美国食品药品管理局（FDA）近日批准Victoza (liraglutide，利拉鲁肽)注射剂用于部分成年患者2型糖尿病的治疗。Victoza属胰高血糖素样肽1(GLP-1)类似物药物（注射剂，每日注射一次），能够在患者进食后促使其胰腺分泌更多胰岛素，对于没有进行适当的饮食控制和运动的患者，Victoza不被推荐单独用于糖尿病的初期治疗。
FDA药品审评与研究中心新陈代谢与内分泌室主任、医学博士Mary Parks说，“糖尿病是引起死亡和致残的一个主要原因，每年新诊断出的糖尿病患者超过了1500万人。对于预防或控制长期的糖尿病并发症来看，控制血糖水平是非常重要的，Victoza为部分2型糖尿病患者提供了控制血糖水平的备选方案。”
Victoza最常见的不良反应包括头痛、恶心和腹泻。其他不良反应包括荨麻疹等过敏样反应。有3900位患者参加的5个临床试验结果显示，使用Victoza的患者发生胰腺炎（胰腺的一种炎症）的可能性要大于使用其他治疗药物的患者。当患者出现严重腹痛，伴随或未伴随恶心、呕吐时，应停止使用Victoza，当确诊为胰腺炎后，不应再次使用Victoza进行治疗。有胰腺炎病史的患者应慎用。动物试验显示，Victoza会引起大鼠和小鼠出现甲状腺瘤。因此，尚不能确认是否会引起人甲状腺瘤或癌，为此，在继续进行研究以证明可以扩大使用之前，Victoza不能作为治疗2型糖尿病的一线药物，也不能用于治疗已患甲状腺髓样癌的患者。

诺和诺德公司于2009年7月8日宣布，欧洲药品管理局（EMEA）人用药品委员会（CHMP）表决通过了对Victoza®的积极评价，建议颁发入市许可，将该药用于治疗2型糖尿病。
Victoza®是利拉鲁肽的商标名，它是第一个人胰高糖素样肽-1(GLP-1)类似物，每日皮下注射一次，用于治疗2型糖尿病。对Victoza®的积极评价包括：
1、对于单独服用最大剂量的二甲双胍或磺脲类药物仍不能控制血糖的患者来说，Victoza®与二甲双胍或者与磺脲类药物联合使用，可改善血糖控制；
2、对于即使采用“二甲双胍＋磺脲类药物”或“二甲双胍＋噻唑烷二酮”联合治疗也不能控制血糖的患者来说，Victoza®与“二甲双胍＋磺脲类药物”或者与“二甲双胍＋噻唑烷二酮”联合使用，可进一步改善血糖控制。
诺和诺德公司有望在大约两个月以内收到欧盟委员会正式颁发的入市许可。得到欧盟委员会批准以后，诺和诺德公司打算今年夏季在一些欧洲国家的市场上开始销售Victoza®。
“CHMP的积极评价令人高兴，我们相信欧洲的很多2型糖尿病患者将很快得到Victoza®，” 诺和诺德公司执行副总裁兼首席科学官Mads Krogsgaard Thomsen说。“对6500多位患者的临床研究表明，Victoza®可显著降低血糖和体重，而发生低血糖症的风险却很小。由此看来，我们确信Victoza®是2型糖尿病患者可以选择的一种很有价值的新药。”
1月29日诺和诺德公司公布了2008年财务业绩和2009年财务业绩预测；目前，这一预测尚未因CHMP的积极评价而改变。诺和诺德公司将于2009年4月30日公布今年第一季度的财务数据，届时将对2009年的财务业绩预测数据做出更新。

*关于Victoza®
Victoza®是第一个人胰高糖素样肽-1(GLP-1)类似物，每日皮下注射一次，用于治疗2型糖尿病。患者血糖水平过高时，Victoza®可刺激胰岛素的分泌，降低食欲。2008年5月23日，诺和诺德公司向美国食品药品管理局提交了新药申请，向欧洲药品管理局提交了入市申请，请求他们批准将Victoza®用于治疗2型糖尿病。2008年7月14日还向日本有关当局提交了新药申请。

Victoza^® (VIC-tow-za)

(liraglutide [rDNA origin]) Injection

Read this Medication Guide and Patient Instructions for Use that come with Victoza before you start using Victoza and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have questions about Victoza after reading this information, ask your healthcare provider or pharmacist.

What is the most important information I should know about Victoza?

Serious side effects may happen in people who take Victoza, including:

• Possible thyroid tumors, including cancer. During the drug testing process, the medicine in Victoza caused rats and mice to develop tumors of the thyroid gland. Some of these tumors were cancers. It is not known if Victoza will cause thyroid tumors or a type of thyroid cancer called medullary thyroid cancer in people. If medullary thyroid cancer occurs, it may lead to death if not detected and treated early. If you develop tumors or cancer of the thyroid, your thyroid may have to be surgically removed.

• Before you start taking Victoza, tell your healthcare provider if you or any of your family members have had thyroid cancer, especially medullary thyroid cancer, or Multiple Endocrine Neoplasia syndrome type 2. Do not take Victoza if you or any of your family members have medullary thyroid cancer, or if you have Multiple Endocrine Neoplasia syndrome type 2. People with these conditions already have a higher chance of developing medullary thyroid cancer in general and should not take Victoza.
• While taking Victoza, tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer.

2. Inflammation of the pancreas (pancreatitis), which may be severe and lead to death.

Before taking Victoza, tell your healthcare provider if you have had:

• pancreatitis
• stones in your gallbladder (gallstones)
• a history of alcoholism
• high blood triglyceride levels

These medical conditions can make you more likely to get pancreatitis in general. It is not known if having these conditions will lead to a higher chance of getting pancreatitis while taking Victoza.

