英文药名：Nuwiq(human coagulation factor VIII recombinant DNA, simoctocog alfa)

中文药名：注射用抗血友病因子/人凝血因子VIII(重组)冻干粉

生产厂家：Octapharma USA，Inc
药品介绍
NUWIQ®，抗血友病因子(重组) 为静脉注射溶液冻干粉
欧盟批准Octapharma公司的重组人凝血因子Ⅷ产品(商品名：Nuwiq)上市，用于治疗和预防儿童和成人血友病A(先天性凝血因子Ⅷ缺乏)患者。
美国批准日期：2015年9月4日  欧洲批准日期：2014年8月5日
适应证和用途
NUWIQ是一种重组抗血友病因子[血液凝固因子VIII(因子VIII)]适用在成年和儿童有血友病A为：
⑴ 按需要治疗和出血发作的控制
⑵ 围手术期出血的处理
⑶ 常规预防减低出血发作的频数
NUWIQ不适用于为血管性血友病[von Willebrand Disease]的治疗
剂量和给药方法
重建后为静脉使用
⑴ NUWIQ的每小瓶标记有因子VIII效力的实际量国际单位(IU)。
⑵ 对青少年和成年用以下公式确定剂量：
需要的IU = 体重(kg) × 想要的因子VIII升高(%)(IU/dL)×0.5(IU/kg每IU/dL)
⑶对常规预防给药：

⑷ 频数和治疗时间取决于FVIII缺乏的严重程度，出血定位和程度，和患者的临床情况。
剂型和规格
可得到NUWIQ为白色无菌，无-热源，冻干粉为重建在一次性使用小瓶含标称250，500，1000或2000IU因子VIII效力
禁忌证
对产品或其组分有明显的危及生命超敏性反应，包括过敏性反应患者禁忌用NUWIQ。
警告和注意事项
⑴ 可能超敏性反应，包括过敏性反应。若出现症状，终止NUWIQ和给予适当治疗。
⑵ 可能发生因子VIII中和抗体(抑制剂)的发生发展。如未达到期望血浆因子 VIII活性水平，或如用适当剂量出血未能控制，进行一种测量因子VIII抑制剂浓度分析。
⑶ 监视所有患者对因子VIII活性和因子VIII抑制剂抗体的发生。
不良反应
在临床试验中最常发生不良反应(>0.5%)是感觉异常，头痛，注射部位炎症，注射部位疼痛，非-中和抗-因子FIII抗体形成，背痛，眩晕，和口干。
特殊人群中使用
儿童使用：在儿童年龄2 - ≤12岁较低回收，较短半衰期和较快清除。为预防性治疗在年龄2至5岁儿童患者应考虑较高剂量和/或一个更频给药时间表。

