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Marqibo(vinCRIStine sulfate LIPOSOME injection)

2013-04-06 01:06:45 作者：新特药房来源：互联网浏览次数：392 文字大小：【大】【中】【小】

简介： 英文药名：Marqibo(vinCRIStine sulfate LIPOSOME injection) 中文药名：硫酸长春新碱脂质体注射液生产厂家：Talon Therapeutics药品介绍FDA于2012年8月9日Marqibo（硫酸长春新碱脂质体注射液）获准 ...

关键字：硫酸长春新碱脂质体注射液 Marqibo 白血病

英文药名：Marqibo(vinCRIStine sulfate LIPOSOME injection)

中文药名：硫酸长春新碱脂质体注射液

生产厂家：Talon Therapeutics
药品介绍
FDA于2012年8月9日Marqibo（硫酸长春新碱脂质体注射液）获准用于治疗白血病患者复发2次以上或病情恶化的患者，或在经过2种以上抗白血病药物治疗方案后病情仍有进展的患者。该药主要成分为常用抗肿瘤药长春新碱，由一种类似细胞膜成分的脂质体包裹，每周注射一次，是由南加州旧金山市的Talon Therapeutics公司生产的。
Marqibo
Generic Name: vincristine sulfate
Dosage Form: injection
WARNING
•For Intravenous Use Only – Fatal if Given by Other Routes [see Warnings and Precautions (5.1)].
•Death has occurred with intrathecal administration.
•Marqibo (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vinCRIStine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage.
Indications and Usage for Marqibo
Adult ALL in Second or Greater Relapse
Marqibo® is indicated for the treatment of adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies. This indication is based on overall response rate. Clinical benefit such as improvement in overall survival has not been verified.
Marqibo Dosage and Administration
For Intravenous Use Only. Fatal if Given by Other Routes.
Marqibo (vinCRIStine sulfate LIPOSOME injection) has different dosage recommendations than vincristine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage.
Recommended Dosage
The recommended dose of Marqibo is 2.25 mg/m2 intravenously over 1 hour once every 7 days.
Marqibo is liposome-encapsulated vincristine.
Dose modifications: Peripheral Neuropathy
Marqibo is contraindicated in patients with demyelinating conditions including Charcot-Marie-Tooth syndrome [see Contraindications (4)]. Patients with preexisting severe neuropathy should be treated with Marqibo only after careful risk-benefit assessment [see Warnings and Precautions (5.3)]. For dose or schedule modifications guidelines for patients who experience peripheral neuropathy, see Table 1.
Preparation and Handling
2.3.1 Items Required by the Pharmacy to Prepare Marqibo
•Marqibo Kit
•Water bath1
•Calibrated thermometer1 (0°C to 100°C)
•Calibrated electronic timer1
•Sterile venting needle or other suitable device equipped with a sterile 0.2 micron filter
•1 mL or 3 mL sterile syringe with needle, and
•5 mL sterile syringe with needle.
The manufacturer will provide the water bath, calibrated thermometer, and calibrated electronic timer to the medical facility at the initial order of Marqibo and will replace them every 2 years.
2.3.2 Preparation Instructions for Marqibo (vinCRIStine sulfate LIPOSOME injection), 5 mg/31 mL (0.16 mg/mL)
Procedures for handling and disposal of anticancer drugs should be followed [see References (15)].
Call [1 888 292 9617] if you have questions about the preparation of Marqibo. Marqibo takes approximately 60 to 90 minutes to prepare. The preparer should have dedicated uninterrupted time to prepare Marqibo due to the extensive monitoring of temperature and time required for the preparation.
Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in Marqibo. The preparation steps of Marqibo that involve mixing the Sodium Phosphate Injection, Sphingomyelin/Cholesterol Liposome Injection, and VinCRIStine Sulfate Injection must be done in a biological safety cabinet or by established pharmacy safety procedures for the preparation of sterile injectable formulations and hazardous drugs. However, the preparation steps that involve placement of the vial in the water bath must be done outside of the sterile area.
Do not use with in-line filters. Do not mix with other drugs.
1.Fill a water bath with water to a level of at least 8 cm (3.2 inches) measured from the bottom and maintain this minimum water level throughout the procedure. The water bath must remain outside of the sterile area.
2.Place a calibrated thermometer in the water bath to monitor water temperature and leave it in the water bath until the procedure has been completed.
3.Preheat water bath to 63°C to 67°C. Maintain this water temperature until completion of the procedure using the calibrated thermometer.