While taking Victoza:

Stop taking Victoza and call your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may happen with or without vomiting. The pain may be felt going from your abdomen through to your back. This type of pain may be a symptom of pancreatitis.

What is Victoza?

• Victoza is an injectable prescription medicine that may improve blood sugar (glucose) in adults with type 2 diabetes mellitus, and should be used along with diet and exercise.
• Victoza is not recommended as the first choice of medication for treating diabetes.
• Victoza is not insulin.
• It is not known if Victoza is safe and effective when used with insulin.
• Victoza is not for use in people with type 1 diabetes or people with diabetic ketoacidosis.
• It is not known if Victoza is safe and effective in children. Victoza is not recommended for use in children.

Who should not use Victoza?

Do not use Victoza if:

• you or any of your family members have a history of medullary thyroid cancer.
• you have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). This is a disease where people have tumors in more than one gland in their body.

Talk with your healthcare provider if you are not sure if you have any of these conditions.

What should I tell my healthcare provider before using Victoza?

Before taking Victoza, tell your healthcare provider if you:

• have any of the conditions listed in the section “What is the most important information I should know about Victoza?”
• are allergic to liraglutide or any of the other ingredients in Victoza. See the end of this Medication Guide for a list of ingredients in Victoza.
• have severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems with digesting food.
• have or have had kidney or liver problems.
• have any other medical conditions.
• are pregnant or plan to become pregnant. It is not known if Victoza will harm your unborn baby. Tell your healthcare provider if you become pregnant while taking Victoza.
• are breastfeeding or plan to breastfeed. It is not known if Victoza passes into your breast milk. You and your healthcare provider should decide if you will take Victoza or breastfeed. You should not do both without talking with your healthcare provider first.

Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Victoza slows stomach emptying and can affect medicines that need to pass through the stomach quickly. Victoza may affect the way some medicines work and some other medicines may affect the way Victoza works. Tell your healthcare provider if you take other diabetes medicines, especially sulfonylurea medicines or insulin.

Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine.

How should I use Victoza?

• Use Victoza exactly as prescribed by your healthcare provider. Your dose should be increased after using Victoza for one week. After that, do not change your dose unless your healthcare provider tells you to.
• Victoza is injected 1 time each day, at any time during the day.
• You can take Victoza with or without food.
• Victoza comes in a prefilled pen.
• Your healthcare provider must teach you how to inject Victoza before you use it for the first time. If you have questions or do not understand the instructions, talk to your healthcare provider or pharmacist. See the Patient Instructions for Use that come with this Medication Guide for detailed information about the right way to use your Victoza pen.
• Pen needles are not included. You may need a prescription to get pen needles from your pharmacist. Ask your healthcare provider which needle size is best for you.
• When starting a new prefilled Victoza pen, you must follow the “First Time Use for Each New Pen” (see the detailed Patient Instructions for Use that comes with this Medication Guide). You only need to do this 1 time with each new pen. You should also do this if you drop your pen. If you do the “First Time Use for Each New Pen” before each injection, you will run out of medicine too soon.
• Inject your dose of Victoza under the skin (subcutaneous injection) in your stomach area (abdomen), upper leg (thigh), or upper arm, as instructed by your healthcare provider. Do not inject into a vein or muscle.
• If you take too much Victoza, call your healthcare provider right away. Too much Victoza may cause severe nausea and vomiting.
• Follow your healthcare provider’s instructions for diet, exercise, how often to test your blood sugar, and when to get your HbA_1c checked. If you stop using Victoza your blood sugar levels may increase. First talk to your healthcare provider if you want to stop taking Victoza.
• Your dose of diabetes medicines may need to be changed if your body is under certain types of stress. Tell your healthcare provider if you:
  • have fever
  • have trauma
  • have an infection
  • plan to have or have had surgery
• Never share your Victoza pen or needles with another person. You may give an infection to them, or get an infection from them

What are the possible side effects of Victoza?

Victoza may cause serious side effects, including:

• See “What is the most important information I should know about Victoza?”
• Low blood sugar (hypoglycemia). Your risk for getting low blood sugar is higher if you take Victoza with another medicine that can cause low blood sugar, such as a sulfonylurea. In some people, the blood sugar may get so low that they need another person to help them. The dose of your sulfonylurea medicine may need to be lowered while you use Victoza. Signs and symptoms of low blood sugar may include:

• shakiness
• sweating
• headache
• drowsiness
• weakness
• dizziness
• confusion
• irritability
• hunger
• fast heartbeat
• feeling jittery

Talk to your healthcare provider about how to recognize and treat low blood sugar. Make sure that your family and other people who are around you a lot know how to recognize and treat low blood sugar.

Common side effects of Victoza include:

• headache
• nausea
• diarrhea

Nausea is most common when first starting Victoza, but decreases over time in most people as their body gets used to the medicine. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the side effects with Victoza. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Victoza?

Before use:

• Store your new, unused Victoza pen in the refrigerator at 36ºF to 46ºF (2ºC to 8ºC).
• Do not freeze Victoza or use Victoza if it has been frozen. Do not store Victoza near the refrigerator cooling element.

Pen in use:

• Store your Victoza pen for 30 days either at 59ºF to 86ºF (15ºC to 30ºC), or in a refrigerator at 36ºF to 46ºF (2°C to 8°C).
• When carrying the pen away from home, store the pen at a temperature between 59ºF to 86ºF (15ºC to 30ºC) and keep it dry.
• If Victoza has been exposed to temperatures above 86ºF (30ºC), it should be thrown away.
• Protect your Victoza pen from heat and sunlight.
• Keep the pen cap on when your Victoza pen is not in use.
• Use your Victoza pen within 30 days after the first day it is stored outside the refrigerator. After these 30 days, throw away your Victoza pen even if some medicine is left in the pen.
• Do not use Victoza after the expiration date printed on the carton.