Nuwiq 250 IU 500 IU 1000 IU 2000 IU powder and solvent for solution for injection
1. Name of the medicinal product
Nuwiq 250 IU powder and solvent for solution for injection.
Nuwiq 500 IU powder and solvent for solution for injection.
Nuwiq 1000 IU powder and solvent for solution for injection.
Nuwiq 2000 IU powder and solvent for solution for injection.
2. Qualitative and quantitative composition
Nuwiq 250 IU
Each vial contains nominally 250 IU human coagulation factor VIII (rDNA), simoctocog alfa.
Nuwiq contains approximately 100 IU/ml of human coagulation factor VIII (rDNA), simoctocog alfa after reconstitution.
Nuwiq 500 IU
Each vial contains nominally 500 IU human coagulation factor VIII (rDNA), simoctocog alfa.
Nuwiq contains approximately 200 IU/ml of human coagulation factor VIII (rDNA), simoctocog alfa after reconstitution.
Nuwiq 1000 IU
Each vial contains nominally 1000 IU human coagulation factor VIII (rDNA), simoctocog alfa.
Nuwiq contains approximately 400 IU/ml of human coagulation factor VIII (rDNA), simoctocog alfa after reconstitution.
Nuwiq 2000 IU
Each vial contains nominally 2000 IU human coagulation factor VIII (rDNA), simoctocog alfa.
Nuwiq contains approximately 800 IU/ml of human coagulation factor VIII (rDNA), simoctocog alfa after reconstitution.
The potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specific activity of Nuwiq is approximately 9500 IU/mg protein.
Simoctocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 1440 amino acids. The amino acid sequence is comparable to the 90 + 80 kDa form of human plasma factor VIII (i.e. B-domain deleted). Nuwiq is produced by recombinant DNA technology in genetically modified human embryonic kidney (HEK) 293F cells. No animal or human derived materials are added during the manufacturing process or to the final medicinal product.
Excipient(s) with known effect:
7.35 mg sodium per ml reconstituted solution (18.4 mg sodium per vial).
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Powder and solvent for solution for injection.
Powder: white to off-white friable powder.
Solvent: water for injections, a clear, colourless liquid.
4. Clinical particulars
4.1 Therapeutic indications
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).
Nuwiq can be used for all age groups.
4.2 Posology and method of administration
Posology
Treatment should be under the supervision of a physician experienced in the treatment of haemophilia.
Previously untreated patients
The safety and efficacy of Nuwiq in previously untreated patients have not yet been established.
Posology
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient's clinical condition.
The number of units of factor VIII administered is expressed in International Units (IU), which is related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor VIII in plasma).
One International Unit (IU) of factor VIII activity is equivalent to the quantity of factor VIII in one ml of normal human plasma.
On-demand treatment
The calculation of the required dose of factor VIII is based on the empirical finding that 1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by approximately 2% of normal activity or 2 IU/dl. The required dose is determined using the following formula:

The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.
In the case of the following haemorrhagic events, factor VIII activity should not fall below the given plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery.

Degree of haemorrhage/ Type of surgical procedure	Factor VIII level required (%) (IU/dL)	Frequency of doses (hours)/ Duration of therapy (days)
Haemorrhage
Early haemarthrosis, muscle bleeding or oral bleeding	20–40	Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.
More extensive haemarthrosis, muscle bleeding or haematoma	30–60	Repeat infusion every 12 to 24 hours for 3 to 4 days or more until pain and acute disability are resolved.
Life threatening haemorrhages	60–100	Repeat infusion every 8 to 24 hours until threat is resolved.
Surgery
Minor surgery including tooth extraction	30–60	Every 24 hours, at least 1 day, until healing is achieved.
Major surgery	80–100 (pre- and postoperative)	Repeat infusion every 8–24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60%(IU/dL).

Prophylaxis
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.
During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries.
Paediatric population
The posology is the same in adults and children, however, shorter dose intervals or higher doses may be necessary for children. Currently available data are described in sections 4.8, 5.1 and 5.2.
No data are available in children below the age of 2 years.
Method of administration
Intravenous use.
It is recommended that not more than 4 ml per minute be administered.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Hypersensitivity
As with any intravenous protein product, allergic type hypersensitivity reactions are possible. Nuwiq contains traces of human host cell proteins other than factor VIII. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.
In case of shock, standard medical treatment for shock should be implemented.
Inhibitors
The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the exposure to factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.
Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIII product to another in previously treated patients with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor patients carefully for inhibitor occurrence following any product switch.
In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options, such as immune tolerance induction (ITI), should be considered. Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors.
Catheter-related complications
If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
It is strongly recommended that every time that Nuwiq is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the medicinal product.
Paediatric population
The listed warnings and precautions apply both to adults and children.
Excipient related considerations (sodium content)
This medicinal product contains less than 1 mmol sodium (23 mg) per vial.
However depending on the body weight and posology, the patient could receive more than one vial. This should be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed with Nuwiq.
4.6. Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with Nuwiq.
Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breast feeding is not available. Therefore, Nuwiq should be used during pregnancy and breast-feeding only if clearly indicated. There are no fertility data available.
4.7 Effects on ability to drive and use machines
Nuwiq has no influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
Hypersensitivity or allergic reactions (which may include angiooedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have rarely been observed with FVIII preparations and may in some cases progress to severe anaphylaxis (including shock).
Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.
Tabulated list of adverse reactions
During clinical studies with Nuwiq in previously treated paediatric (2 to 11 years, n = 58), adolescent (12 to 17 years, n = 3) and adult patients (n = 74) with severe haemophilia A, a total of 8 adverse drug reactions (ADRs) (6 in adults, 2 in children) were reported in 5 patients (3 adults, 2 children).
Table 1 presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).
Frequencies have been evaluated according to the following convention: 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), not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. Frequency of occurring per patient of adverse drug reactions (ADRs) in clinical trials in 135 previously treated patients with severe haemophilia A

