部份右丙亚胺中文资料（仅供参考）
药品名称：
Savene20毫克/毫升粉末浓缩物和稀释剂的输注液。
定性和定量组成
每毫升含有20毫克右雷佐生重构用25ml注射用水后。每管含有500毫克的右丙亚胺（盐酸盐）。
辅料稀释剂：钾98毫克/500毫升钠1.61克/ 500ml适用辅料。
药物剂型
散浓缩和稀释为输液。
Savene粉：白色至灰白色。Savene稀释剂：等渗稀释剂透明（295 mOsml/ L，pH值约）。
临床
治疗适应症
为蒽环的外渗的治疗
剂量和给药方法
使用癌症化疗剂的医师的监督下进行给药。Savene应每天连续3天给予一次。
推荐剂量是：第1天：1000毫克/米2第2天：1000毫克/米2天3：500毫克/米2有在外渗的治疗减少/增加剂量或日程的修改没有经验。
对于患者的身体表面面积大于2平方米的单剂量不应超过2000毫克。指示的剂量应在末端/面积比其他给药方式为静脉滴注的1或2小时的过程中成为一个大静脉（一）从该（a）有关（a）由外渗。
第一次输注应当尽快发起并在任何情况下，在事件发生后的第6个小时之内。
冷却过程，如：
冰袋，必须从Savene给药前至少15分钟的区域，以便允许足够的血流除去。
日处理2和3应该开始在同一时刻（+/- 3小时）第1天。
输注前，Savene粉末必须用25毫升的水重新配制用于注射，以产生每毫升无菌水20毫克右雷佐生的浓度。重建后，将溶液应进一步稀释在袋与Savene稀释剂。
特殊病人群体：儿科患者Savene不推荐用于儿童由于缺乏安全性和有效性的数据。肾功能不全患者有Savene患者肾功能损害及在这些患者中的使用没有经验，不建议。
肾功能下降可能导致淘汰率下降和长时间的全身暴露。肝损伤患者有Savene患者肝功能受损及其在这些患者中的使用没有经验，不建议。老年患者的安全性和有效性尚未研究在老年人中。
禁忌
过敏活性物质或任何赋形剂。妇女没有使用避孕措施生育能力。
哺乳。伴随接种黄热病疫苗。
特别警告和使用注意事项
检查应定期治疗，直到解决之后进行。如果外渗通过比通过相同的静脉通路，如蒽环类等发泡剂化合物怀疑。
长春新碱，丝裂霉素，和长春瑞滨，Savene不会有效地对抗由这些化合物的反应。 Savene将施用给接受治疗的细胞毒性与含有蒽环类化学疗法和其细胞毒性潜力（与最低点可逆血液学毒性尤其所得在11.12天）的患者，然后添加到该管理的其他的化疗。
因此，必须使病人定期血液监测。在临床研究中，他们没有被招募患者的白细胞和血小板减少>通用毒性标准（CTC），1级。
因为你可能会遇到肝功能障碍（增加转氨酶和胆红素）（尤其是在超过1000毫克/ m2的剂量右丙亚胺的），建议肝功能右丙亚胺的每个管理患者的前常规分析知肝功能障碍等。
由于肾功能障碍可减少消除右雷佐生的速率，患者的初始肾功能受损应监测监测血液学毒性症状。由于右丙亚胺具有一定的致突变活性，男人则宜接受治疗的概念，并在长达三个月的治疗后避免。
育龄妇女必须在治疗期间使用有效方法。使用这种产品，一般不建议联合减毒活疫苗，或与苯妥英钠。二甲基亚砜（DMSO）不应在谁施用右雷佐生治疗蒽环类诱发的外渗的患者中使用。
由于Savene稀释剂含有钾（98毫克/ 500毫升）的血钾水平，必须密切患者高钾血症的风险监控。
它也含有钠（1.61克/500毫升）中可能会伤害到病人低钠饮食。
包装规格
20mg/ml*3瓶和10瓶
生产商
英国Clinigen
Savene 20 mg/ml powder for concentrate and diluent for solution for infusion
1. Name of the medicinal product
Savene 20 mg/ml powder for concentrate and diluent for solution for infusion.
2. Qualitative and quantitative composition
Each vial contains 500 mg dexrazoxane (589 mg dexrazoxane hydrochloride).
Each ml contains 20 mg of dexrazoxane after reconstitution with 25 ml of Savene diluent.