Do not store the Victoza pen with the needle attached. Always safely remove and safely throw away the needle after each injection. This may help prevent contamination, infection and leakage. It also helps to make sure that you get the correct dose of Victoza. See the Patient Instructions for Use for information about how to dispose of used pen needles and used Victoza pens.

Keep your Victoza pen, pen needles, and all medicines out of the reach of children.

General information about Victoza

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Victoza for a condition for which it was not prescribed. Do not give Victoza to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information you should know about using Victoza. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Victoza that is written for health professionals.

For more information, go to victoza.com or call 1-877-484-2869.

What are the ingredients in Victoza?

Active Ingredient: liraglutide

Inactive Ingredients: disodium phosphate dihydrate, propylene glycol, phenol and water for injection

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

For information about Victoza contact:

Novo Nordisk Inc.

100 College Road West

Princeton, NJ 08540

1-877-484-2869

Issued: January 2010

Version: 1

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Victoza^® is a registered trademark of Novo Nordisk A/S.

Victoza^® is covered by US Patent Nos. 6,268,343, 6,458,924 and 7,235,627 and other patents pending.

Victoza^® pen is covered by US Patent Nos. 6,004,297, 6,235,004, 6,582,404 and other patents pending.

© 2010 Novo Nordisk A/S

PATIENT INSTRUCTIONS FOR USE

Victoza (liraglutide [rDNA origin]) injection

First read the Medication Guide that comes with your Victoza pen and then read these Patient Instructions for Use for information about how to use your Victoza pen the right way.

These instructions do not take the place of talking with your healthcare provider about your medical condition or your treatment.

Your Victoza pen contains 3 mL of Victoza and will deliver doses of 0.6 mg, 1.2 mg or 1.8 mg. The number of doses that you can take with a Victoza pen depends on the dose of medicine that is prescribed for you. Your healthcare provider will tell you how much Victoza to take.

Victoza pen should be used with Novo Nordisk disposable needles. Talk to your healthcare provider or pharmacist for more information about needles for your Victoza pen.

Important Information

• Do not share your Victoza pen or needles with anyone else. You may give an infection to them or get an infection from them.
• Always use a new needle for each injection.
• Keep your Victoza pen and all medicines out of the reach of children.
• If you drop your Victoza pen, repeat “First Time Use For Each New Pen” (steps A through D).
• Be careful not to bend or damage the needle.
• Do not use the cartridge scale to measure how much Victoza to inject.
• Be careful when handling used needles to avoid needle stick injuries.
• You can use your Victoza pen for up to 30 days after you use it the first time.

Caring for your Victoza pen

• After removing the needle, put the pen cap on your Victoza pen and store your Victoza pen without the needle attached.

• Do not try to refill your Victoza pen - it is prefilled and is disposable.
• Do not try to repair your pen or pull it apart.
• Keep your Victoza pen away from dust, dirt and liquids.
• If cleaning is needed, wipe the outside of the pen with a clean, damp cloth.

How should I store Victoza?

Before use:

• Store your new, unused Victoza pen in the refrigerator at 36ºF to 46ºF (2ºC to 8ºC).
• If Victoza is stored outside of refrigeration (by mistake) prior to first use, it should be used or thrown away within 30 days.
• Do not freeze Victoza or use Victoza if it has been frozen. Do not store Victoza near the refrigerator cooling element.

Pen in use:

• Store your Victoza pen for 30 days at 59ºF to 86ºF (15ºC to 30ºC), or in a refrigerator at 36ºF to 46ºF (2°C to 8°C).
• When carrying the pen away from home, store the pen at a temperature between 59ºF to 86ºF (15ºC to 30ºC).
• If Victoza has been exposed to temperatures above 86ºF (30°C), it should be thrown away.
• Protect your Victoza pen from heat and sunlight.
• Keep the pen cap on when your Victoza pen is not in use.
• Use a Victoza pen for only 30 days. Throw away a used Victoza pen after 30 days, even if some medicine is left in the pen.

First Time Use for Each New Pen

Step A. Check the Pen

• Take your new Victoza pen out of the refrigerator.
• Wash hands with soap and water before use.
• Check pen label before each use to make sure it is your Victoza pen.
• Pull off pen cap.

• Check Victoza in the cartridge. The liquid should be clear, colorless and free of particles. If not, do not use.
• Wipe the rubber stopper with an alcohol swab.

Step B. Attach the Needle

• Remove protective tab from outer needle cap.
• Push outer needle cap containing the needle straight onto the pen, then screw needle on until secure.

• Pull off outer needle cap. Do not throw away.

• Pull off inner needle cap and throw away. A small drop of liquid may appear. This is normal.

Step C. Dial to the Flow Check Symbol

• Turn dose selector until flow check symbol (--) lines up with pointer.

Step D. Prepare the Pen

• Hold pen with needle pointing up.
• Tap cartridge gently with your finger a few times to bring any air bubbles to the top of the cartridge.

• Keep needle pointing up and press dose button until 0 mg lines up with pointer. Repeat steps C and D, up to 6 times, until a drop of Victoza appears at the needle tip.

If you still see no drop of Victoza, use a new pen and contact Novo Nordisk at 1-877-484-2869.

Continue to Step G under "Routine Use" ?

Routine Use

Step E. Check the Pen

• Take your Victoza pen from where it is stored.
• Wash hands with soap and water before use.
• Check pen label before each use to make sure it is your Victoza pen.
• Pull off pen cap.

• Check Victoza in the cartridge. The liquid should be clear, colorless and free of particles. If not, do not use.
• Wipe the rubber stopper with an alcohol swab.

Step F. Attach the Needle

• Remove protective tab from outer needle cap.
• Push outer needle cap containing the needle straight onto the pen, then screw needle on until secure.

• Pull off outer needle cap. Do not throw away.

• Pull off inner needle cap and throw away. A small drop of liquid may appear. This is normal.

Step G. Dial the Dose

• Victoza pen can give a dose of 0.6 mg (starting dose), 1.2 mg or 1.8 mg. Be sure that you know the dose of Victoza that is prescribed for you.

• Turn the dose selector until your needed dose lines up with the pointer (0.6 mg, 1.2 mg or 1.8 mg).

• You will hear a "click" every time you turn the dose selector. Do not set the dose by counting the number of clicks you hear.
• If you select a wrong dose, change it by turning the dose selector backwards or forwards until the correct dose lines up with the pointer. Be careful not to press the dose button when turning the dose selector. This may cause Victoza to come out.

Step H. Injecting the Dose

• Insert needle into your skin in the stomach, thigh or upper arm. Use the injection technique shown to you by your healthcare provider. Do not inject Victoza into a vein or muscle.
• Press down on the center of the dose button to inject until 0 mg lines up with the pointer.
• Be careful not to touch the dose display with your other fingers. This may block the injection.
• Keep the dose button pressed down and make sure that you keep the needle under the skin for a full count of 6 seconds to make sure the full dose is injected. Keep your thumb on the injection button until you remove the needle from your skin.

Step I. Withdraw Needle

• You may see a drop of Victoza at the needle tip. This is normal and it does not affect the dose you just received. If blood appears after you take the needle out of your skin, apply light pressure, but do not rub the area.

Step J. Remove and Dispose of the Needle

• Carefully put the outer needle cap over the needle. Unscrew the needle.

• Safely remove the needle from your Victoza pen after each use.
• Place used needles in a closeable, puncture-resistant container. If your Victoza pen is empty or if you have been using it for 30 days (even if it is not empty), throw away the used pen. You may use a sharps container (such as a red biohazard container), a hard plastic container (such as an empty detergent bottle), or metal container with a screw top (such as an empty coffee can).
• Ask your healthcare provider for instructions on the right way to dispose of your used needles, pens, and the container. Do not throw the disposal container in the household trash. Do not recycle.

处方资料：

一般描述：Victoza含利拉鲁肽(liraglutide)，人GLP-1的一种类似物和作用如同一种GLP-1受体激动剂。利拉鲁肽的多肽前体，通过一种工艺过程生产其中包括在酿酒酵母(Saccharomyces cerevisiae)重组DNA的表达，已被工程化，与在34位赖氨酸被精氨酸取代的天然人GLP-1是97%同源。通过附着一个C-16脂肪酸(棕榈酸palmitic acid)与一个谷氨酸连接物(spacer)连接在多肽前体26位处遗留的赖氨酸残基上制成利拉鲁肽。利拉鲁肽的分子式为C172H265N43O51而相对分子质量是3751.2。结构式(图1)为：

 
图1 利拉鲁肽的结构式

1.    适应证：
Victoza是一种胰高血糖素样肽-1(GLP-1)受体激动剂，适用于2型糖尿病成年中辅助饮食和运动，改善血糖控制。

使用重要限制：
1)    因为啮齿类甲状腺C-细胞瘤发现与人的相关性不确定，考虑只对潜在获益胜过潜在风险患者开Victoza的处方。不推荐Victoza作为对食物和运动控制不佳患者的一线治疗。
2)    Victoza的临床试验中用Victoza比用对比药有更多病例胰腺炎。尚未在胰腺炎史患者中充分研究已确定对胰腺炎患者用Victoza是否高危。有病史者应慎用。
3)    Victoza不是取代胰岛素。Victoza不应用作1型糖尿病或糖尿病酮症酸中毒治疗，因在这些情况可能无效。
4)    尚未研究Victoza与胰岛素联用.

2.剂量和用法：
1)    每天给药1次，在任何时间与进餐无关。
2)    在腹部，大腿或上臂皮下注射。
3)    可改变注射部位和时间不调整剂量。
4)    初始每天0.6 mg共1周。初始期为减轻胃肠道症状又不影响血糖控制调整剂量。一周后，增加剂量至1.2 mg。如1.2 mg
剂量未造成可接受的血糖控制，剂量可增至1.8 mg。
5)    当开始用Victoza时考虑减低同时给予的促胰岛素分泌药物剂量以减少低葡萄糖血症风险。

3.剂型和规格：为皮下注射溶液，预装，多次给药笔输送剂量0.6 mg，1.2 mg或1.8 mg(6 mg/mL，3 mL)。

4.禁忌证：甲状腺髓样癌(MTC)个人或家族史或2型多发性内分泌肿瘤综合征(MEN 2)患者禁用。

5.警告和注意事项：
1)    动物中甲状腺C－细胞肿瘤：与人相关性未知。告诉患者关于甲状腺髓性癌风险和甲状腺肿瘤症状。
2)    胰腺炎：在临床试验中，Victoza-治疗患者比对比药物-治疗患者有更多胰腺炎病例。如怀疑胰腺炎，应中止Victoza和其它潜在怀疑药物。如确证胰腺炎不应从新用Victoza。有胰腺炎史患者慎用。
3)    严重低血糖：使用Victoza与一种促胰岛素分泌药物(如一种磺酰脲类)可能发生低葡萄糖血症。考虑减低促胰岛素分泌药剂量减少低葡萄糖血症风险。
4)    大血管病变结果：尚无结论性证据研究确定Victoza或任何其它抗糖尿病药物减低大血管风险。