Nervous system disorders	Parasthesia Headache	Uncommon
Ear and labyrinth disorders	Vertigo	Uncommon
Gastrointestinal disorders	Dry mouth	Uncommon
Musculoskeletal and connective tissue disorders	Back pain	Uncommon
General disorders and administration site conditions	Injection site inflammation Injection site pain	Uncommon
Investigations	Non-neutralising anti factor VIII antibody positive	Uncommon

* All these ADRs occurred only once. As the total number of studied patients is 135, the frequency cannot be less than “uncommon” if an ADR occurs once.
Description of selected adverse reactions
A non-neutralizing anti-Factor VIII antibody was detected in one adult patient (see Table 1). The sample was tested by the central laboratory at eight dilutions. The result was positive only at dilution factor 1 and the antibody titre was very low. Inhibitory activity, as measured by the modified Bethesda assay, was not detected in this patient. Clinical efficacy and in-vivo recovery of Nuwiq was not affected in this patient.
Paediatric population
Frequency, type and severity of adverse reactions in children are assumed to be the same as in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
No cases of overdose have been reported.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antihaemorrhagics: blood coagulation factor VIII, ATC code: B02BD02.
The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient's circulation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as results of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby temporarily enabling a correction of the factor VIII deficiency and correction of the bleeding tendencies.
The immunogenicity of Nuwiq was evaluated in clinical trials in 135 previously treated patients with severe haemophilia A (74 adult and 61 paediatric patients). None of the patients developed inhibitors.
In a clinical study in 32 adult patients with severe haemophilia A, the median consumption of Nuwiq for prophylaxis was 468.7 IU/kg/month. The median dose to treat break-through bleeding episodes was 33.0 IU/kg in these patients who were on prophylaxis. In another clinical study, 22 adult patients were treated on demand. In total 986 bleeding episodes were treated with a median dose of 30.9 IU/kg. In general, minor bleeds required slightly lower, and more severe bleeds required up to three-fold higher median doses.
Paediatric population
Data have been obtained in 29 previously treated children between 2 and 5 years of age, 31 children between 6 and 12 years of age and one adolescent of 14 years. The median dose per prophylactic infusion was 37.8 IU/kg. Twenty patients used median doses of more than 45 IU/kg. The median consumption of Nuwiq for prophylaxis per month was 521.9 IU/kg. A higher median dose of Nuwiq was required to treat bleedings in children (43.9 IU/kg) than in adults (33.0 IU/kg), and a higher median dose was required to treat moderate to major than minor bleedings (78.2 IU/kg vs. 41.7 IU/kg). Younger children in general required higher median doses (6-12 years: 43.9 IU/kg; 2-5 years: 52.6 IU/kg).
The European Medicines Agency has deferred the obligation to submit the results of studies with Nuwiq in one or more subsets of the paediatric population in treatment of Haemophilia A (congenital Factor VIII deficiency) (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Table 2. PK parameters for Nuwiq (Dose: 50 IU/kg) in adult previously treated patients (age 18-65 years) with severe haemophilia A (n = 20)

PK parameter	Chromogenic assay
	Mean ± SD	Median (range)
AUC (hr*IU/ml)	22.6 ± 8.0	22.3 (8.4 – 38.1)
T1/2 (hr)	14.7 ± 10.4	12.5 (5.4 – 55.6)
IVR (%/IU/kg)	2.5 ± 0.4	2.5 (1.7 – 3.2)
CL (ml/hr/kg)	3.0 ± 1.2	2.7 (1.5 – 6.4)

