and very soluble in acetone and dimethylformamide.

CLINICAL PHARMACOLOGY

Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G2 phase of the cell cycle, thus preventing cells from entering mitosis.

Teniposide causes dose-dependent single- and double-stranded breaks in DNA and DNA-protein cross-links. The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate.

Teniposide has a broad spectrum of in vivo antitumor activity against murine tumors, including hematologic malignancies and various solid tumors. Notably, teniposide is active against sublines of certain murine leukemias with acquired resistance to cisplatin, doxorubicin, amsacrine, daunorubicin, mitoxantrone, or vincristine.

Plasma drug levels declined biexponentially following intravenous infusion (155 mg/m2 over 1 to 2.5 hours) of VUMON given to 8 children (4-11 years old) with newly diagnosed acute lymphoblastic leukemia (ALL). The observed average pharmacokinetic parameters and associated coefficients of variation (CV%) based on a two-compartmental model analysis of the data are as follows:

There appears to be some association between an increase in serum alkaline phosphatase or gamma glutamyl-transpeptidase and a decrease in plasma clearance of teniposide. Therefore, caution should be exercised if VUMON is to be administered to patients with hepatic dysfunction.

In adults, at doses of 100 to 333 mg/m2/day, plasma levels increased linearly with dose. Drug accumulation in adult patients did not occur after daily administration of VUMON for 3 days. In pediatric patients, maximum plasma concentrations (Cmax) after infusions of 137 to 203 mg/m2 over a period of 1 to 2 hours exceeded 40 mcg/mL; by 20 to 24 hours after infusion plasma levels were generally <2 mcg/mL.

Renal clearance of parent teniposide accounts for about 10% of total body clearance. In adults, after intravenous administration of 10 mg/kg or 67 mg/m2 of tritium-labeled teniposide, 44% of the radiolabel was recovered in urine (parent drug and metabolites) within 120 hours after dosing. From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose.

Mean steady-state volumes of distribution range from 8 to 44 L/m2 for adults and 3 to 11 L/m2 for children. The blood-brain barrier appears to limit diffusion of teniposide into the brain, although in a study in patients with brain tumors, CSF levels of teniposide were higher than CSF levels reported in other studies of patients who did not have brain tumors.

Teniposide is highly protein bound. In vitro plasma protein binding of teniposide is >99%. The high affinity of teniposide for plasma proteins may be an important factor in limiting distribution of drug within the body. Steady-state volume of distribution of the drug increases with a decrease in plasma albumin levels. Therefore, careful monitoring of children with hypoalbuminemia is indicated during therapy. Levels of teniposide in saliva, CSF, and malignant ascites fluid are low relative to simultaneously measured plasma levels.

The pharmacokinetic characteristics of teniposide differ from those of etoposide, another podophyllotoxin. Teniposide is more extensively bound to plasma proteins and its cellular uptake is greater. Teniposide also has a lower systemic clearance, a longer elimination half-life, and is excreted in the urine as parent drug to a lesser extent than etoposide.

In a study at St. Jude Children's Research Hospital (SJCRH), 9 children with acute lymphocytic leukemia (ALL) failing induction therapy with a cytarabine-containing regimen, were treated with VUMON plus cytarabine. Three of these patients were induced into complete remission with durations of remission of 30 weeks, 59 weeks, and 13 years. In another study at SJCRH, 16 children with ALL refractory to vincristine/prednisone-containing regimens were treated with VUMON plus vincristine and prednisone. Three of these patients were induced into complete remission with durations of remission of 5.5, 37, and 73 weeks. In these 2 studies, patients served as their own control based on the premise that long-term complete remissions could not be achieved by re-treatment with drugs to which they had previously failed to respond.

INDICATIONS AND USAGE

VUMON (teniposide injection), in combination with other approved anticancer agents, is indicated for induction therapy in patients with refractory childhood acute lymphoblastic leukemia.

CONTRAINDICATIONS

VUMON is generally contraindicated in patients who have demonstrated a previous hypersensitivity to teniposide and/or Cremophor® EL (polyoxyethylated castor oil).

WARNINGS

VUMON is a potent drug and should be used only by physicians experienced in the administration of cancer chemotherapeutic drugs. Blood counts, as well as renal and hepatic function tests, should be carefully monitored prior to and during therapy.

Patients being treated with VUMON (teniposide injection) should be observed frequently for myelosuppression both during and after therapy. Dose-limiting bone marrow suppression is the most significant toxicity associated with VUMON therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent dose of VUMON: hemoglobin, white blood cell count and differential, and platelet count. If necessary, repeat bone marrow examination should be performed prior to the decision to continue therapy in the setting of severe myelosuppression.

Physicians should be aware of the possible occurrence of a hypersensitivity reaction variably manifested by chills, fever, urticaria, tachycardia, bronchospasm, dyspnea, hypertension or hypotension, and facial flushing. This reaction may occur with the first dose of VUMON and may be life threatening if not treated promptly with antihistamines, corticosteroids, epinephrine, intravenous fluids, and other supportive measures as clinically indicated. The exact cause of these reactions is unknown. They may be due to the Cremophor® EL (polyoxyethylated castor oil) component of the vehicle or to teniposide itself. Patients who have experienced prior hypersensitivity reactions to VUMON are at risk for recurrence of symptoms and should only be re-treated with VUMON if the antileukemic benefit already demonstrated clearly outweighs the risk of a probable hypersensitivity reaction for that patient. When a decision is made to re-treat a patient with VUMON in spite of an earlier hypersensitivity reaction, the patient should be pretreated with corticosteroids and antihistamines and receive careful clinical observation during and after VUMON infusion. In the clinical experience with VUMON at SJCRH and the National Cancer Institute (NCI), re-treatment of patients with prior hypersensitivity reactions has been accomplished using measures described above. To date, there is no evidence to suggest cross-sensitization between VUMON and VePesid®.

One episode of sudden death, attributed to probable arrhythmia and intractable hypotension, has been reported in an elderly patient receiving VUMON combination therapy for a non-leukemic malignancy. (See ADVERSE REACTIONS.) Patients receiving VUMON treatment should be under continuous observation for at least the first 60 minutes following the start of the infusion and at frequent intervals thereafter. If symptoms or signs of anaphylaxis occur, the infusion should be stopped immediately, followed by the administration of epinephrine, corticosteroids, antihistamines, pressor agents, or volume expanders at the discretion of the physician. An aqueous solution of epinephrine 1:1000 and a source of oxygen should be available at the bedside.

For parenteral administration, VUMON should be given only by slow intravenous infusion (lasting at least 30 to 60 minutes) since hypotension has been reported as a possible side effect of rapid intravenous injection, perhaps due to a direct effect of Cremophor® EL. If clinically significant hypotension develops, the VUMON infusion should be discontinued. The blood pressure usually normalizes within hours in response to cessation of the infusion and administration of fluids or other supportive therapy as appropriate. If the infusion is restarted, a slower administration rate should be used and the patient should be carefully monitored.

Acute central nervous system depression, hypotension, and metabolic acidosis have been observed in patients receiving investigational infusions of high-dose VUMON who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the VUMON formulation may place patients receiving higher than recommended doses of VUMON at risk for central nervous system depression.

Pregnancy

Pregnancy Category D

VUMON may cause fetal harm when administered to a pregnant woman. VUMON has been shown to be teratogenic and embryotoxic in laboratory animals. In pregnant rats, intravenous administration of VUMON, 0.1 to 3 mg/kg (0.6-18 mg/m2), every second day from day 6 to day 16 post coitum caused dose-related embryotoxicity and teratogenicity. Major anomalies included spinal and rib defects, deformed extremities, anophthalmia, and celosomia.

There are no adequate and well-controlled studies in pregnant women. If VUMON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with VUMON.

PRECAUTIONS

General

In all instances where the use of VUMON is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of VUMON therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.

VUMON must be administered as an intravenous infusion. Care should be taken to ensure that the intravenous catheter or needle is in the proper position and functional prior to infusion. Improper administration of VUMON may result in extravasation causing local tissue necrosis and/or thrombophlebitis. In some instances, occlusion of central venous access devices has occurred during 24-hour infusion of VUMON at a concentration of 0.1 to 0.2 mg/mL. Frequent observation during these infusions is necessary to minimize this risk.

Laboratory Tests

Periodic complete blood counts and assessments of renal and hepatic function should be done during the course of VUMON treatment. They should be performed prior to therapy and at clinically appropriate intervals during and after therapy. There should be at least one determination of hematologic status prior to therapy with VUMON.

Drug Interactions

In a study in which 34 different drugs were tested, therapeutically relevant concentrations of tolbutamide, sodium salicylate, and sulfamethizole displaced protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering VUMON to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Children at SJCRH with ALL in remission who received maintenance therapy with VUMON at weekly or twice weekly doses (plus other chemotherapeutic agents), had a relative risk of developing secondary acute nonlymphocytic leukemia (ANLL) approximately 12 times that of patients treated according to other less intensive schedules.

A short course of VUMON for remission-induction and/or consolidation therapy was not associated with an increased risk of secondary ANLL, but the number of patients assessed was small. The potential benefit from VUMON must be weighed on a case by case basis against the potential risk of the induction of a secondary leukemia. The carcinogenicity of teniposide has not been studied in laboratory animals. Compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic and teniposide should be considered a potential carcinogen in humans. Teniposide has been shown to be mutagenic in various bacterial and mammalian genetic toxicity tests. These include positive mutagenic effects in the Ames/Salmonella and B. subtilis bacterial mutagenicity assays. Teniposide caused gene mutations in both Chinese hamster ovary cells and mouse lymphoma cells and DNA damage as measured by alkaline elution in human lung carcinoma derived cell lines. In addition, teniposide induced aberrations in chromosome structure in primary cultures of human lymphocytes in vitro and in L5178y/TK +/- mouse lymphoma cells in vitro. Chromosome aberrations were observed in vivo in the embryonic tissue of pregnant Swiss albino mice treated with teniposide. Teniposide also caused a dose-related increase in sister chromatid exchanges in Chinese hamster ovary cells, and it has been shown to be embryotoxic and teratogenic in rats receiving teniposide during organogenesis. Treatment of pregnant rats intravenously with doses between 1.0 and 3.0 mg/kg/day on alternate days from day 6 to 16 post coitum caused retardation of embryonic development, prenatal mortality, and fetal abnormalities.

Pregnancy

Pregnancy Category D

See WARNINGS.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of VUMON therapy to the mother.

Pediatric Use

Adverse events were evaluated in 7 studies involving 303 patients (age range 0.5 months to 20 years) who received VUMON as a single agent (see ADVERSE REACTIONS). No association between any particular age group and adverse effects was reported in any of these investigations.

Patients with Down Syndrome

Patients with both Down syndrome and leukemia may be especially sensitive to myelosuppressive chemotherapy, therefore, initial dosing with VUMON should be reduced in these patients. It is suggested that the first course of VUMON should be given at half the usual dose. Subsequent courses may be administered at higher dosages depending on the degree of myelosuppression and mucositis encountered in earlier courses in an individual patient.

ADVERSE REACTIONS

The table below presents the incidences of adverse reactions derived from an analysis of data contained within literature reports of 7 studies involving 303 pediatric patients in which VUMON was administered by injection as a single agent in a variety of doses and schedules for a variety of hematologic malignancies and solid tumors. The total number of patients evaluable for a given event was not 303 since the individual studies did not address the occurrence of each event listed. Five of these 7 studies assessed VUMON activity in hematologic malignancies, such as leukemia. Thus, many of these patients had abnormal hematologic status at start of therapy with VUMON and were expected to develop significant myelosuppression as an endpoint of treatment.

Hematologic Toxicity

VUMON, when used with other chemotherapeutic agents for the treatment of ALL, results in severe myelosuppression. Early onset of profound myelosuppression with delayed recovery can be expected when using the doses and schedules of VUMON necessary for treatment of refractory ALL, since bone marrow hypoplasia is a desired endpoint of therapy. The occurrence of acute non-lymphocytic leukemia (ANLL), with or without a preleukemic phase, has been reported in patients treated with VUMON in combination with other antineoplastic agents. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility.)

Gastrointestinal Toxicity

Nausea and vomiting are the most common gastrointestinal toxicities, having occurred in 29% of evaluable pediatric patients. The severity of this nausea and vomiting is generally mild to moderate.

Hypotension

Transient hypotension following rapid intravenous administration has been reported in 2% of evaluable pediatric patients. One episode of sudden death, attributed to probable arrhythmia and intractable hypotension, has been reported in an elderly patient receiving VUMON combination therapy for a non-leukemic malignancy.

No other cardiac toxicity or electrocardiographic changes have been documented. No delayed hypotension has been noted.

Allergic Reactions

Hypersensitivity reactions characterized by chills, fever, tachycardia, flushing, bronchospasm, dyspnea, and blood pressure changes (hypertension or hypotension) have been reported to occur in approximately 5% of evaluable pediatric patients receiving intravenous VUMON. The incidence of hypersensitivity reactions to VUMON appears to be increased in patients with brain tumors and in patients with neuroblastoma.

Central Nervous System

Neurotoxicity has been reported, including severe cases of neuropathy in patients due to an interaction of vincristine sulfate and VUMON when administered concomitantly.

Acute central nervous system depression and hypotension have been observed in patients receiving investigational infusions of high-dose VUMON who were pretreated with antiemetic drugs. The depressant effects of the antiemetic agents and the alcohol content of the VUMON formulation may place patients receiving higher than recommended doses of VUMON at risk for central nervous system depression.

Alopecia

Alopecia, sometimes progressing to total baldness, was observed in 9% of evaluable pediatric patients who received VUMON as single-agent therapy. It was usually reversible.

Other Reactions

The following reactions have been reported: headache, confusion, and asthenia.

OVERDOSAGE

Acute central nervous system depression, hypotension, and metabolic acidosis have been observed in patients who were receiving higher than recommended doses of VUMON, and who were also pretreated with antiemetic drugs.

There is no known antidote for VUMON overdosage. The anticipated complications of overdosage are secondary to bone marrow suppression. Treatment should consist of supportive care, including blood products and antibiotics as indicated.

DOSAGE AND ADMINISTRATION

NOTE: Contact of undiluted VUMON with plastic equipment or devices used to prepare solutions for infusion may result in softening or cracking and possible drug product leakage. This effect has not been reported with diluted solutions of VUMON.

In order to prevent extraction of the plasticizer DEHP [di(2-ethylhexyl) phthalate], solutions of VUMON should be prepared in non-DEHP containing LVP containers such as glass or polyolefin plastic bags or containers.

VUMON solutions should be administered with non-DEHP containing intravenous administration sets.

In one study, childhood ALL patients failing induction therapy with a cytarabine-containing regimen were treated with the combination of VUMON 165 mg/m2 and cytarabine 300 mg/m2 intravenously, twice weekly for 8 to 9 doses. In another study, patients with childhood ALL refractory to vincristine/prednisone-containing regimens were treated with the combination of VUMON 250 mg/m2 and vincristine 1.5 mg/m2 intravenously, weekly for 4 to 8 weeks and prednisone 40 mg/m2 orally for 28 days.

Adequate data in patients with hepatic insufficiency and/or renal insufficiency are lacking, but dose adjustments may be necessary for patients with significant renal or hepatic impairment.

Preparation and Administration Precautions

Caution should be exercised in handling and preparing the solution of VUMON. Several guidelines on proper handling and disposal of anticancer drugs have been published.1–4 Skin reactions associated with accidental exposure to VUMON may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling ampules containing VUMON. If VUMON solution contacts the skin, immediately wash the skin thoroughly with soap and water. If VUMON contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below.

Preparation for Intravenous Administration

VUMON must be diluted with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, to give final teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, or 1.0 mg/mL. Solutions prepared in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP at teniposide concentrations of 0.1 mg/mL, 0.2 mg/mL, or 0.4 mg/mL are stable at room temperature for up to 24 hours after preparation. VUMON solutions prepared at a final teniposide concentration of 1.0 mg/mL should be administered within 4 hours of preparation to reduce the potential for precipitation. Refrigeration of VUMON solutions is not recommended. Stability and use times are identical in glass and plastic parenteral solution containers.

Although solutions are chemically stable under the conditions indicated, precipitation of teniposide may occur at the recommended concentrations, especially if the diluted solution is subjected to more agitation than is recommended to prepare the drug solution for parenteral administration. In addition, storage time prior to administration should be minimized and care should be taken to avoid contact of the diluted solution with other drugs or fluids. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Precipitation has been reported during 24-hour infusions of VUMON diluted to teniposide concentrations of 0.1 to 0.2 mg/mL, resulting in occlusion of central venous access catheters in several patients. Heparin solution can cause precipitation of teniposide, therefore, the administration apparatus should be flushed thoroughly with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP before and after administration of VUMON.

Hypotension has been reported following rapid intravenous administration; it is recommended that the VUMON solution be administered over at least a 30- to 60-minute period. VUMON should not be given by rapid intravenous injection.

In a 24-hour study under simulated conditions of actual use of the product relative to dilution strength, diluent and administration rates, dilutions at 0.1 to 1.0 mg/mL were chemically stable for at least 24 hours. Data collected for the presence of the extractable DEHP [di(2-ethylhexyl) phthalate] from PVC containers show that levels increased with time and concentration of the solutions. The data appeared similar for 0.9% Sodium Chloride Injection, USP, and 5% Dextrose Injection, USP. Consequently, the use of PVC containers is not recommended.

Similarly, the use of non-DEHP intravenous administration sets is recommended. Lipid administration sets or low DEHP-containing nitroglycerin sets will keep patient’s exposure to DEHP at low levels and are suitable for use. The diluted solutions are chemically and physically compatible with the recommended intravenous administration sets and LVP containers for up to 24 hours at ambient room temperature and lighting conditions. Because of the potential for precipitation, compatibility with other drugs, infusion materials, or intravenous pumps cannot be assured.

Stability

Unopened ampules of VUMON are stable until the date indicated on the package when stored under refrigeration (2°-8°C) in the original package. Freezing does not adversely affect the product.

HOW SUPPLIED

VUMON® (teniposide injection)

Storage

Store the unopened ampules under refrigeration (2°-8°C). Retain in original package to protect from light.

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
3. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.

VePesid® is the registered trademark of Bristol-Myers Squibb Company.