6. 不良反应：

6.1 临床试验经验
因为临床试验是在广泛不同情况下进行的，某药临床试验观察到不良反应率不能与另药临床试验发生率直接比较而且可能不反映实践中观察到的发生率。

在52-周单药治疗试验和4项26-周添加联合治疗试验评价Victoza的安全性。单药治疗试验中，患者每天用Victoza 1.2 mg、每天Victoza 1.8 mg、或每天格列美脲(glimepiride)8 mg治疗。添加至二甲双胍试验中，患者用Victoza 0.6 mg、Victoza 1.2 mg、Victoza 1.8 mg、安慰剂、或格列美脲4 mg治疗。添加至格列美脲试验中患者用Victoza 0.6 mg、Victoza 1.2 mg、Victoza 1.8 mg、安慰剂、或罗格列酮(rosiglitazone)4 mg治疗。添加至二甲双胍+格列美脲试验中患者用Victoza 1.8 mg、安慰剂、或甘精胰岛素(insulin glargine)治疗。添加至二甲双胍+罗格列酮试验中患者用Victoza 1.2 mg、Victoza 1.8 mg或安慰剂[见临床研究(14)]。

撤药
5项对照试验26周或更长时间中，Victoza-治疗患者由于不良事件撤药发生率是7.8%和对对比药-治疗是3.4%患者。这种撤药差别是由于胃肠道不良反应，Victoza治疗患者发生5.0%和对比药-治疗患者0.5%。Victoza-治疗患者导致撤药最常见不良反应是恶心(2.8%相比对比药0%)和呕吐(1.5%相比对比药0.1%)。由于胃肠道不良事件撤药主要发生在试验的头2-3个月期间。
表1和2总结在5项26周或更长时间对照试验中报道Victoza-治疗患者≥5%的不良事件。

5项26周时间或更长临床治疗中，Victoza-治疗患者报道胃肠道不良事件41%而且是剂量相关。对比药治疗患者胃肠道不良事件发生17%。Victoza-治疗患者中更常发生事件包括恶心、呕吐、腹泻、消化不良和便秘。26周时间或更长临床治疗中，报道恶心患者百分率随时间降低。Victoza-治疗患者约13%和对比药治疗患者2%治疗头2周报道恶心。

免疫原性

与蛋白和多肽药物潜在免疫原性质一致，用Victoza治疗患者可能发生抗利拉鲁肽抗体。5项26周时间或更长临床治疗中约50-70% Victoza-治疗患者在治疗结束是检验是否有抗利拉鲁肽抗体。8.6% Victoza-治疗患者被检出低滴度(浓度无需稀释血清)抗利拉鲁肽抗体。跨越所有临床治疗患者胃进行采样方法统一，而这可能导致发生低估抗体患者百分率。在52-周单药治疗试验中Victoza-治疗患者有6.9%发生抗利拉鲁肽抗体与天然胰高血糖素肽-1(GLP-1)交叉反应而26-周添加联合治疗治疗的Victoza-治疗患者有4.8%。这些交叉反应抗体未检验对天然GLP-1的中和作用，因而未评估临床上明显中和天然GLP-1潜能。体外分析，52-周单药治疗试验Victoza-治疗患者有2.3%而26-周添加联合治疗Victoza-治疗患者有1.0%的抗体对利拉鲁肽有中和作用。
发生抗利拉鲁肽抗体Victoza-治疗患者，最常见类别不良事件是感染，发生率40%患者，相比抗体阴性Victoza-治疗，安慰剂-治疗和阳性对照-治疗患者分别为36%，34%和35%。Victoza-治疗抗体阳性患者中发生频率较大的特异性感染主要是非严重上呼吸道感染，Victoza-治疗抗体阳性患者发生11%；而抗体阴性Victoza-治疗，安慰剂-治疗和阳性对照-治疗患者分别为7%，7%和5%。Victoza-治疗抗体阴性患者中最常见类别不良事件是胃肠道事件，抗体阴性Victoza-治疗，安慰剂-治疗和阳性对照-治疗患者分别发生43%，18%和19%。当比较所有抗体阳性和所有抗体阴性患者时，抗体形成不伴有Victoza对平均HbA1c疗效减低。然而，3例抗利拉鲁肽抗体滴度最高的患者用Victoza治疗HbA1c没有减低。
Victoza临床治疗中，可能与免疫原性有关不良事件的并发(如荨麻疹，血管水肿)，Victoza-治疗患者中发生0.8%和对比药治疗患者为0.4%。Victoza-治疗患者荨麻疹约占事件组合的一半。发生抗利拉鲁肽抗体患者不像是发生高于未发生抗利拉鲁肽抗体患者并发来自免疫原性事件。

注射部位反应

在5项至少26周时间临床治疗中约2% Victoza治疗患者报道注射部位反应(如注射部位皮疹，红斑)。由于注射部位反应终止Victoza-治疗患者少于0.2%。

乳头状甲状腺癌

Victoza临床治疗中，用Victoza治疗患者报道6例乳头状甲状腺癌和对比药-治疗患者报道1例(1.9相比0.6 例每1000患者-年)。这些乳头状甲状腺癌的最大直径大多数是 <1 cm和在甲状腺切除术后手术病理学标本中被诊断，方案指定用血清降钙素或甲状腺超声检查使及时发现。

低血糖症

至少26周临床治疗中，需要他人帮助治疗的低血糖症，Victoza-治疗患者7例(2.6例每1000患者-年)和对比药治疗患者没有。 Six of these 7 用Victoza治疗患者其中6/7例服用磺酰脲类。其它1例用Victoza与二甲双胍联用，但对低血糖症可能有另外解释(此事件发生在住院期间和输注胰岛素后)(表3)。另外2例低血糖症需要他人帮助治疗随后被报道患者没有同时用磺酰脲类。两例患者接受Victoza，1例单药治疗和另1例与二甲双胍联用。两例患者有低血糖症发另外解释(1例在葡萄糖耐量试验期间频繁静脉采样接受胰岛素，而另1例有颅内出血和进食不确定)。