AUC = Area under the curve (FVIII:C), T1/2 = Terminal half-life,
IVR = Incremental in vivo recovery, CL = Clearance, SD = Standard deviation
Table 3. PK parameters for Nuwiq (Dose: 50 IU/kg) in previously treated children aged 6 to 12 years with severe haemophilia A (n = 12)

PK parameter	Chromogenic assay
	Mean ± SD	Median (range)
AUC (hr*IU/ml)	13.2 ± 3.4	12.8 (7.8 – 19.1)
T1/2 (hr)	10.0 ± 1.9	9.9 (7.6 – 14.1)
IVR (%/IU/kg)	1.9 ± 0.4	1.9 (1.2 – 2.6)
CL (ml/hr/kg)	4.3 ± 1.2	4.2 (2.8 – 6.9)

AUC = Area under the curve (FVIII:C), T1/2 = Terminal half-life,
IVR = Incremental in vivo recovery, CL = Clearance, SD = Standard deviation
Table 4. PK parameters for Nuwiq (Dose: 50 IU/kg) in previously treated children aged 2 to 5 years with severe haemophilia A (n = 13)

PK parameter	Chromogenic assay
	Mean ± SD	Median (range)
AUC (hr*IU/ml)	11.7 ± 5.3	10.5 (4.9 – 23.8)
T1/2 (hr)	9.5 ± 3.3	8.2 (4.3 – 17.3)
IVR (%/IU/kg)	1.9 ± 0.3	1.8 (1.5 – 2.4)
CL (ml/hr/kg)	5.4 ± 2.4	5.1 ( 2.3 – 10.9)

AUC = Area under the curve (FVIII:C), T1/2 = Terminal half-life,
IVR = Incremental in vivo recovery, CL = Clearance, SD = Standard deviation
Paediatric population
As known from the literature, recovery and half-life was lower in young children than in adults and clearance higher, which may be due in part to the known higher plasma volume per kilogram body weight in younger patients.
Weight adjusted subgroups
Table 5. Weight-adjusted PK parameters for Nuwiq (Dose: 50 IU/kg) in adult previously treated patients (age 18-65 years) with severe haemophilia A (n = 20)

PK parameter	All (n=20)	Normal weight (n=14)	Pre-adipose (n=4)	Adipose (n=2)
Chromogenic assay Mean ± SD
AUC (hr*IU/ml)	22.6 ± 8.0	20.4 ± 6.9	24.9 ± 8.9	33.5 ± 6.5
T1/2 (hr)	14.7 ± 10.4	14.7 ± 12.1	13.4 ± 5.9	17.2 ± 4.8
IVR (%/IU/kg)	2.5 ± 0.4	2.4 ± 0.4	2.7 ± 0.4	2.8 ± 0.3
CL (ml/hr/kg)	3.0 ± 1.2	3.2 ± 1.3	2.6 ± 1.0	1.8 ± 0.4
Chromogenic assay Median (range)
AUC (hr*IU/ml)	22.3 (8.4 – 38.1)	21.2 (8.4 – 32.6)	23.3 (17.4 – 35.5)	33.5 (28.9 – 38.1)
T1/2 (hr)	12.5 (5.4 – 55.6)	12.3 (5.4 – 55.6)	11.2 (9.3 – 22.0)	17.2 (13.8 – 20.6)
IVR (%/IU/kg)	2.5 (1.7 – 3.2)	2.4 (1.7 – 3.1)	2.8 (2.3 – 3.2)	2.8 (2.6 – 3.0)
CL (ml/hr/kg)	2.7 (1.5 – 6.4)	2.8 (1.7 – 6.4)	2.5 (1.6 – 3.7)	1.8 (1.5 – 2.0)