Excipients with known effects:
Diluent bottle:
Potassium 98 mg/500 ml or 5.0 mmol/l
Sodium 1.61 g/500 ml or 140 mmol/l
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Powder for concentrate and diluent for solution for infusion.
Powder vial:
White to off-white lyophilisate.
Diluent bottle:
Clear isotonic solution (295 mOsml/l, pH approx. 7.4).
4. Clinical particulars
4.1 Therapeutic indications
Savene is indicated in adults for the treatment of anthracycline extravasation.
4.2 Posology and method of administration
Savene must be administered under the supervision of a physician experienced in the use of anti-cancer medicinal products.
Posology
Treatment should be given once daily for 3 consecutive days. The recommended dose is:
Day 1: 1000 mg/m2
Day 2: 1000 mg/m2
Day 3: 500 mg/m2
The first infusion should be initiated as soon as possible, within the first six hours after the accident.
Treatment Day 2 and Day 3 should start at the same hour (+/- 3 hours) as Day 1.
There is no experience with dose reduction/increase or modification of the schedule in the treatment of extravasation. For patients with a body surface area of more than 2 m2 the single dose should not exceed 2000 mg.
Renal impairment
No studies have been performed in patients with impaired renal function and treatment use in such patients is not recommended (see section 4.4). Decreased renal function may lead to decreased rate of elimination and prolonged systemic exposure.
Hepatic impairment
Dexrazoxane has not been studied in patients with impaired hepatic function and its use in such patients is not recommended (see section 4.4).
Elderly
Safety and efficacy have not been evaluated in the elderly and the use of dexrazoxane in such patients is not recommended.
Paediatric population
The safety and efficacy of Savene in children below the age of 18 years has not been established and no data are available.
Method of administration
For intravenous use after reconstitution and dilution.
For instructions on the reconstitution and dilution of Savene before administration, see section 6.6.
The indicated dose should be administered as an intravenous infusion over 1-2 hours into a large vein of an extremity or area other than the one affected by the extravasation. Cooling procedures such as ice packs should have been removed from the area at least 15 min before the Savene administration in order to allow sufficient blood flow.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients.
• Women of childbearing potential not using contraceptive measures (see section 4.6).
• Breast-feeding (see section 4.6).
• Concomitant vaccination with yellow fever vaccine (see section 4.5).
4.4 Special warnings and precautions for use
Continuous monitoring
Local examination should be performed on a regular basis after treatment until resolution.
If there is suspicion of extravasation by vesicant compounds other than anthracyclines through the same IV access, e.g. vincristine, mitomycin, and vinorelbine, Savene would not be effective against the effects from these compounds.
Since Savene will be administered to patients undergoing cytotoxic therapy with anthracyclines its cytotoxic potential (especially resulting in reversible haematological toxicity with a nadir occurring on days 11-12) will therefore add to that of the other chemotherapy administered. Haematological monitoring should therefore be undertaken regularly.
Hepatic and renal-function monitoring
Since liver dysfunction (increases in transaminases and bilirubin) may occur (especially after doses of above 1 000 mg/m2 dexrazoxane), it is recommended that routine liver function tests be performed before each administration of dexrazoxane in patients with known liver function disorders.
Since renal dysfunction may decrease the rate of elimination of dexrazoxane, patients with initial impaired renal function should be monitored for signs of haematological toxicity.
Anaphylactic reaction
Anaphylactic reaction including angioedema, skin reactions, bronchospasm, respiratory distress, hypotension and loss of consciousness have been observed in patients treated with dexrazoxane and anthracyclines (see section 4.8). Previous history of allergy to dexrazoxane should be carefully considered prior to administration (see section 4.3).
Potassium and sodium contents
Savene diluent contains potassium (98 mg/500 ml). This must be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet. Plasma potassium level must be closely monitored in patients at risk of hyperkalaemia.
It also contains sodium (1.61 g/500 ml) which may be harmful to patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
Concomitant use contraindicated:
Yellow fever vaccine: Risk of fatal generalised vaccinial disease (see section 4.3).
Concomitant use not recommended:
• Other live attenuated vaccines: risk of systemic, possible fatal disease. This risk is increased in subjects who are already immunosuppressed by their underlying disease. Use an inactivated vaccine where this exists (poliomyelitis) (see section 4.4).