临床治疗合并分析中，恶性肿瘤发生率(每1,000患者-年)(来自双盲和开放研究阶段，基于研究者报道事件，医疗史，病理学报告，和手术报告)对Victoza是10.9，对安慰剂6.3，和对阳性对比药7.2。在除外乳头状甲状腺癌事件[见不良反应(6.1)], 没有特定的癌症细胞类型为主。几个恶性肿瘤事件被报道暴露于研究药物超过1年，Victoza-治疗患者中6例事件(4例结肠，1例前列腺和1例鼻咽)，安慰剂无事件和阳性对比药1例事件(结肠)。未确定病因。

实验室检验

在5项至少26周临床治疗，轻度升高的血清胆红素浓度(升高不超过参比范围上限2倍)，Victoza治疗患者发生4.0%，安慰剂-治疗患者2.1%和阳性-对比药治疗患者3.5%。这个发现不伴有其它肝功能异常。这个孤立发现的意义不知道。

12 临床药理学

12.1 作用机制

利拉鲁肽是一种酰化人胰高血糖素-样肽-1(GLP-1)受体激动剂有97%氨基酸序列同源于内源性人GLP-1(7-37)。GLP-1(7-37)代表<20%的总循环内源性GLP-1。像GLP-1(7-37)一样，利拉鲁肽活化GLP-1受体，一种膜-结合细胞表面受体耦合至腺苷酸环化酶刺激在胰腺β细胞内G-蛋白Gs。有葡萄糖浓度升高时，利拉鲁肽增加细胞内环一磷酸腺苷酸(cAMP)导致胰岛素释放。当血糖浓度降低时，胰岛素分泌消退和接近正常血糖。利拉鲁肽还以依赖葡萄糖方式减低胰高血糖素分泌。血糖降低机制还涉及胃排空延后。

GLP-1(7-37)由于被无处不在的内源性酶，二肽肽酶IV(DPP-IV)和中性内肽酶(NEP)降解，半衰期仅1.5-2分钟。利拉鲁肽和天然GLP-1不一样，对两种肽酶代谢酶降解都稳定和皮下给药后血浆半衰期13小时。of 利拉鲁肽的药代动力学图形使之适于每天1次给药，是自身伴延缓吸收，血浆蛋白结合和对DPP-IV和NEP代谢降解稳定性的结果。

12.2 药效学

Victoza的药效学图形与其单次皮下给药后观察到药代动力学图形一致，Victoza降低空腹、餐前和餐后葡萄糖在一天内自始至终[见临床药理学(12.3)]。
在用0.6、1.2和1.8 mg Victoza或安慰剂治疗至稳态后，标准餐前和后至5小时测定空腹和餐后葡萄糖。 与安慰剂比较，Victoza 1.2 mg后餐后血浆葡萄糖AUC0-300min为35%较低和Victoza 1.8 mg后低于38%。

葡萄糖-依赖胰岛素分泌
10例2型糖尿病患者用减缓(graded)葡萄糖输注期间研究单剂量7.5 μg/kg(~0.7 mg)Victoza对胰岛素分泌率(ISR)的影响。在这些患者平均ISR反应以依赖葡萄糖方式增加(图2)。
 

胰高血糖素分泌

Victoza通过刺激胰岛素分泌和降低胰高血糖素分泌降低血糖。单剂量Victoza 7.5 μg/kg (~ 0.7 mg)不损害胰高血糖素反应降低葡萄糖浓度。

胃排空 
Victoza引起胃排空延后, 因此减缓餐后葡萄糖在循环中出现速率。

心脏电生理(QTc)
一项QTc研究中检验Victoza对心复极化的影响。Victoza在稳态浓度用每天给药至1.8 mg不产生QTc延长。

12.3 药代动力学

吸收 - 皮下给药后，在给药后8-12小时达到利拉鲁肽发最大浓度。对皮下单剂量0.6 mg，利拉鲁肽的平均峰值(Cmax)和总(AUC)暴露分别为35 ng/mL和960 ng?h /mL。治疗剂量范围0.6 mg至1.8 mg，皮下单次给药后，利拉鲁肽的Cmax和AUC呈正比例增加。在1.8 mg Victoza，利拉鲁肽的24小时平均稳态浓度约为128 ng/mL。上臂和腹部，和上臂和大腿间AUC0-∞等同。从大腿AUC0-∞是22%低于从腹部。然而，认为这3处皮下注射部位间利拉鲁肽暴露有可比性。利拉鲁肽皮下给药后的绝对生物利用度约为55%。

分布 - Victoza 0.6 mg皮下给药后平均表观分布容积约为13 L。静脉给予Victoza后平均表观分布容积是0.07 L/kg。利拉鲁肽被广泛结合至血浆蛋白(>98%)。

代谢 -给予单次[3H]-利拉鲁肽剂量至健康受试者后最初24小时期间，血浆中主要组分是完整的利拉鲁肽。利拉鲁肽被内源性代谢与大蛋白相似方式，没有特异性器官为主要消除途径。

消除 - [3H]-利拉鲁肽给药后，在尿或粪中不能检测到完整利拉鲁肽。在尿或粪中只有小量给药的放射性以利拉鲁肽-相关代谢物(分别6%和5%)排泄。尿和粪大多数的放射性在头6-8天被排泄。单剂量利拉鲁肽皮下给药后平均表观清除率约为1.2 L/h与消除半衰期约13小时，使Victoza适宜于每天给药1次。

特殊人群

老年 – 根据在健康老年受试者(65至83岁)一项药代动力学研究和18至80岁患者的群体药代动力学分析年龄对Victoza的药代动力学没有影响[见特殊人群中使用(8.5)]。

性别 – 根据群体药代动力学分析的结果，与男性比较，女性有34%较低体重-校正Victoza的清除率。根据暴露反应资料，不需要根据性别调整剂量。

种族和种族 -根据包括高加索人、黑人、亚裔和西班牙/非-西班牙裔受试者的群体药代动力学分析的结果，种族和种族对Victoza的药代动力学没有影响。

体重-  根据群体药代动力学分析的结果体重明显影响的药代动力学。利拉鲁肽的暴露基线体重增加而降低。然而，临床试验评价中体重范围40 – 160 kg ，Victoza 1.2 mg和1.8 mg每天剂量提供适当全身暴露。尚未在利拉鲁肽体重>160 kg患者中研究。

儿童 - 尚未在儿童患者中研究Victoza[见特殊人群中使用(8.4)]。

肾损伤 – 在不同程度肾损伤受试者中评价单剂量Victoza的药代动力学。试验中包括有轻度受试者(估算的肌酐清除率50-80 mL/min)至严重(估算的肌酐清除率<30 mL/min)肾损伤和有终末肾疾病需要透析的受试者。与健康受试者比较，在轻度、中度、和严重肾损伤和终末肾病中利拉鲁肽AUC分别平均较低35%、19%、29%和30%[见特殊人群中使用 (8.6)] 。

肝损伤 -在有不同程度肝损伤受试者中评价单剂量Victoza的药代动力学。试验中包括受试者有轻度(Child Pugh计分5-6)至严重(Child Pugh计分 > 9)肝损伤。与健康受试者比较， in有轻度、中度和严重肝损伤受试者中利拉鲁肽AUC分别平均为11%、14%和42%较低[见特殊人群中使用(8.7)]。

在体外评估药物-药物相互作用

Victoza有低潜在的与细胞色素P450(CYP)和血浆蛋白结合相关的药代动力学药物-药物相互作用。

在体内评估药物-药物相互作用

用Victoza 1.8 mg/day在稳态时进行药物-药物相互作用研究。同时治疗的给药前，受试者进行一个0.6 mg 每周剂量增加达到最大剂量1.8 mg/day。定时给予相互作用药物所以Victoza的Cmax(8-12 h)将与共同给予药物的吸收峰相合。

地高辛(Digoxin)
在稳态时Victoza给药后7小时给予单剂量地高辛1 mg。同时给予Victoza导致地高辛AUC减低16%；Cmax减低31%。地高辛达峰中位时间(Tmax)从1 h延后至1.5 h。

赖诺普利(Lisinopril)
在Victoza给药稳态后5分钟给予单剂量赖诺普利20 mg。与Victoza共同给药导致赖诺普利AUC减低15%；Cmax减低27%。用Victoza，赖诺普利中位Tmax从6 h延后至8 h。

阿托伐他汀(Atorvastatin)
单剂量阿托伐他汀40 mg后，给药5小时后在稳态时给予Victoza，Victoza不改变阿托伐他汀的总暴露(AUC)。用Victoza 1 h至3 h，阿托伐他汀Cmax减低38%和中位Tmax延后。

对乙酰氨基酚(Acetaminophen)
Victoza不改变单剂量对乙酰氨基酚1000 mg后对乙酰氨基酚的总暴露(AUC)，在Victoza稳态后8小时给予，对乙酰氨基酚Cmax减低31%和中位Tmax被延后15分钟。

灰黄霉素(Griseofulvin)
在Victoza稳态时共同给予单剂量灰黄霉素500 mg，Victoza不改变灰黄霉素的总暴露(AUC)，灰黄霉素 Cmax增加37%而中位Tmax无变化。

口服避孕药
进食条件和给Victoza稳态后7小时给予含0.03 mg炔雌醇(ethinylestradiol)和0.15 mg左炔诺孕酮(levonorgestre)单剂量口服避孕药复方产品。Victoza分别降低炔雌醇和左炔诺孕酮Cmax 12%和13%。Victoza对炔雌醇总暴露(AUC)无影响。Victoza增加左炔诺孕酮AUC0-∞ 18%。Victoza延后炔雌醇和左炔诺孕酮Tmax均为1.5 h。

14 临床研究

总共3978例2型糖尿病患者参加在5项双盲(这些试验之一为开放甘精胰岛素阳性对照组)，随机化, 对照临床试验，1项52周时间和4项26周时间。进行这些Victoza在2型糖尿病中作为单药治疗和与1种或2种口服抗-糖尿病药联用的多国试验评价对血糖疗效和安全性。4项添加联合治疗试验纳入既往曾用抗-糖尿病治疗的患者，而在单药治疗试验中约2/3的患者既往也曾用抗-糖尿病治疗。这些5项试验中总共272/3978例(7%)患者对抗-糖尿病治疗是新的。在这些5项临床试验，患者年龄范围从19-80岁和54%是男性。约77%患者是高加索人，和6%是黑人。在2项试验其中种族27%患者是西班牙/拉丁裔和73%是非-西班牙/拉丁裔。In each of 这些试验中，与安慰剂比较，用Victoza治疗各自产生血红蛋白A1c和空腹血糖(FPG)临床上和统计上显著改善。Victoza对血压没有不良作用。

所有Victoza-治疗患者开始用0.6 mg/天。随机化至这些较高剂量患者每周间隔剂量增加0.6 mg达到1.2 mg或1.8 mg。Victoza 0.6 mg对控制血糖无效和仅意向为开始剂量减轻胃肠道不耐受性[见剂量和给药方法(2)]。

14.1 单药治疗

在52-周试验中，746例患者被随机化至Victoza 1.2 mg、Victoza 1.8 mg、或格列美脲8 mg。被随机化至格列美脲患者最初用2 mg每天治疗共2周，增加至4 mg每天另外2周，而最终增加至8 mg每天。与格列美脲比较，用Victoza 1.8 mg和1.2 mg治疗导致统计上显著减低HbA1c(表4)。Victoza 1.8 mg治疗组中由于无效治疗终止的患者百分率是3.6%，Victoza 1.2 mg治疗组为6.0%，而格列美脲-治疗组为10.1%。

图3对完成52-周试验患者平均HbA1c和52周时(单药治疗)对向前携带末次观察数据(LOCF, 意向治疗)

14.2 联合治疗

添加至二甲双胍

在此26-周试验中，1091例患者被随机化至Victoza 0.6 mg、Victoza 1.2 mg、Victoza 1.8 mg、安慰剂、或格列美脲4 mg (美国被批准最大剂量一半)，所有作为添加至二甲双胍。由3-周初期强制的二甲双胍调整剂量期接着是另外3周维持期组成的磨合期后6周随机化。在调整剂量期时，二甲双胍的剂量增加至2000 mg/day。
用Victoza 1.2 mg和1.8 mg治疗作为添加至二甲双胍相对于安慰剂添加至二甲双胍导致平均HbA1c显著减低和导致相对于格列美脲4 mg添加至二甲双胍相似的平均HbA1c减低(表5)。Victoza 1.8 mg+二甲双胍治疗组中由于无效终止治疗患者百分率为5.4%，Victoza 1.2 mg+二甲双胍治疗组为3.3%，安慰剂+二甲双胍治疗组为23.8%而格列美脲+二甲双胍治疗组为3.7%。

添加至磺酰脲类(磺酰脲类)

在这个26-周试验中，1041例患者被随机化至Victoza 0.6 mg、Victoza 1.2 mg、Victoza 1.8 mg、安慰剂、或罗格列酮4 mg(美国被批准最大剂量一半)，所有作为添加至格列美脲。在初期2-周，强制-调整格列美脲剂量期接着另外2周维持期组成的4-周磨合期后随机化。在调整剂量期时，格列美脲的剂量被增加至4 mg/天。随机后在不可接受的低血糖事件或其他不良事件，格列美脲的剂量可能减低(研究者判辩)从4 mg/day至3 mg/day或2 mg/day(最小)。
用Victoza 1.2 mg和1.8 mg治疗作为添加至格列美脲与安慰剂添加至格列美脲比较导致统计上显著减低平均HbA1c(表6)。在Victoza 1.8 mg+格列美脲治疗组由于治疗无效终止患者百分率为3.0%，Victoza 1.2 mg+格列美脲治疗组为3.5%，安慰剂+格列美脲治疗组为17.5%而罗格列酮+格列美脲治疗组为6.9%。

添加至二甲双胍和磺酰脲类

在这个26-周试验中，581例患者被随机化至Victoza 1.8 mg、安慰剂、或甘精胰岛素、所有作为添加至二甲双胍和格列美脲。在3-周强制二甲双胍和格列美脲调整剂量期接着是另外3周维持期组成的6-周磨合期后随机化。调整剂量期时二甲双胍和格列美脲的剂量被分别增加至2000 mg/day和4 mg/day。随机后，患者随机化至Victoza 1.8 mg进行为期2周Victoza剂量调整。试验期间，固定Victoza和二甲双胍剂量，尽管格列美脲和甘精胰岛素剂量可被调整。在治疗的头8周基于调整天患者自身测定的空腹血糖调整甘精胰岛素每周2次。在8周后，调整甘精胰岛素的频数由研究者判辩，但甘精胰岛素剂量被修订最小量，必要时在第12和18周。只有20%甘精胰岛素-治疗患者达到预先指定的目标空腹血糖≤100 mg/dL。所以，大多数患者甘精胰岛素没有达到调整的优化。

与安慰剂比较，用Victoza治疗作为添加至格列美脲和二甲双胍导致平均HbA1c统计上显著减低，添加至格列美脲和二甲双胍 (表7)。Victoza 1.8 mg+二甲双胍+格列美脲治疗组由于治疗无效终止患者百分率为0.9% , 甘精胰岛素+二甲双胍+格列美脲治疗组为0.4%,而安慰剂+二甲双胍+格列美脲治疗组为11.3%.

添加至二甲双胍和噻唑烷二酮类(Thiazolidinedione)

在这个26-周试验中，533例患者被随机化至Victoza 1.2 mg、Victoza 1.8 mg或安慰剂，所有作为添加至罗格列酮(8 mg)+二甲双胍(2000 mg)。患者进行 9 周磨合期 (3-周强制剂量递增，接着6-周给药维持期) 用罗格列酮(开始4 mg和在2周内增至8 mg/day)和二甲双胍(开始500 mg每周增量500 mg至最终剂量2000 mg/day)。只有耐受最终剂量罗格列酮(8 mg/day)和二甲双胍(2000 mg/day)和完成6-周给予维持期的患者随机进入试验。
用Victoza治疗添加至二甲双胍和罗格列酮与安慰剂添加至二甲双胍和罗格列酮比较平均HbA1c产生统计上显著减低(表8)。Victoza 1.8 mg+二甲双胍+罗格列酮治疗组，由于治疗无效终止的患者百分率为1.7%， Victoza 1.2 mg+二甲双胍+罗格列酮治疗组为1.7%，而安慰剂+二甲双胍+罗格列酮治疗组为1***%.