Normal weight: BMI 18.5-25 kg/m2, Pre-adipose: BMI 25-30 kg/m2, Adipose: BMI > 30 kg/m2, SD = Standard deviation
5.3 Preclinical safety data
In preclinical studies, Nuwiq was used to safely and effectively restore haemostasis in dogs with haemophilia. Toxicology studies showed that local intravenous administration and systemic exposure were well tolerated in laboratory animals (rats and cynomolgus monkeys).
Specific studies with long-term repeated administration such as reproduction toxicity, chronic toxicity, and carcinogenicity were not performed with Nuwiq due to the immune response to heterologous proteins in all non-human mammalian species.
No studies were performed on the mutagenic potential of Nuwiq.
Ex vivo evaluations using a commercial assay kit to quantify T cell response to protein therapeutics indicate a low risk of immunogenicity.
6. Pharmaceutical particulars
6.1 List of excipients
Powder:
Sucrose
Sodium chloride
Calcium chloride dihydrate
Arginine hydrochloride
Sodium citrate dihydrate
Poloxamer 188
Solvent:
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Only the provided injection sets should be used because treatment failure can occur as a consequence of human coagulation factor VIII adsorption to the internal surfaces of some injection equipment.
6.3 Shelf life
2 years
After reconstitution, chemical and physical in-use stability has been demonstrated for 24 hours when stored at room temperature.
From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
Keep the reconstituted solution at room temperature. Do not refrigerate after reconstitution.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Each pack of Nuwiq 250 IU contains:
- Powder: 250 IU powder in 8 ml type 1 glass vial, closed with coated bromobutyl stopper and sealed with aluminium flip-off cap
- Solvent: 2.5 ml water for injections in a pre-filled borosilicate glass syringe
- 1 sterile vial adapter for reconstitution with 1 butterfly needle and 2 alcohol swabs
Pack size of 1.
Each pack of Nuwiq 500 IU contains:
- Powder: 500 IU powder in 8 ml type 1 glass vial, closed with coated bromobutyl stopper and sealed with aluminium flip-off cap
- Solvent: 2.5 ml water for injections in a pre-filled borosilicate glass syringe
- 1 sterile vial adapter for reconstitution with 1 butterfly needle and 2 alcohol swabs
Pack size of 1.
Each pack of Nuwiq 1000 IU contains:
- Powder: 1000 IU powder in 8 ml type 1 glass vial, closed with coated bromobutyl stopper and sealed with aluminium flip-off cap
- Solvent: 2.5 ml water for injections in a pre-filled borosilicate glass syringe
- 1 sterile vial adapter for reconstitution with 1 butterfly needle and 2 alcohol swabs
Pack size of 1.
Each pack of Nuwiq 2000 IU contains:
- Powder: 2000 IU powder in 8 ml type 1 glass vial, closed with coated bromobutyl stopper and sealed with aluminium flip-off cap
- Solvent: 2.5 ml water for injections in a pre-filled borosilicate glass syringe
- 1 sterile vial adapter for reconstitution with 1 butterfly needle and 2 alcohol swabs
Pack size of 1.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
The powder should only be reconstituted with the supplied solvent (2.5 ml water for injections) using the supplied injection set. The vial should be gently rotated until all powder is dissolved. After reconstitution, the solution should be drawn back into the syringe.
Reconstituted medicinal product should be inspected visually for particulate matter and discoloration prior to administration. The reconstituted medicinal product is a clear, colourless solution, free from foreign particles and has a pH of 6.5 to 7.5. Do not use solutions that are cloudy or have deposits.
Instructions for preparation and administration
1. Allow the solvent syringe (water for injections) and the powder in the closed vial to reach room temperature. You can do this by holding them in your hands until they feel as warm as your hands. Do not use any other way to heat the vial and pre-filled syringe. This temperature should be maintained during reconstitution.
2. Remove the plastic flip-top cap from the powder vial to expose the central portions of the rubber stopper. Do not remove the gray stopper or metal ring around the top of the vial.

3. Wipe the top of the vial with an alcohol swab. Allow the alcohol to dry.
4. Peel back the paper cover from the vial adapter package. Do not remove the adapter from the package.

5. Place the powder vial on an even surface and hold it. Take the adapter package and place the vial adapter over the centre of the rubber stopper of the powder vial. Press down firmly the adapter package until the adapter spike penetrates the rubber stopper. The adapter snaps to the vial when done.

6. Peel back the paper cover from the pre-filled syringe package. Hold the plunger rod at the end and do not touch the shaft. Attach the threaded end of the plunger rod to the solvent syringe plunger. Turn the plunger rod clockwise until a slight resistance is felt.

7. Break off the tamper-proof plastic tip from the solvent syringe by snapping the perforation of the cap. Do not touch the inside of the cap or the syringe tip. In case the solution is not used immediately close the filled syringe with the tamper-proof plastic tip for storage.

8. Remove the adapter packaging and discard.
9. Firmly connect the solvent syringe to the vial adapter by turning clockwise until resistance is felt.

10. Slowly inject all solvent into the powder vial by pressing down the plunger rod.

11. Without removing the syringe, gently move or swirl the vial in circles a few times to dissolve the powder. Do not shake. Wait until all the powder dissolves completely.
12. Visually inspect the final solution for particles before administration. The solution should be clear and colourless, practically free from visible particles. Do not use solutions that are cloudy or have deposits.
13. Turn the vial attached to the syringe upside down, and slowly draw the final solution into the syringe. Make sure that the entire content of the vial is transferred to the syringe.

14. Detach the filled syringe from the vial adapter by turning counter clockwise and discard the empty vial.
15. The solution is now prepared for immediate use. Do not refrigerate.
16. Clean the chosen injection site with one of the provided alcohol swabs.
17. Attach the provided infusion set to the syringe.
Insert the needle of the infusion set into the chosen vein. If you have used a tourniquet to make the vein easier to see, this tourniquet should be released before you start injecting the solution.
No blood must flow into the syringe due to the risk of formation of fibrin clots.
18. Inject the solution into the vein at a slow speed, not faster than 4 ml per minute.
If you use more than one vial of powder for one treatment, you may use the same injection needle again. The vial adapter and the syringe are for single use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Octapharma AB
Elersvägen 40
112 75 Stockholm
Sweden
8. Marketing authorisation number(s)
Nuwiq 250 IU EU/1/14/936/001
Nuwiq 500 IU EU/1/14/936/002
Nuwiq 1000 IU EU/1/14/936/003
Nuwiq 2000 IU EU/1/14/936/004
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 22.07.2014
10. Date of revision of the text
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
FDA批准Nuwiq(human coagulation factor VIII recombinant DNA, simoctocog alfa)用于血友病治疗
美国 FDA 批准 Octapharma 静脉注射药物Nuwiq用于血友病A成年及儿童患者。Nuwiq的批准包括按需治疗及出血发作控制；用于减少出血发作频次的常规预防；及出血的围术期管理。
Nuwiq是源于人细胞系的首个B-结构域缺失重组因子VIII（FVIII），它未进行化学修饰或与其它蛋白融合，这款药物旨在治疗先天性FVIII缺乏的血友病A患者。Octapharma多年来一直致力于出血性疾病领域，其解决血友病A挑战的努力十年来从未动摇，Octapharma USA总裁Nielsen称。
在Nuwiq的开发中，早期开发战略是完整的，随着FDA的批准，这些初步目标已经实现。Nuwiq在全球临床试验中已证明安全性及有效性，在未来的岁月里，它有可能积极地影响到患者的生活质量。Octapharma 致力于为血友病A提供能够提高与拯救生命的治疗药物，公司期望将Nuwiq带到美国市场。
Nuwiq去年获得欧盟委员会批准
欧盟委员会于2014年8月率先批准这款治疗药物。Nuwiq目前已在许多国家获得批准，包括英国、澳大利亚、加拿大、德国、意大利、瑞典及阿根廷。
我们很高兴用于血友病A成年及儿童患者的治疗选择继续向前推进，有越来越多的治疗药物能够在美国获得批准，美国国家血友病基金会首席执行官 Bias 称。为出血疾病社区开发提高生命产品的持续努力绝对是至关重要的。为患者及供应商提供治疗选择、对患有血友病A的患者来说是极其重要的。