• Dimethylsulfoxide (DMSO) should not be used in patients who are administered dexrazoxane to treat anthracycline extravasation (see section 5.3)
• Phenytoin: cytotoxic agents may reduce the absorption of phenytoin leading to an exacerbation of convulsions. Dexrazoxane is not recommended in combination with phenytoin.
Concomitant use to assess carefully:
Ciclosporine, tacrolimus: Excessive immunosuppression with risk of lymphoproliferative disease.
Interactions common to all cytotoxics:
• Due to an increased thrombotic risk in patients with malignant diseases, the use of anticoagulants treatment is frequent. Patients treated with anticoagulants should be monitored more frequently as cytotoxic agents may interact with oral anticoagulants.
• Dexrazoxane may add to the toxicity induced by the chemotherapy cycle during which the accident took place, requiring careful monitoring of haematological parameters (see section 4.4).
Interaction specific to dexrazoxane:
When tested in five major cytochrome P450 isoenzymes CYP1A, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, none of these were inhibited by dexrazoxane.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in males and females
Women of childbearing potential must use contraceptive measures during treatment and must inform their doctor immediately if they become pregnant (see section 4.3).
Since dexrazoxane possesses mutagenic activity, men being treated with dexrazoxane are advised not to father a child during and up to three months after treatment and/or should use contraceptives for the same time period.
Pregnancy
There are no data from the use of dexrazoxane in pregnant women. Dexrazoxane may cause foetal harm when administered to pregnant women. Few pre-clinical data are available with respect to reproductive toxicity (see section 5.3). Dexrazoxane should not be administered to pregnant women unless clearly necessary.
Breast-feeding
It is not known whether dexrazoxane is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed infants exposed to dexrazoxane, mothers must discontinue breast-feeding during Savene therapy (see section 4.3).
4.7 Effects on ability to drive and use machines
Dizziness, somnolence and syncope have been reported in a few patients included in Savene studies TT01 and TT02 (see section 4.8). Dexrazoxane is considered to have a limited influence on the ability to drive and use machines.
4.8 Undesirable effects
A number of published reports comprising more than 1000 patients have demonstrated a uniform pattern of dose dependent adverse reactions. Most common adverse reactions are nausea/vomiting, bone marrow suppression (neutropenia, thrombocytopenia), injection site reactions, diarrhoea, stomatitis and increase in hepatic transaminases (ALT/AST). All adverse reactions have been rapidly reversible.
The following information is based on two clinical studies, TT01 and TT02, of Savene administered to extravasation patients already receiving cycles of chemotherapeutic agents.
The adverse reactions were those typically seen with standard chemotherapy and also with dexrazoxane: Nausea/vomiting in about one third of the patients, neutropenia and thrombocytopenia in about half of the patients, more rarely increased concentration of liver enzymes (ALT/AST).
Adverse reactions observed in the two studies are listed below.
Incidence of adverse reactions (MedDRA) in studies TT01 and TT02 (n=80 patients)
(Note that numbers for Blood and Lymphatic System Disorders are described in a separate table of laboratory examinations)
Adverse reactions reported are listed according to the following frequency:
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000)

System Organ Classes (SOC)	Frequency	Adverse reactions
Infections and infestations	Very common	Postoperative infection
	Common	Infection
		Neutropenic infection
Immune system disorders	Not known	Anaphylactic reactions
	Not known	Hypersensitivity
Metabolism and nutrition disorders	Common	Decreased appetite
Nervous system disorders	Common	Dizziness
		Sensory loss
		Syncope
		Tremor
Vascular disorders	Common	Phlebitis
		Superficial thrombophlebitis
		Venous thrombosis limb
Respiratory, thoracic and mediastinal disorders	Common	Dyspnoea
		Pneumonia
Gastrointestinal disorders	Very common	Nausea
	Common	Vomiting
		Diarrhoea
		Stomatitis
		Dry mouth
Skin and subcutaneous tissue disorders	Common	Alopecia
		Pruritus
Musculoskeletal and connective tissue disorders	Common	Myalgia
Reproductive system and breast disorders	Common	Vaginal haemorrhage
General disorders and administration site conditions	Very common	Injection site pain
	Common	Pyrexia
		Injection site phlebitis
		Injection site erythema
		Fatigue
		Injection site induration
		Injection site swelling
		Oedema peripheral
		Somnolence
Investigations	Common	Weight decreased
Injury, poisoning and procedural complications	Common	Wound complication

Incidence of laboratory abnormalities in TT01 and TT02 (n=80 patients)

Lab test	No of patients with post baseline value	CTC grade 3-4
		N	%
Haemoglobin	80	2	2.5%
WBC	80	36	45.0%
Neutrophils	78	36	46.2%
Platelets	80	17	21.3%
Sodium (Hypo)	79	5	6.3%
Potassium (Hypo)	79	2	2.5%
Potassium (Hyper)	79	0	0.0%
Alkaline Phosphatase	77	0	0.0%
Bilirubin	77	1	1.3%
AST	57	2	3.5%
ALT	71	3	3.9%
Creatinine	76	2	2.6%
LDH	78	0	0.0%
Calcium Total (Hypo)	28	2	7.1%

4.9 Overdose
Signs and symptoms of overdosage are likely to consist of leucopenia, thrombocytopenia, nausea, vomiting, diarrhoea, skin reactions and alopecia. Treatment should be symptomatic.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic agents, ATC code: V03AF02
Two pharmacodynamic properties of dexrazoxane are described in the literature:
1. Prevention of anthracycline cardiotoxicity, and
2. Antineoplastic action
Mechanism of action
Dexrazoxane has two major mechanisms of action:
1. Chelation of iron, especially through its ring-opened metabolite thus reducing the iron-dependent oxidative stress causing anthracycline-induced cardiotoxicity.