4.Visually inspect each vial in the Marqibo Kit for particulate matter and discoloration prior to preparation, whenever solution and container permit. Do not use if a precipitate or foreign matter is present.
5.Remove all the caps on the vials and swab the vials with sterile alcohol pads.
6.Vent the Sodium Phosphate Injection vial with a sterile venting needle equipped with a sterile 0.2 micron filter or other suitable venting device in the biological safety cabinet. Always position venting needle point well above liquid level before adding Sphingomyelin/Cholesterol Liposome Injection and VinCRIStine Sulfate Injection.
7.Withdraw 1 mL of Sphingomyelin/Cholesterol Liposome Injection.
8.Inject 1 mL of Sphingomyelin/Cholesterol Liposome Injection into the Sodium Phosphate Injection vial.
9.Withdraw 5 mL of VinCRIStine Sulfate Injection.
10.Inject 5 mL of VinCRIStine Sulfate Injection into the Sodium Phosphate Injection vial.
11.Remove the venting needle and gently invert the Sodium Phosphate Injection vial 5 times to mix. DO NOT SHAKE.
12.Fit Flotation Ring around the neck of the Sodium Phosphate Injection vial.
13.Confirm that the water bath temperature is at 63°C to 67°C using the calibrated thermometer. Remove the Sodium Phosphate Injection vial containing VinCRIStine Sulfate Injection, Sphingomyelin/Cholesterol Liposome Injection, and Sodium Phosphate Injection from the biological safety cabinet and place into the water bath for 10 minutes using the calibrated electronic timer. Monitor the temperature to ensure the temperature is maintained at 63°C to 67°C.
14.IMMEDIATELY after placing the Sodium Phosphate Injection vial into the water bath, record the constitution start time and water temperature on the Marqibo Overlabel.
15.At the end of the 10 minutes, confirm that the water temperature is 63°C to 67°C using the calibrated thermometer. Remove the vial from the water bath (use tongs to prevent burns) and remove the Flotation Ring.
16.Record the final constitution time and the water temperature on the Marqibo Overlabel.
17.Dry the exterior of the Sodium Phosphate Injection vial with a clean paper towel, affix Marqibo (vinCRIStine sulfate LIPOSOME injection) Overlabel, and gently invert 5 times to mix. DO NOT SHAKE.
18.Permit the constituted vial contents to equilibrate for at least 30 minutes to controlled room temperature (15°C to 30°C, 59°F to 86°F).
19.Marqibo (vinCRIStine sulfate LIPOSOME injection) contains 5 mg/31 mL (0.16 mg/mL) vincristine sulfate. ONCE PREPARED, STORE AT CONTROLLED ROOM TEMPERATURE (15°C to 30°C, 59°F to 86°F) FOR NO MORE THAN 12 HOURS.
20.Swab the top of the vial now containing Marqibo with a sterile alcohol pad and return the vial back into the biological safety cabinet.
21.Calculate the patient's Marqibo dose based on the patient's actual body surface area (BSA) and remove the volume corresponding to the patient's Marqibo dose from an infusion bag containing 100 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
22.Inject the dose of Marqibo into the infusion bag to result in a final volume of 100 mL.
23.Complete the information required on the Infusion Bag Label and apply to the infusion bag.
24.Finish administration of the diluted product within 12 hours of the initiation of Marqibo preparation.
25.Empty, clean, and dry the water bath after each use.
26.Deviations in temperature, time, and preparation procedures may fail to ensure proper encapsulation of vincristine sulfate into the liposomes. In the event that the preparation deviates from the instructions in the above steps, the components of the kit should be discarded and a new kit should be used to prepare the dose.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present.
Dosage Forms and Strengths
Marqibo is prepared from the components in the Marqibo Kit. Following the preparation procedure according to section 2.3.2, each single-dose vial of Marqibo (vinCRIStine sulfate LIPOSOME injection) contains 5 mg/31 mL (0.16 mg/mL) vincristine sulfate.
Contraindications
Marqibo is contraindicated in patients with demyelinating conditions including Charcot-Marie-Tooth syndrome.
Marqibo is contraindicated in patients with hypersensitivity to vincristine sulfate or any of the other components of Marqibo (vinCRIStine sulfate LIPOSOME injection).
Marqibo is contraindicated for intrathecal administration.
Warnings and Precautions
For Intravenous Use Only
Fatal if Given by Other Routes. Death has occurred with intrathecal use.
Extravasation Tissue Injury
Only administer through a secure and free-flowing venous access line. If extravasation is suspected, discontinue infusion immediately and consider local treatment measures.
Neurologic Toxicity
Sensory and motor neuropathies are common and are cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, hyporeflexia, areflexia, neuralgia, jaw pain, decreased vibratory sense, cranial neuropathy, ileus, burning sensation, arthralgia, myalgia, muscle spasm, or weakness, both before and during treatment. Orthostatic hypotension may occur. The risk of neurologic toxicity is greater if Marqibo is administered to patients with preexisting neuromuscular disorders or when other drugs with risk of neurologic toxicity are being given. In the studies of relapsed and/or refractory adult ALL patients, Grade ≥ 3 neuropathy events occurred in 32.5% of patients. Worsening neuropathy requires dose delay, reduction, or discontinuation of Marqibo [see Dosage and Administration (2.2)].
Myelosuppression
Monitor complete blood counts prior to each dose of Marqibo. If Grade 3 or 4 neutropenia, thrombocytopenia, or anemia develops, consider Marqibo dose modification or reduction as well as supportive care measures.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) may occur in patients with ALL receiving Marqibo. Anticipate, monitor for, and manage.
Constipation and Bowel Obstruction
Ileus, bowel obstruction, and colonic pseudo-obstruction have occurred. Marqibo can cause constipation [see Adverse Reactions (6)]. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction, and/or paralytic ileus, considering adequate dietary fiber intake, hydration, and routine use of stool softeners, such as docusate. Additional treatments, such as senna, bisacodyl, milk of magnesia, magnesium citrate, and lactulose may be considered.
Fatigue
Marqibo can cause severe fatigue. Marqibo dose delay, reduction, or discontinuation may be necessary.
Hepatic Toxicity
Fatal liver toxicity and elevated levels of aspartate aminotransferase have occurred. Elevated levels of aspartate aminotransferase of Grade ≥3 occurred in 6-11% of patients in clinical trials. Monitor hepatic function tests. Reduce or interrupt Marqibo for hepatic toxicity.
Embryofetal Toxicity
Marqibo can cause fetal harm when administered to a pregnant woman. Vincristine sulfate liposome injection was teratogenic or caused embryo-fetal death in animals. Women of childbearing potential should avoid becoming pregnant while being treated with Marqibo. There are no adequate and well-controlled studies of Marqibo in pregnant women and there were no reports of pregnancy in any of the clinical studies in the Marqibo clinical development program. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
Adverse Reactions
The following adverse reactions are also discussed in other sections of the labeling:
•For intravenous use only [see Warnings and Precautions (5.1)]
•Extravasation tissue injury [see Warnings and Precautions (5.2)]
•Peripheral Neuropathy [see Warnings and Precautions (5.3)]
•Myelosuppression [see Warnings and Precautions (5.4)]
•Tumor lysis syndrome [see Warnings and Precautions (5.5)]
•Constipation and bowel obstruction [see Warnings and Precautions (5.6)]
•Fatigue [see Warnings and Precautions (5.7)]
•Hepatic toxicity [see Warnings and Precautions (5.8)]
Clinical Trials Safety Experience
Because 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 clinical practice.
Integrated Summary of Safety in Relapsed and/or Refractory Ph- Adult Acute Lymphoblastic Leukemia
Marqibo, at a dose of 2.25 mg/m2 weekly, was studied in a total of 83 patients in two trials: study 1 and study 2. Adverse reactions were observed in 100% of patients. The most common adverse reactions (>30%) were constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia (32%).
Adverse reactions of Grade 3 or greater were reported in 96% of patients. Adverse reactions of Grade 3 or greater and occurring in ≥ 5% of patients are summarized in Table 2.
A total of 75.9% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included febrile neutropenia (20.5%), pyrexia (13.3%), hypotension (7.2%), respiratory distress (6.0%), and cardiac arrest (6.0%).
Dose reduction, delay, or omission occurred in 53% of patients during the treatment.
Twenty-eight percent of patients experienced adverse reactions leading to treatment discontinuation. The most common adverse reactions that caused treatment discontinuation were peripheral neuropathy (10%), leukemia-related (7%), and tumor lysis syndrome (2%).
Adverse reactions related to neuropathy and leading to treatment discontinuation were decreased vibratory sense, facial palsy, hyporeflexia, constipation, asthenia, fatigue, and musculoskeletal pain, each reported in at least 1 patient.
Deaths occurred in 23% of patients in study 1. The non-leukemia related causes of deaths were brain infarct (1), intracerebral hemorrhage (2), liver failure (1), multi system organ failure (2), pneumonia and septic shock (3), respiratory failure (4), pulmonary hemorrhage (1), and sudden cardiac death (1).
Drug Interactions
No formal drug interaction studies have been conducted with Marqibo. Marqibo is expected to interact with drugs known to interact with non-liposomal vincristine sulfate.
Simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included non-liposomal vincristine sulfate have been reported to reduce blood levels of phenytoin and to increase seizure activity.
CYP3A Interactions
Vincristine sulfate, the active agent in Marqibo, is a substrate for cytochrome P450 3A isozymes (CYP3A); therefore, the concomitant use of strong CYP3A inhibitors should be avoided (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). Similarly, the concomitant use of strong CYP3A inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John's Wort).
P-glycoprotein Interactions
Vincristine sulfate, the active agent in Marqibo, is also a substrate for P-glycoprotein (P-gp). The effect of concomitant use of potent P-gp inhibitors or inducers has not been investigated; it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of Marqibo. Therefore the concomitant use of potent P-gp inhibitors or inducers should be avoided.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.9)]
Based on its mechanism of action and findings from animal studies, Marqibo can cause fetal harm when administered to pregnant women.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. In an embryofetal developmental study, pregnant rats were administered vincristine sulfate liposome injection intravenously during the period of organogenesis at vincristine sulfate doses of 0.022 to 0.09 mg/kg/day. Drug-related adverse effects included fetal malformations (skeletal and visceral), decreases in fetal weights, increased numbers of early resorptions and post-implantation losses, and decreased maternal body weights Malformations were observed at doses ≥ 0.044 mg/kg/day in animals at systemic exposures approximately 20-40% of those reported in patients at the recommended dose.
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 discontinue the drug taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of Marqibo in pediatric patients have not been established.
Geriatric Use
Safety and effectiveness in elderly individuals have not been established. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Renal Impairment
The influence of renal impairment on the safety, efficacy, and pharmacokinetics of Marqibo has not been evaluated.
Hepatic Impairment
Non-liposomal vincristine sulfate is excreted primarily by the liver. The influence of severe hepatic impairment on the safety and efficacy of Marqibo has not been evaluated.
The pharmacokinetics of Marqibo was evaluated in patients with moderate hepatic dysfunction (Child-Pugh B) secondary to melanoma liver metastases. The dose-adjusted maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of Marqibo in patients with moderate hepatic impairment was comparable to the Cmax and AUC of patients with ALL who had otherwise normal hepatic function.
Overdosage
When Marqibo (vinCRIStine sulfate LIPOSOME injection) was administered at a dose of 2.4 mg/m2, severe toxicities including motor neuropathy of Grade 3, grand mal seizure of Grade 4, and elevated aspartate aminotransferase and hyperbilirubinemia of Grade 4 were reported in 1 patient each. There is no known antidote for overdosage.
Marqibo Description
Marqibo (vinCRIStine sulfate LIPOSOME injection) is vincristine encapsulated in sphingomyelin/cholesterol liposomes for intravenous administration.
The active ingredient in Marqibo is vincristine sulfate. Vincristine sulfate is a vinca alkaloid isolated as a 1:1 sulfate salt from the periwinkle plant (Catharanthus roseus). It is a hygroscopic, white to slightly yellowish crystalline powder that is soluble in water. It has a molecular weight of 923.04 (salt form) / 824.98 (base form) and a molecular formula of C46H56N4O10 • H2SO4. The chemical name for vincristine sulfate is 22-oxovincaleukoblastine and it has the following chemical structure:
Vincristine is encapsulated in a Sphingomyelin/Cholesterol liposome. The lipid components in the liposome are sphingomyelin and cholesterol at a molar ratio of approximately 60:40 (mol:mol).
After preparation, each vial of Marqibo contains 5 mg vincristine sulfate, 500 mg mannitol, 73.5 mg sphingomyelin, 29.5 mg cholesterol, 36 mg sodium citrate, 38 mg citric acid, 355 mg sodium phosphate, and 225 mg sodium chloride.
Marqibo (vinCRIStine sulfate LIPOSOME injection) appears as a white to off-white, translucent suspension, essentially free of visible foreign matter and aggregates, comprised of sphingomyelin/cholesterol liposomes, with an approximate liposome mean diameter of 100 nm. Greater than 95% of the drug is encapsulated in the liposomes.
The Marqibo Kit component vials for the preparation of Marqibo (vinCRIStine sulfate LIPOSOME injection) include:
•VinCRIStine Sulfate Injection, USP (5 mg/5 mL). Each VinCRIStine Sulfate Injection vial consists of 5 mg/5 mL vincristine sulfate (which is equivalent to 4.5 mg/5 mL vincristine free base) and 500 mg/5 mL mannitol.
•Sphingomyelin/Cholesterol Liposome Injection (103 mg/mL). Each Sphingomyelin/Cholesterol Liposome Injection vial consists of 73.5 mg/mL sphingomyelin, 29.5 mg/mL cholesterol, 33.6 mg/mL citric acid, 35.4 mg/mL sodium citrate, and not more than 0.1% ethanol.
•Sodium Phosphate Injection (355 mg/25 mL). Each Sodium Phosphate Injection vial consists of 355 mg/25 mL dibasic sodium phosphate and 225 mg/25 mL sodium chloride.
Marqibo - Clinical Pharmacology
Mechanism of Action
Marqibo is a sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine sulfate. Non-liposomal vincristine sulfate binds to tubulin, altering the tubulin polymerization equilibrium, resulting in altered microtubule structure and function. Non-liposomal vincristine sulfate stabilizes the spindle apparatus, preventing chromosome segregation, triggering metaphase arrest and inhibition of mitosis.
Pharmacokinetics
The plasma pharmacokinetics of Marqibo was investigated in 13 adult patients with relapsed ALL who received a Marqibo dose of 2.25 mg/m2 administered as a 1-hour intravenous infusion. The calculated pharmacokinetic parameters for total plasma vincristine sulfate are given in Table 3. The vincristine sulfate levels reported in Table 3 reflect liposome-encapsulated drug that may not be immediately bioavailable and may not be directly comparable to plasma levels of vincristine sulfate after administration of non-liposomal vincristine sulfate, which is immediately bioavailable.
The plasma clearance (CL) of Marqibo is slow, 345 mL/h, at a dose of 2.25 mg/m2. This is in comparison to the rapid clearance of non-liposomal vincristine sulfate at 189 mL/min/m2 (11,340 mL/h). The slow clearance of Marqibo contributes to a much higher AUC for Marqibo relative to non-liposomal vincristine sulfate.
Following intravenous administration of Marqibo, urinary excretion was a minor route of elimination for vincristine sulfate and its metabolite. Less than 8% of the administered Marqibo dose was eliminated in urine over a 96-hour observation period, which is similar to the urinary excretion of non-liposomal vincristine sulfate. Following non-liposomal vincristine sulfate infusion, the main route of vincristine sulfate excretion was the fecal route, accounting for 69% of the administered dose over 72 hours.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity studies have been conducted with Marqibo or non-liposomal vincristine sulfate. Based on the mechanism of action and genotoxicity findings in nonclinical studies conducted with non-liposomal vincristine sulfate, Marqibo may be carcinogenic.
No genotoxicity studies have been conducted with Marqibo. Non-liposomal vincristine was genotoxic in some in vitro and in vivo studies.
The single- and repeat-dose animal toxicology study results indicate that Marqibo can impair male fertility, consistent with the literature on non-liposomal vincristine sulfate. Administration of vincristine liposome injection causes testicular degeneration and atrophy, and epididymal aspermia in rats.
Gonadal dysfunction has been reported in both male and female post-pubertal patients who received multi-agent chemotherapy including non-liposomal vincristine sulfate. The degree to which testicular or ovarian functions are affected is age-, dose-, and agent-dependent. Recovery may occur in some but not all patients.
Animal Toxicology and/or Pharmacology
In a repeat-dose comparative toxicology study in rats, vincristine sulfate liposome injection or non-liposomal vincristine sulfate was administered to animals intravenously once per week for 6 weeks. Clinical signs of toxicity consistent with neurotoxicity were greater with vincristine sulfate liposome injection than with non-liposomal vincristine sulfate at equal vincristine sulfate doses of 2 mg/m2/week and included uncoordinated movements, weakness, reduced muscle tone, and limited usage of the limbs. Neurological testing indicated drug-induced peripheral neurotoxicity with both drugs. Based on the histopathology examination after 6 weekly doses, vincristine sulfate liposome injection induced greater peripheral neurotoxicity (nerve fiber degeneration) and secondary skeletal muscle atrophy than the equal dose of non-liposomal vincristine sulfate. In a separate tissue distribution study in rats, administration of 2 mg/m2 of intravenous liposomal or non-liposomal vincristine sulfate showed greater accumulation of vincristine sulfate in sciatic and tibial nerves (as well as the lymph nodes, spleen, and bone marrow) of the animals following vincristine sulfate liposome injection.
Clinical Studies
Acute Lymphoblastic Leukemia
Marqibo was studied in an international, open-label, multi-center, single-arm trial (Study 1). Eligible patients were 18 years of age or older with Philadelphia chromosome negative ALL in second or greater relapse or whose disease progressed after two or greater treatment lines of anti-leukemia therapy. Patients had to have achieved a complete remission (CR) to at least one prior anti-leukemia chemotherapy, defined by a leukemia-free interval of equal or more than 90 days. Patients were not eligible for immediate hematopoietic stem cell transplantation (HSCT) at the time of screening and enrollment.
Patients received intravenous Marqibo monotherapy at 2.25 mg/m2 over 60 minutes every 7 days. Concomitant corticosteroids were not permitted beyond Day 5.
The treated population included 65 patients who received at least 1 dose of Marqibo. All of the treated patients had received prior vincristine sulfate and 80% had evidence of residual neuropathy at study baseline. Among treated patients, 51% were male, 86% were white, 45% were under 30 years of age, 11% were age 65 or older, 48% had undergone prior HSCT, 51% had received 3 or more prior therapies, and 45% were refractory to their immediate prior therapy. Disease characteristics were 85% precursor B-cell ALL and 15% precursor T-cell ALL. In addition, 22 of 65 (34%) treated patients did not receive asparaginase products prior to enrollment. Efficacy results are shown in Table 4.
REFERENCES
1.NIOSH Alert: Preventing occupational exposure 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. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3.American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. (2006) 63:1172-1193.
4.Polovich M, White JM, Kelleher LO (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.
How Supplied/Storage and Handling
The Marqibo Kit (NDC # 20536-322-01) contains:
•Vial containing VinCRIStine Sulfate Injection, USP 5 mg/5 mL (1 mg/mL) – NDC # 20536-323-01
•Vial containing Sphingomyelin/Cholesterol Liposome Injection 103 mg/mL – NDC # 20536-324-01
•Vial containing Sodium Phosphate Injection 355 mg/25 mL (14.2 mg/mL) – NDC # 20536-325-01
•Flotation Ring
•Overlabel for Sodium Phosphate Injection vial containing constituted Marqibo (vinCRIStine sulfate LIPOSOME injection), 5 mg/31 mL (0.16 mg/mL)
•Infusion Bag Label
Storage
Store the Marqibo Kit in the refrigerator at 2°C to 8°C – Do Not Freeze

FDA批准硫酸长春新碱脂质体注射液用于白血病治疗
近日；FDA已经批准硫酸长春新碱脂质体注射液用于一种罕见的血液及骨髓癌症的治疗。FDA在一份声明中说，该药适用于治疗已接受两次或更多抗白血病治疗后仍然复发或病情仍有进展的费城染色体阴性成年人急性淋巴细胞白血病（ALL）。这种疾病（ALL）是一种呈“快速进展性”的血液和骨髓癌症，在儿童中较成年人更常见。国家癌症研究所估计今年美国将新增超过6,000例ALL患者，约有1,400名因ALL死亡。
这一每周静脉注射一次的孤儿药获得了FDA的加速审批，孤儿药指用于治疗全国患者少于200,000人的药品。在批准过程中，生产商还获得了税收抵免和患者用药费用减免（的政策优惠）。该药的审批因受到一个FDA咨询小组对药效的质疑而充满不确定性。不过该小组最终勉强同意推荐该药获得批准。
包括148例患者的三组完整实验评价了该药的安全性和有效性。其中一组实验中，65名曾接受两次或以上标准疗法而又复发的白血病患者显示了良好效果，其中至少一种前期疗法持续了90天甚至更长时间才有效果。受试者中有15.4%完全缓解，其伴随或不伴随血细胞数量不完全恢复的中位期为28天，复发、死亡或接受下一次治疗首次出现的中位时间为56天。在两组安全性评价试验中，常见副反应为便秘、恶心、血细胞减少、发热、神经损伤、疲劳、腹泻、食欲降低和失眠。76%患者出现严重副作用，包括伴随发热的白细胞降低、低血压、呼吸窘迫和心脏骤停。
Marqibo将带有黑框警告，指出仅用于静脉注射，其他给药途径可能致死。该警告还提醒医疗护理者注意由于硫酸长春新碱单独应用中用量不同引发的潜在用药过量风险。该产品由加利福尼亚州的南旧金山Talon制药生产。