2. Inhibition of topoisomerase II.
It is not known to what extent each of these mechanisms contributes to the preventive effect on tissue destruction following anthracycline extravasation.
The chelating property is probably also responsible for an increased urinary excretion of iron and zinc and a decreased serum concentration of calcium as described in a few studies.
The following efficacy data relate to Savene used as treatment of anthracycline extravasation:
The clinical programme for Savene (dexrazoxane) included two open, single-arm, multicentre studies.
The overall purpose of each trial was to investigate the efficacy of intravenous Savene in preventing tissue damage from accidentally extravasated anthracycline, and thus preventing the patients from undergoing the routinely used surgical excision of the affected tissue.
Due to the rarity of the condition only historical data could be used for comparison (demonstrating surgical rates of 35-50 %, in one country 100% in biopsy proven cases)
In both studies the dosage regimen was the same. Treatment with Savene had to be started within 6 hours from the incident and was repeated after 24 and 48 hours. The first and second doses were 1000 mg/m2 and the third was 500 mg/m2.
A requirement for inclusion in the efficacy part of the study was that the anthracycline extravasation was proven by fluorescence microscopy of one or more biopsies.
For study purposes, patients with extravasations from a central venous access device (CVAD) were not included in the efficacy evaluation.
Patients with neutropenia and thrombocytopenia > CTC grade 1 (Common Toxicity Criteria) have not been included in the clinical studies.
In study TT01, 23 patients were entered and received treatment with Savene. Eighteen were evaluable for efficacy and safety and a further five patients were evaluable for toxicity only. None of the patients required surgical intervention.
In study TT02, 57 patients entered the study and received the first dose of Savene. 36 patients were evaluable for efficacy. Only one of the 36 patients required surgery.
In both studies all patients had received anthracycline. Overall, the most commonly received anthracycline was epirubicin (56 % of the patients).
In both studies dexrazoxane treatment prevented the development of necrosis, allowed cancer treatment to continue as scheduled in the majority of patients (70.4 %), and reduced the occurrence of sequelae (only few and mild long-term sequelae were observed).
5.2 Pharmacokinetic properties
Savene must only be administered intravenously.
Bibliographical data demonstrate that serum kinetics of dexrazoxane after intravenous administration follow an open two-compartment model independent of schedule and dose. The apparent volumes of distribution are 0.13-1.3 l/kg (median 0.49 l/kg). Volume of distribution is independent of dose. AUCs were dose-proportional. Tissue distribution is rapid, with the highest levels of unchanged parent compound and hydrolysed product appearing in liver and kidneys. About 2% of dexrazoxane is protein-bound.
Biotransformation: Dexrazoxane undergoes intracellular hydrolysis first to its two one-ring open intermediates (B and C) and then to the two-ring opened form (ADR-925) which has a structure similar to EDTA and is a strong chelator of iron and divalent cations as calcium ions.
Elimination: Dexrazoxane displays biphasic elimination kinetics. Initial elimination half lives (alpha) are 0.18-1 h (median 0.34 h) and terminal elimination half lives 1.9-9.1 h (median 2.8 h). Total urinary recovery of unchanged dexrazoxane is 34-60 %. Systemic clearance is independent of dose. The pharmacokinetics of the metabolites is derived from a single study with five patients. The mean elimination half-lives of the one-ring opened metabolite B and metabolite C are 0.9-3.9 h (n=5) and 0.5-0.8 h (n=3), respectively. The elimination half-life of the two-ring opened metabolite ADR-925 is not given in literature. ADR-925 is reported to increase three-fold within 15 min after infusion of 1500 mg/m2 and remain relatively constant on a plateau for 4 hours and then decreased to about half at 24 hours. Clearance may be reduced in patients with low creatinine clearance.
In-vitro studies on dexrazoxane in human microsomes have shown high stability of dexrazoxane indicating that major metabolism via cytochrome P450 is unlikely.
There is insufficient data available to draw any definite conclusions regarding intrinsic pharmaco-kinetic factors such as age, gender, race and weight. Inter- and intra-individual pharmacokinetic variabilities have not been studied systematically. Based on a limited number of patients, inter-individual variability calculated as the coefficient of variation (CV %) was estimated to be approximately 30 % for the main pharmacokinetic parameters.
5.3 Preclinical safety data
Dexrazoxane has been shown to possess mutagenic activity. The carcinogenic potential of dexrazoxane has not been investigated, however, razoxane (the racemic mixture of dexrazoxane and levrazoxane) has been reported to be associated with the development of secondary malignancies in mice (lymphoid neoplasms) and rats (uterine carcinomas) after administration for a prolonged period of time. Both of these effects are expected for this class of compound.
Repeat-dose toxicity studies have shown that primary target organs were tissues that undergo rapid cell division: bone marrow, lymphoid tissue, testes and digestive tract. Myelosuppression is thus common. The apparent effects were greater during chronic than acute administration. The toxicity in combination with doxorubicin was additive and not synergistic.
The related razoxane has been demonstrated to be embryotoxic in mice, rats and rabbits and teratogenic in rats and mice.
When mice with experimental daunorubicin extravasation were treated with dexrazoxane systemically combined with topical treatment with DMSO on the daunorubicin-affected skin area, 67 % of the mice developed small skin wounds, whereas dexrazoxane treatment alone completely prevented the daunorubicin-induced skin necrosis in another group of mice. Thus, dimethylsulfoxide (DMSO) should not be used in patients who are administered dexrazoxane to treat anthracycline extravasation.
6. Pharmaceutical particulars
6.1 List of excipients
Powder vial
none
Diluent bottle
Sodium chloride
Potassium chloride
Magnesium chloride hexahydrate
Sodium acetate trihydrate
Sodium gluconate
Sodium hydroxide
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
Powder and diluent:
3 years.
After reconstitution and dilution:
Chemical and physical in-use stability has been demonstrated for 4 hours when stored at 2 to 8 °C.
From a microbiological point of view the product should be used immediately.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 4 hours at 2 to 8 °C.
6.4 Special precautions for storage
Store below 25 °C.
Keep the vials and bottles in the outer carton in order to protect from light.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Savene powder:
Amber-coloured, 36-ml, glass type I vial with stopper made of chlorobutyl rubber and a flip-off or tear-off cap.
Savene diluent:
500 ml solution in bottles made of Type-I (Ph.Eur.) glass.
Pack sizes:
Savene is available as an emergency kit consisting of 10 vials of Savene powder and 3 bottles of Savene diluent.
6.6 Special precautions for disposal and other handling
Before infusion, Savene powder must be reconstituted with 25 ml Savene diluent to give a concentration of 20 mg dexrazoxane per ml. The concentrate is slightly yellow. The concentrate should then be diluted further in the remaining Savene diluent.
Caution must be exercised during reconstitution and dilution and the normal procedures for proper handling of cytotoxic medicinal products should be adopted. The preparation should not be handled by pregnant staff. Use of gloves and other protective clothing to prevent skin contact is recommended. Skin reactions have been reported following contact with dexrazoxane. If the powder or solution contacts the skin or mucous membranes, wash immediately and thoroughly with water.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Clinigen Healthcare Ltd
Pitcairn House
Crown Square, First Avenue
Burton-on-Trent, Staffordshire
DE14 2WW
United Kingdom
8. Marketing authorisation number(s)
EU/1/06/350/001
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation 28/07/2006
Date of latest renewal 28/07/2011
10. Date of revision of the text
12/01/2015
Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu