دالتپارین سدیم
Dalteparin (Fragmin)
دالتپارین سدیم

نام ژنریک

Dalteparin Sodium

شکل دارویی

اشكال دارويي:


Injection: 10000 U/ml, 2500 U/0.2ml, 5000 U/0.2ml, 7500 U/0.3 ml

موارد مصرف

موارد و مقدار مصرف


الف) پروفيلاكسي از ترومبوز وريد عمقي در بيماراني كه تحت جراحي شكم قرار گرفته و در خطر عوارض ترومبوآمبوليك قرار دارند (شامل بيماران با سن بالاتر از 40 سال، چاق، كساني كه تحت بيهوشي عمومي به مدت بيشتر از 30 دقيقه قرار مي‌گيرند، و در بيماران با سابقه ترومبوز وريد عمقي (DVT) يا آمبولي ريوي).


بزرگسالان: 2500 واحد زيرجلدي روزانه، كه 1 تا 2 ساعت قبل از جراحي شروع شده و به صورت يك بار در روز براي مدت 5 تا 10 روز ادامه مي‌يابد. در موارد جراحي شكم كه در خطر بالاي عوارض ترومبوآمبوليك قرار دارند (مانند بيماريهاي بدخيم)، 5000 واحد زيرجلدي روزانه كه شب قبل از جراحي
آغاز شده و سپس روزانه براي 5 تا 10 روز ادامه مي‌يابد، يا 2500 واحد در عرض 2-1 ساعت قبل از جراحي و سپس تكرار 2500 واحد زيرجلدي 12 ساعت بعد و سپس 5000 واحد زيرجلدي روزانه به مدت 5 تا 10 روز ادامه يابد.


ب) پروفيلاكسي از ترومبوز وريد عمقي در بيماراني كه تحت جراحي جايگزيني هيپ قرار مي‌گيرند.


بزرگسالان: 2500 واحد زيرجلدي در عرض 2 ساعت قبل از جراحي، دوز دوم به ميزان 2500 واحد در شب قبل از عمل تجويز شود.(حداقل با 6 ساعت از دوز اول) اگر جراحي شب انجام مي‌شود، دوز دوم را حذف كنيد. در روز بعد از عمل دارو را با دوز 5000 واحد زيرجلدي روزانه آغاز كرده و به مدت 5 تا 10 روز ادامه دهيد.


پ) پيشگيري از عوارض ايسكميك در بيماران با آنژين ناپايدار يا سكتة قلبي non-Q-wave كه آسپيرين دريافت مي‌كنند.


بزرگسالان: u/kg 120 زيرجلدي هر 12 ساعت همراه با 165-75 ميلي‌گرم آسپرين، كه تا زمان پايدار شدن وضعيت بيمار معمولاً 5 تا 8 روز ادامه يابد. بيشتر از 10000 واحد در يك دوز تجويز نكنيد.


ت) بيماراني كه به دليل بي‌حركتي طولاني مدت ضمن بيماريهاي حاد در معرض خطرات ترومبوآمبوليك هستند.


بزرگسالان: 5000 واحد زيرجلدي روزانه، معمولاً براي 12 تا 14 روز تجويز مي‌شود.

موارد منع مصرف

موارد منع مصرف و احتياط


موارد منع مصرف: حساسيت به دارو يا ديگر تركيبات فرمولاسيون، ترومبوسيتوپني به دليل آنتي‌بادي ضد دالته‌پارين (كه در آزمايشگاه اثبات شود)، حساسيت به هپارين يا مشتقات خوكي، بيماران با خونريزي وسيع و فعال، بيماران با آنژين ناپايدار، سكته قلبي non-Q-wave يا ترومبوآمبولي حاد وريدي كه تحت بيهوشي موضعي قرار مي‌گيرند، مصرف وريدي يا عضلاني دارو.


موارد احتياط: بيماران با آندوكارويت باكتريايي، اختلالات ارثي يا اكتسابي خونريزي دهنده، ضايعات اولسراتيو يا آنژيوديسپلاستيك خونريزي دهنده دستگاه گوارش، فشار خون شديد كنترل نشده، سكته مغزي هموارژيك، يا استفاه بلافاصله بعد از جراحي مغز، نخاع، چشم، بيماراني كه همزمان داروهاي ضد پلاكت دريافت مي‌كنند، خونريزي اخير گوارشي، ترومبوسيتوپني يا نقص عملكرد پلاكت‌ها، بيماري شديد كبدي، رتينوپاتي ديابتي يا ناشي از فشار خون بالا، يا در بيماراني كه تحت جراحي‌هاي تهاجمي قرار مي‌گيرند، رسيك خونريزي بالاست و اين دارو بايد با احتياط به كار رود. و در صورت بروز خونريزي بايد مصرف آن قطع شود.


در بيماران با سابقه حساسيت به پارابن‌ها با احتياط به كار رود.


موارد نادري از ترومبوسيتوپني گزارش شده است. در بيماران با سابقه ترومبوسيتوپني ناشي از هپارين با احتياط به كار رود. پلاكت بيمار به دقت مانيتور شود. و اگر ترومبوسيتوپني وابسته به دارو مشاهده شد، مصرف آن قطع شود. موارد نادري از ترومبوسيتوپني همراه با ترومبوز نيز گزارش شده است. در بيماران با سابقه ترومبوسيتوپني ارثي يا ناشي از دارو با احتياط به كار رود.


بيماران سرطاني با ترومبوسيتوپني، جهت درمان ترومبوآمبولي حاد وريدي، نياز به تعديل دوز دارند.


در بيماران با نارسايي كليوي شديد با احتياط به كار رود. ايمني و اثربخشي دارو در كودكان اثبات نشده است.


دارو نبايد به صورت واحد به واحد با ساير انواع هپارين جايگزين شود.


بيماراني كه تحت بيهوشي نخاعي يا اپي‌دورال قرار مي‌گيرند، در معرض خطر هماتوم و سپس پاراليز ناشي از مصرف اين دارو قرار دارند.


بيماران بايد به دقت از نظر علائم خونريزي و نارسايي نورولوژيك در اين شرايط بررسي شوند.

عوارض جانبی دارو

عوارض جانبي


اعصاب مرکزي: تب.


قلبي- عروقي: خونريزي.


خون: ترومبوسيتوپني، عوارض خونريزي دهنده.


پوست: اكيموز، هماتوم، عوارض محل تزريق، خارش، راش.


مسموميت و درمان


مصرف بيش از اندازه باعث عوارض خونريزي دهنده مي‌شود. معمولاً، اين عوارض با تزريق آهسته وريدي پروتامين سولفات (محلول 1%) متوقف مي‌شوند. يك ميلي‌گرم از پروتامين به ازاي هر 100 واحد ضد فاكتور 10 فعال دالته‌پارين تجويز شود. اگر 4-2 ساعت بعد از تجويز اول، APTT طولاني بود، دوز دوم پروتامين به ميزان mg 5/0 به ازاي هر 100 واحد دالته‌پارين تجويز مي‌شود. حتي با دوز دوم ممكن است، برخلاف هپارين معمولي همچنان APTT طولاني باقي بماند. پروتامين مي‌تواند باعث افت فشار خون و واكنشهاي آنافيلاكتوئيد شود. بيمار را به دقت مانيتور كنيد.

موارد قابل توجه

-

تداخل دارویی

تداخل دارويي


مصرف همزمان ضد انعقادهاي خوراكي (مانند آسپيرين، وارفارين، NSAIDs) و مهاركننده‌هاي پلاكت، ريسك خونريزي را افزايش مي‌دهد. با احتياط همراه هم استفاده شوند.

مکانیزم اثر

تداخل دارويي


مصرف همزمان ضد انعقادهاي خوراكي (مانند آسپيرين، وارفارين، NSAIDs) و مهاركننده‌هاي پلاكت، ريسك خونريزي را افزايش مي‌دهد. با احتياط همراه هم استفاده شوند.

فارماكوكینتیك

فارماكوكينتيك


جذب: فراهمي زيستي مطلق دارو كه به صورت فعاليت ضد فاكتور 10 فعال اندازه‌گيري مي‌شود، حدود 87% است.


پخش: حجم توزيع دارو بر مبناي فعاليت ضد فاكتور 10 فعال ml/kg 60-40 است.


متابوليسم: شناخته شده نيست.


دفع: نيمه‌ عمر دفع دارو 5-3 ساعت است.

سایر اطلاعات

طبقه‌بندي فارماكولوژيك: مشتقات هپارين با وزن مولكولي كم.


طبقه‌بندي درماني: ضد انعقاد.


طبقه‌بندي مصرف در بارداري: رده B


نام‌هاي تجاري: Fragmin


ملاحظات اختصاصي


1- دارو را به هيچ وجه عضلاني تجويز نكنيد.


2- دارو نبايد به صورت واحد به واحد با ساير انواع هپارين جايگزين شود.


3- بيماراني كه تحت بيهوشي نخاعي يا اپي‌دورال قرار مي‌گيرند، بعد از مصرف اين دارو در معرض خطر هماتوم اپي‌دورال يا نخاعي قرار دارند، كه مي‌تواند باعث پاراليز دائمي شود.


4- دارو را با ساير فرآورده‌هاي تزريقي مخلوط نكنيد، مگر اينكه اطلاعات مبني بر سازگاري دارو موجود باشد.


5- بهتر است موقع تزريق بيمار در وضعيت خوابيده يا نشسته باشد. دارو را به صورت زيرجلدي و عميق تجويز كنيد. نواحي تزريق شامل يك ناحيه U شكل اطراف ناف، قسمت فوقاني ـ خارجي ران پا و قسمت فوقاني ـ خارجي باسن مي‌باشد. به صورت دوره‌اي محل تزريق را تغيير دهيد. زماني كه تزريق در شكم يا ران انجام مي‌شود، بهتر است، ابتدا پوست كشيده و جمع شده و سپس تزريق انجام شود. تمام طول سوزن را با زاويه 45 تا 90 درجه وارد كنيد.


6- به صورت دوره‌اي CBC (شامل پلاكت) و مدفوع را از نظر خون بررسي كنيد. مانيتورينگ منظم APTT, INR, PT لازم نيست. سطح ضد فاكتور 10 فعال ممكن است زماني كه كنترل انعقادي مطلوب نيست، چك شود.


7- بيمار به دقت از نظر ترومبوسيتوپني و عوارض نورولوژيك بررسي شود.


8- در صورت بروز وقايع ترومبوآمبوليك ضمن مصرف دارو،‌ دارو را قطع كنيد.


نكات قابل توصيه به بيمار


1- لازم است كه محل تزريق دارو هر روز در يك ناحيه (شكم، ران، باسن) انجام شود.


2- در صورت مشاهده هرگونه خونريزي، سريعاً به پزشك خود گزارش دهيد.


3- از مصرف داروهاي بدون نسخه حاوي آسپرين يا NSAIDs، بدون مشورت با پزشك خود، خودداري كنيد.


مصرف در كودكان: ايمني و اثربخشي دارو در كودكان اثبات نشده است.


مصرف در شيردهي: ترشح دارو در شير مشخص نيست. با احتياط استفاده شود.


مصرف در بارداري: ويالهاي با مصرف چندين بار (مولتي دوز) حاوي بنزيل الكل بوده كه ممكن است باعث سندرم gasping در نوزادان نارس شود. بنزيل الكل از سد جفت عبور مي‌كند. در نتيجه بهتر است دارو در دوران حاملگي استفاده نشود.


اثر بر آزمايشهاي تشخيصي


دارو باعث افزايش سطح ALT و AST مي‌شود. ميزان پلاكت كاهش مي‌يابد.

Dalteparin (Fragmin)

FRAGMIN
(dalteparin sodium) Injection for Subcutaneous Use Only

WARNING

SPINAL/EPIDURAL HEMATOMAS

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

  • Use of indwelling epidural catheters
  • Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants.
  • A history of traumatic or repeated epidural or spinal punctures
  • A history of spinal deformity or spinal surgery

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

DRUG DESCRIPTION

FRAGMIN Injection (dalteparin sodium injection) is a sterile, low molecular weight heparin. It is available in single-dose, prefilled syringes preassembled with a needle guard device, and multiple-dose vials. With reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard, each syringe contains either 2500, 5000, 7500, 10,000, 12,500, 15,000 or 18,000 anti-Factor Xa international units (IU), equivalent to 16, 32, 48, 64, 80, 96 or 115.2 mg dalteparin sodium, respectively. Each multiple-dose vial contains either 10,000 or 25,000 anti-Factor Xa IU per 1 mL (equivalent to 64 or 160 mg dalteparin sodium, respectively), for a total of 95,000 anti-Factor Xa IU per vial.

Each prefilled syringe also contains Water for Injection and sodium chloride, when required, to maintain physiologic ionic strength. The prefilled syringes are preservative-free. Each multiple-dose vial also contains Water for Injection and 14 mg of benzyl alcohol per mL as a preservative. The pH of both formulations is 5.0 to 7.5. [See Dosage Forms and Strengths and HOW SUPPLIED]

Dalteparin sodium is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic purification process. It is composed of strongly acidic sulfated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5000 and about 90% of the material within the range 2000–9000. The molecular weight distribution is:

< 3000 daltons 3.0–15%
3000 to 8000 daltons 65.0–78.0%
> 8000 daltons 14.0–26.0%

What are the possible side effects of dalteparin (Fragmin)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using dalteparin and call your doctor at once if you have a serious side effect such as:

  • unusual bleeding (nose, mouth, vagina, or rectum), bleeding from wounds or needle injections, any bleeding that will not stop;
  • easy bruising, purple or red pinpoint spots under your skin;
  • pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;
  • black or bloody...

Read All Potential Side Effects and See Pictures of Fragmin »

What are the precautions when taking dalteparin (Fragmin)?

Before using dalteparin, tell your doctor or pharmacist if you are allergic to it; or to heparins or pork products; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: serious active bleeding.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: artificial heart valves, bleeding or blood disorders (low platelet counts), certain eye problems (hypertensive or diabetic retinopathy), uncontrolled severe high blood pressure, infection of the heart, kidney...

Read All Potential Precautions of Fragmin »

Last reviewed on RxList: 12/2/2010
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

FRAGMIN (dalteparin) ® Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy [see Clinical Studies].

Prophylaxis of Deep Vein Thrombosis

FRAGMIN (dalteparin) is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):

  • In patients undergoing hip replacement surgery [see Clinical Studies];
  • In patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies];
  • In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness [see Clinical Studies].

Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer

FRAGMIN (dalteparin) is also indicated for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT and/or PE), to reduce the recurrence of VTE in patients with cancer. In these patients, the FRAGMIN (dalteparin) therapy begins with the initial VTE treatment and continues for six months [see Clinical Studies].

Limitations of Use

FRAGMIN (dalteparin) is not indicated for the acute treatment of VTE.

DOSAGE AND ADMINISTRATION

FRAGMIN (dalteparin) is administered by subcutaneous injection. It must not be administered by intramuscular injection.

FRAGMIN (dalteparin) Injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.

Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of FRAGMIN (dalteparin) activity and, therefore, unsuitable for monitoring the anticoagulant effect of FRAGMIN. [See WARNINGS AND PRECAUTIONS].

Adult Dosage

Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of FRAGMIN (dalteparin) Injection is 120 IU/kg of body weight, but not more than 10,000 IU, subcutaneously every 12 hours with concurrent oral aspirin (75 to 165 mg once daily) therapy. Treatment should be continued until the patient is clinically stabilized. The usual duration of administration is 5 to 8 days. Concurrent aspirin therapy is recommended except when contraindicated.

Table 1 lists the volume of FRAGMIN (dalteparin) , based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.

Table 1 : Volume of FRAGMIN (dalteparin) to be Administered by Patient Weight, Based on 9.5 mL Vial (10,000 IU/mL)

Patient weight (lb) < 110 110 to 131 132 to 153 154 to 175 176 to 197 ≥ 198
Patient weight (kg) < 50 50 to 59 60 to 69 70 to 79 80 to 89 ≥ 90
Volume of FRAGMIN (mL) 0.55 0.65 0.75 0.90 1.0 1.0

Prophylaxis of Venous Thromboembolism Following Hip Replacement Surgery

Table 2 presents the dosing options for patients undergoing hip replacement surgery. The usual duration of administration is 5 to 10 days after surgery; up to 14 days of treatment with FRAGMIN (dalteparin) have been well tolerated in clinical trials.

Table 2 : Dosing Options for Patients Undergoing Hip Replacement Surgery

Timing of First Dose of FRAGMIN Dose of FRAGMIN to be Given Subcutaneously
10 to 14 Hours Before Surgery Within 2 Hours Before Surgery 4 to 8 Hours After Surgery1 Postoperative Period2
Postoperative Start     2500 IU3 5000 IU once daily
Preoperative Start - Day of Surgery   2500 IU 2500 IU3 5000 IU once daily
Preoperative Start - Evening Before Surgery4 5000 IU   5000 IU 5000 IU once daily
1 Or later, if hemostasis has not been achieved.
2 Up to 14 days of treatment was well tolerated in controlled clinical trials, where the usual duration of treatment was 5 to 10 days postoperatively.
3 Allow a minimum of 6 hours between this dose and the dose to be given on Postoperative Day 1. Adjust the timing of the dose on Postoperative Day 1 accordingly.
4 Allow approximately 24 hours between doses.

Abdominal Surgery

In patients undergoing abdominal surgery with a risk of thromboembolic complications, the recommended dose of FRAGMIN (dalteparin) is 2500 IU administered by subcutaneous injection once daily, starting 1 to 2 hours prior to surgery and repeated once daily postoperatively. The usual duration of administration is 5 to 10 days.

In patients undergoing abdominal surgery associated with a high risk of thromboembolic complications, such as malignant disorder, the recommended dose of FRAGMIN (dalteparin) is 5000 IU subcutaneously the evening before surgery, then once daily postoperatively. The usual duration of administration is 5 to 10 days. Alternatively, in patients with malignancy, 2500 IU of FRAGMIN (dalteparin) can be administered subcutaneously 1 to 2 hours before surgery followed by 2500 IU subcutaneously 12 hours later, and then 5000 IU once daily postoperatively. The usual duration of administration is 5 to 10 days.

Medical Patients During Acute Illness

In medical patients with severely restricted mobility during acute illness, the recommended dose of FRAGMIN (dalteparin) is 5000 IU administered by subcutaneous injection once daily. In clinical trials, the usual duration of administration was 12 to 14 days.

Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer

In patients with cancer and symptomatic venous thromboembolism, the recommended dosing of FRAGMIN (dalteparin) is as follows: for the first 30 days of treatment administer FRAGMIN (dalteparin) 200 IU/kg total body weight subcutaneously once daily. The total daily dose should not exceed 18,000 IU. Table 3 lists the dose of FRAGMIN (dalteparin) to be administered once daily during the first month for a range of patient weights

Month 1

Table 3 : Dose of FRAGMIN (dalteparin) to be Administered Subcutaneously by Patient Weight during the First Month

Body Weight (lbs) Body Weight (kg) FRAGMIN (dalteparin) Dose
(IU) (prefilled syringe)
once daily
≤ 124 ≤ 56 10,000
125 to 150 57 to 68 12,500
151 to 181 69 to 82 15,000
182 to 216 83 to 98 18,000
≥ 217 &gle; 99 18,000

Months 2 to 6

Administer FRAGMIN (dalteparin) at a dose of approximately 150 IU/kg, subcutaneously once daily during Months 2 through 6. The total daily dose should not exceed 18,000 IU. Table 4 lists the dose of FRAGMIN (dalteparin) to be administered once daily for a range of patient weights during months 2-6.

Table 4 : Dose of FRAGMIN (dalteparin) to be Administered Subcutaneously by Patient Weight during Months 2-6

Body Weight (lbs) Body Weight (kg) FRAGMIN (dalteparin) Dose
(IU) (prefilled syringe)
once daily
≤ 124 ≤ 56 7,500
125 to 150 57 to 68 10,000
151 to 181 69 to 82 12,500
182 to 216 83 to 98 15,000
≥ 217 ≥ 99 18,000

Safety and efficacy beyond six months have not been evaluated in patients with cancer and acute symptomatic VTE [see WARNINGS AND PRECAUTION and ADVERSE REACTIONS].

Dose reductions for thrombocytopenia in patients with cancer and acute symptomatic VTE

In patients receiving FRAGMIN (dalteparin) who experience platelet counts between 50,000 and 100,000/mm³, reduce the daily dose of FRAGMIN (dalteparin) by 2,500 IU until the platelet count recovers to ≥ 100,000/mm³. In patients receiving FRAGMIN (dalteparin) who experience platelet counts < 50,000/mm³, discontinue FRAGMIN (dalteparin) until the platelet count recovers above 50,000/mm³.

Dose reductions for renal insufficiency in extended treatment of acute symptomatic venous thromboembolism in patients with cancer

In patients with severely impaired renal function (CrCl < 30 mL/min), monitor anti-Xa levels to determine the appropriate FRAGMIN (dalteparin) dose. Target anti-Xa range is 0.5-1.5 IU/mL. When monitoring anti-Xa in these patients, perform sampling 4-6 hrs after FRAGMIN (dalteparin) dosing and only after the patient has received 3-4 doses.

Administration

Subcutaneous injection technique: Patients should be sitting or lying down and FRAGMIN (dalteparin) administered by deep subcutaneous injection. FRAGMIN (dalteparin) may be injected in a U-shape area around the navel, the upper outer side of the thigh or the upper outer quadrangle of the buttock. The injection site should be varied daily. When the area around the navel or the thigh is used, using the thumb and forefinger, you must lift up a fold of skin while giving the injection. The entire length of the needle should be inserted at a 45 to 90 degree angle.

Inspect FRAGMIN (dalteparin) prefilled syringes and vials visually for particulate matter and discoloration prior to administration

After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks. Discard any unused solution after 2 weeks.

Instructions for using the prefilled single-dose syringes preassembled with needle guard devices

Prefilled single-dose syringe - Illustration

Fixed dose syringes

To ensure delivery of the full dose, do not expel the air bubble from the prefilled syringe before injection. Hold the syringe assembly by the open sides of the device. Remove the needle shield. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

Graduated syringes

Hold the syringe assembly by the open sides of the device. Remove the needle shield. With the needle pointing up, prepare the syringe by expelling the air bubble and then continuing to push the plunger to the desired dose or volume, discarding the extra solution in an appropriate manner. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose remaining in the syringe has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

HOW SUPPLIED

Dosage Forms And Strengths

2,500 IU / 0.2 mL single-dose prefilled syringe
5,000 IU / 0.2 mL single-dose prefilled syringe
7,500 IU / 0.3 mL single-dose prefilled syringe
10,000 IU / 0.4 mL single-dose prefilled syringe
10,000 IU / 1 mL single-dose graduated syringe
12,500 IU / 0.5 mL single-dose prefilled syringe
15,000 IU / 0.6 mL single-dose prefilled syringe
18,000 IU / 0.72 mL single-dose prefilled syringe
95,000 IU / 3.8 mL multiple-dose vial
95,000 IU / 9.5 mL multiple-dose vial

Storage And Handling

After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks.

Dosage Form Strength Package Size NDC Number
Single-dose prefilled syringe1 2,500 IU / 0.2 mL 10 Syringes 62856-250-10
5,000 IU / 0.2 mL 10 Syringes 62856-500-10
7,500 IU / 0.3 mL 10 Syringes 62856-750-10
10,000 IU / 0.4 mL 10 Syringes 62856-100-10
Single-dose graduated syringe2 10,000 IU / 1 mL 10 Syringes 62856-101-10
Single-dose prefilled syringe1 12,500 IU / 0.5 mL 10 Syringes 62856-125-10
15,000 IU / 0.6 mL 10 Syringes 62856-150-10
18,000 IU / 0.72 mL 10 Syringes 62856-180-10
Multiple dose vial 95,000 IU / 3.8 mL 3.8 mL vial 62856-251-01
Multiple dose vial 95,000 IU / 9.5 mL 9.5 mL Vial 62856-102-01
1 Single-dose prefilled syringe, affixed with a 27-gauge x ½ inch needle and preassembled with UltraSafe Passive™ Needle Guard devices.
2 Single-dose graduated syringe, affixed with a 27-gauge x ½ inch needle and preassembled with UltraSafe Passive™ Needle Guard devices. UltraSafe Passive™ Needle Guard is a trademark of Safety Syringes, Inc.

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

Manufactured for : Eisai Inc., Woodcliff Lake, NJ 07677. Manufactured by : Pfizer Inc New York, NY 10017. Made in Belgium, (multiple-dose vials), Jointly. manufactured by : Pfizer Inc, New York, NY 10017 and Vetter Pharma-Fertigung, GmbH & Co. KG, Ravensburg, Germany (prefilled syringes)

Last reviewed on RxList: 12/2/2010
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Clinical Trials 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 accurately reflect the rates observed in practice.

Hemorrhage

The incidence of hemorrhagic complications during treatment with FRAGMIN (dalteparin) Injection has been low. The most commonly reported side effect is hematoma at the injection site. The risk for bleeding varies with the indication and may increase with higher doses.

Unstable Angina and Non-Q-Wave Myocardial Infarction

Table 5 summarizes major bleeding reactions that occurred with FRAGMIN (dalteparin) , heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.

Table 5 : Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction

Indication Dosing Regimen
Unstable Angina and Non-Q-Wave MI FRAGMIN (dalteparin) 120 IU/kg/12 hr subcutaneous1
n (%)
Heparin2 intravenous and subcutaneous2
n (%)
Placebo every 12 hr subcutaneous
n (%)
Major Bleeding Reactions3,4 15/1497 (1.0) 7/731 (1.0) 4/760 (0.5)
1 Treatment was administered for 5 to 8 days.
2 Heparin intravenous infusion for at least 48 hours, APTT 1.5 to 2 times control, then 12,500 U subcutaneously every 12 hours for 5 to 8 days
3 Aspirin (75 to 165 mg per day) and beta blocker therapies were administered concurrently.
4 Bleeding reactions were considered major if: 1) accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) a transfusion was required; 3) bleeding led to interruption of treatment or death; or 4) intracranial bleeding

Hip Replacement Surgery

Table 6 summarizes: 1) all major bleeding reactions and, 2) other bleeding reactions possibly or probably related to treatment with FRAGMIN (dalteparin) (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.

Table 6 : Bleeding Reactions Following Hip Replacement Surgery

Indication FRAGMIN vs Warfarin Sodium FRAGMIN vs Heparin
Dosing Regimen Dosing Regimen
Hip Replacement Surgery FRAGMIN2 5000 IU once daily subcutaneous n (%) Warfarin Sodium1 oral n (%) FRAGMIN4 5000 IU once daily subcutaneous n (%) Heparin 5000 U three times a day subcutaneous n (%)
Major Bleeding Reactions3 7/274 (2.6) 1/279 (0.4) 0 3/69 (4.3)
Other Bleeding Reactions5Hematuria 8/274 (2.9) 5/279 (1.8) 0 0
Wound Hematoma 6/274 (2.2) 0 0 0
Injection Site Hematoma 3/274 (1.1) NA 2/69 (2.9) 7/69 (10.1)
1 Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of approximately 2.5.
2 Includes three treated patients who did not undergo a surgical procedure.
3 A bleeding event was considered major if: 1) hemorrhage caused a significant clinical event, 2) it was associated with a hemoglobin decrease of ≥ 2 g/dL or transfusion of 2 or more units of blood products, 3) it resulted in reoperation due to bleeding, or 4) it involved retroperitoneal or intracranial hemorrhage.
4 Includes two treated patients who did not undergo a surgical procedure.
5 Occurred at a rate of at least 2% in the group treated with FRAGMIN (dalteparin) 5000 IU once daily.

Six of the patients treated with FRAGMIN (dalteparin) experienced seven major bleeding reactions. Two of the reactions were wound hematoma (one requiring reoperation), three were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding. None of the patients experienced retroperitoneal or intracranial hemorrhage or died of bleeding complications.

In the third hip replacement surgery clinical trial, the incidence of major bleeding reactions was similar in all three treatment groups: 3.6% (18/496) for patients who started FRAGMIN (dalteparin) before surgery; 2.5% (12/487) for patients who started FRAGMIN (dalteparin) after surgery; and 3.1% (15/489) for patients treated with warfarin sodium.

Abdominal Surgery

Table 7 summarizes bleeding reactions that occurred in clinical trials which studied FRAGMIN (dalteparin) 2500 and 5000 IU administered once daily to abdominal surgery patients.

Table 7 : Bleeding Reactions Following Abdominal Surgery

Indication FRAGMIN vs Placebo FRAGMIN vs FRAGMIN
Dosing Regimen Dosing Regimen
Abdominal Surgery FRAGMIN (dalteparin) 2500 IU
once daily subcutaneous
n (%)
Placebo once daily subcutaneous
n (%)
FRAGMIN (dalteparin) 2500 IU once daily subcutaneous
n (%)
FRAGMIN (dalteparin) 5000 IU
once daily subcutaneous
n (%)
Postoperative 14/182 13/182 89/1025 125/1033
Transfusions (7.7) (7.1) (8.7) (12.1)
Wound 2/79 2/77 1/1030 4/1039
Hematoma (2.5) (2.6) (0.1) (0.4)
Reoperation 1/79 1/78 2/1030 13/1038
Due to Bleeding (1.3) (1.3) (0.2) (1.3)
Injection Site 8/172 2/174 36/1026 57/1035
Hematoma (4.7) (1.1) (3.5) (5.5)
Postoperative 26/459 36/454 81/508 63/498
Transfusions (5.7) (7.9) (15.9) (12.7)
Wound 16/467 18/467 12/508 6/498
Hematoma (3.4) (3.9) (2.4) (1.2)
Reoperation 2/392 3/392 4/508 2/498
Due to Bleeding (0.5) (0.8) (0.8) (0.4)
Injection Site 1/466 5/464 36/506 47/493
Hematoma (0.2) (1.1) (7.1) (9.5)

In a trial comparing FRAGMIN (dalteparin) 5000 IU once daily to FRAGMIN (dalteparin) 2500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding reactions was 4.6% and 3.6%, respectively (n.s.). In a trial comparing FRAGMIN (dalteparin) 5000 IU once daily to heparin 5000 U twice daily, in the malignancy subgroup the incidence of bleeding reactions was 3.2% and 2.7%, respectively for FRAGMIN (dalteparin) and Heparin (n.s.).

Medical Patients with Severely Restricted Mobility During Acute Illness

Table 8 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.

Table 8 : Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness

Indication Dosing Regimen
Medical Patients with Severely Restricted Mobility FRAGMIN (dalteparin) 5000 IU once daily subcutaneous
n (%)
Placebo once daily subcutaneous
n (%)
Major Bleeding Reactions1 at Day 14 8/1848 (0.4) 0/1833 (0)
Major Bleeding Reactions1 at Day 21 9/1848 (0.5) 3/1833 (0.2)
1 A bleeding event was considered major if: 1) it was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) intraocular, spinal/epidural, intracranial, or retroperitoneal bleeding; 3) required transfusion of ≥ 2 units of blood products; 4) required significant medical or surgical intervention; or 5) led to death.

Three of the major bleeding reactions that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with FRAGMIN (dalteparin) and one in the group receiving placebo).

Patients with Cancer and Acute Symptomatic Venous Thromboembolism

Table 9 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding event was considered major if it: 1) was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) occurred at a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); 3) required transfusion of ≥ 2 units of blood products; or 4) led to death. Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding.

At the end of the six-month study, a total of 46 (13.6%) patients in the FRAGMIN (dalteparin) arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the FRAGMIN (dalteparin) arm at Day 71) was fatal.

Table 9 : Bleeding Reactions (Major and Any) (As treated population)1

Study period FRAGMIN 200 IU/kg (max. 18,000 IU) subcutaneous once daily x 1 month, then 150 IU/kg (max. 18,000 IU) subcutaneous once daily x 5 months OAC FRAGMIN 200 IU/kg (max 18,000 IU) subcutaneous once daily x 5-7 days and OAC for 6 months (target INR 2-3)
Number
at risk
Patients with Major Bleeding
n (%)
Patients with Any
Bleeding
n (%)
Number at risk Patients with Major Bleeding
n (%)
Patients with Any Bleeding
n (%)
Total during study 338 19 (5.6) 46 (13.6) 335 12 (3.6) 62 (18.5)
Week1 338 4 (1.2) 15 (4.4) 335 4 (1.2) 12 (3.6)
Weeks 2-4 332 9 (2.7) 17 (5.1) 321 1 (0.3) 12 (3.7)
Weeks 5-28 297 9 (3.0) 26 (8.8) 267 8 (3.0) 40 (15.0)
1 Patients with multiple bleeding episodes within any time interval were counted only once in that interval. However, patients with multiple bleeding episodes that occurred at different time intervals were counted once in each interval in which the event occurred.

Thrombocytopenia

[See WARNINGS AND PRECAUTIONS]

Elevations of Serum Transaminases

In FRAGMIN (dalteparin) clinical trials supporting non-cancer indications, where hepatic transaminases were measured, asymptomatic increases in transaminase levels (SGOT/AST and SGPT/ALT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients during treatment with FRAGMIN (dalteparin) .

In the FRAGMIN (dalteparin) clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with FRAGMIN (dalteparin) for up to 6 months, asymptomatic increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of patients, respectively. The frequencies of Grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCICTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively.

Other

Allergic Reactions: Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bullous eruption) have occurred. Cases of anaphylactoid reactions have been reported.

Local Reactions: Pain at the injection site, the only non-bleeding event determined to be possibly or probably related to treatment with FRAGMIN (dalteparin) and reported at a rate of at least 2% in the group treated with FRAGMIN (dalteparin) , was reported in 4.5% of patients treated with FRAGMIN (dalteparin) 5000 IU once daily vs 11.8% of patients treated with heparin 5000 U twice daily in the abdominal surgery trials. In the hip replacement trials, pain at injection site was reported in 12% of patients treated with FRAGMIN (dalteparin) 5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day.

Post-Marketing Experience

The following adverse reactions have been identified during postapproval use of FRAGMIN (dalteparin) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of dalteparin sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had postoperative indwelling epidural catheters placed for analgesia or received additional drugs affecting hemostasis. In some cases the hematoma resulted in long-term or permanent paralysis (partial or complete). [see BOXED WARNING]

Skin necrosis has occurred. There have been cases of alopecia reported that improved on drug discontinuation.

Read the Fragmin (dalteparin) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Use FRAGMIN (dalteparin) with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding [see WARNING AND PRECAUTIONS].

Last reviewed on RxList: 12/2/2010
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Increased Risk of Hemorrhage

Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture..The risk of these events is higher with the use of post-operative indwelling epidural catheters with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity. [ see BOXED WARNING, ADVERSE REACTIONS and DRUG INTERACTIONS.

Thrombocytopenia

Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN (dalteparin) . The incidence of this complication is unknown at present. In clinical practice, cases of thrombocytopenia with thrombosis, amputation and death have been observed.[See CONTRAINDICATIONS] Closely monitor thrombocytopenia of any degree.

In FRAGMIN (dalteparin) clinical trials supporting non-cancer indications, platelet counts of < 50,000/mm³ occurred in < 1% of patients.

In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the FRAGMIN (dalteparin) treatment arm, platelet counts of < 100,000/mm³ occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm³. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the FRAGMIN (dalteparin) arm and 8.1% of patients in the OAC arm. FRAGMIN (dalteparin) dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm³.

Benzyl Alcohol

Each multiple-dose vial of FRAGMIN (dalteparin) contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants. Because benzyl alcohol may cross the placenta, use caution when administering FRAGMIN (dalteparin) preserved with benzyl alcohol to pregnant women. If anticoagulation with FRAGMIN (dalteparin) is needed during pregnancy, use preservative-free formulations, where possible [See Use In Specific Populations].

Laboratory Tests

Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with FRAGMIN (dalteparin) . When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of FRAGMIN (dalteparin) activity and, therefore, unsuitable for monitoring the anticoagulant effect of FRAGMIN (dalteparin) . Anti-Factor Xa may be used to monitor the anticoagulant effect of FRAGMIN (dalteparin) , such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding occurs during FRAGMIN (dalteparin) therapy.

Nonclinical Toxicology

Carcinogenicity, Mutagenesis, Impairment of Fertility

Dalteparin sodium has not been tested for its carcinogenic potential in long-term animal studies. It was not mutagenic in the in vitro Ames Test, mouse lymphoma cell forward mutation test and human lymphocyte chromosomal aberration test and in the in vivo mouse micronucleus test. Dalteparin sodium at subcutaneous doses up to 1200 IU/kg (7080 IU/m²) did not affect the fertility or reproductive performance of male and female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of FRAGMIN (dalteparin) use in pregnant women. In reproductive and developmental toxicity studies, pregnant rats and rabbits received dalteparin sodium at intravenous doses up to 2400 IU/kg (14,160 IU/m²) (rats) and 4800 IU/kg (40,800 IU/m²) (rabbits). These exposures were 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 IU/kg dalteparin based on the body surface area. No evidence of impaired fertility or harm to the fetuses occurred in these studies. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Cases of “Gasping Syndrome” have occurred in premature infants when large amounts of benzyl alcohol have been administered (99–404 mg/kg/day). The 9.5 mL and the 3.8 mL multiple-dose vials of FRAGMIN (dalteparin) contain 14 mg/mL of benzyl alcohol [see WARNINGS AND PRECAUTIONS].

Nursing Mothers

Based on limited published data dalteparin is minimally excreted in human milk. One study of 15 lactating women receiving prophylactic doses of dalteparin, in the immediate postpartum period, detected small amounts of anti-Xa activity (range < 0.005 to 0.037 IU/mL) in breast milk that were equivalent to a milk/plasma ratio of < 0.025-0.224. Oral absorption of LMWH is extremely low, but the clinical implications, if any, of this small amount of anticoagulant activity on a nursing infant are unknown. Caution should be exercised when FRAGMIN (dalteparin) is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of patients in clinical studies of FRAGMIN (dalteparin) , 5516 patients were 65 years of age or older and 2237 were 75 or older. No overall differences in effectiveness were observed between these subjects and younger subjects. Some studies suggest that the risk of bleeding increases with age. Postmarketing surveillance and literature reports have not revealed additional differences in the safety of FRAGMIN (dalteparin) between elderly and younger patients. Give careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) in geriatric patients, particularly in those with low body weight ( < 45 kg) and those predisposed to decreased renal function [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]

Last reviewed on RxList: 12/2/2010
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

An excessive dosage of FRAGMIN (dalteparin) Injection may lead to hemorrhagic complications. These may generally be stopped by slow intravenous injection of protamine sulfate (1% solution), at a dose of 1 mg protamine for every 100 anti-Xa IU of FRAGMIN (dalteparin) given. If the APTT measured 2 to 4 hours after the first infusion remains prolonged, a second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of FRAGMIN (dalteparin) may be administered. Even with these additional doses of protamine, the APTT may remain more prolonged than would usually be found following administration of unfractionated heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60 to 75%).

Take particular care to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, give protamine sulfate only when resuscitation techniques and treatment for anaphylactic shock are readily available. For additional information, consult the labeling of Protamine Sulfate Injection, USP, products.

CONTRAINDICATIONS

  • Active major bleeding
  • History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis.
  • Hypersensitivity to dalteparin sodium (e.g., pruritis, rash, anaphylactic reactions) [see ADVERSE REACTIONS]
  • In patients undergoing Epidural/Neuraxial anesthesia, do not administer FRAGMIN [See BOXED WARNING];
    • As a treatment for unstable angina and non–Q-wave MI
    • For prolonged VTE prophylaxis.
  • Hypersensitivity to heparin or pork products

Last reviewed on RxList: 12/2/2010
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

Dalteparin is a low molecular weight heparin with antithrombotic properties. It acts by enhancing the inhibition of Factor Xa and thrombin by antithrombin. In humans, dalteparin potentiates preferentially the inhibition of coagulation Factor Xa, while only slightly affecting the activated partial thromboplastin time (APTT).

Pharmacodynamics

Doses of FRAGMIN (dalteparin) Injection of up to 10,000 anti-Factor Xa IU administered subcutaneously as a single dose or two 5000 IU doses 12 hours apart to healthy subjects did not produce a significant change in platelet aggregation, fibrinolysis, or global clotting tests such as prothrombin time (PT), thrombin time (TT) or APTT. Subcutaneous administration of doses of 5000 IU twice daily of FRAGMIN (dalteparin) for seven consecutive days to patients undergoing abdominal surgery did not markedly affect APTT, Platelet Factor 4 (PF4), or lipoprotein lipase.

Pharmacokinetics

Mean peak levels of plasma anti-Factor Xa activity following single subcutaneous doses of 2500, 5000 and 10,000 IU were 0.19 ± 0.04, 0.41 ± 0.07 and 0.82 ± 0.10 IU/mL, respectively, and were attained in about 4 hours in most subjects. Absolute bioavailability in healthy volunteers, measured as the anti-Factor Xa activity, was 87 ± 6%. Increasing the dose from 2500 to 10,000 IU resulted in an overall increase in anti-Factor Xa AUC that was greater than proportional by about one-third.

Peak anti-Factor Xa activity increased more or less linearly with dose over the same dose range. There appeared to be no appreciable accumulation of anti-Factor Xa activity with twice-daily dosing of 100 IU/kg subcutaneously for up to 7 days.

The volume of distribution for dalteparin anti-Factor Xa activity was 40 to 60 mL/kg. The mean plasma clearances of dalteparin anti-Factor Xa activity in normal volunteers following single intravenous bolus doses of 30 and 120 anti-Factor Xa IU/kg were 24.6 ± 5.4 and 15.6 ± 2.4 mL/hr/kg, respectively. The corresponding mean disposition half-lives were 1.47 ± 0.3 and 2.5 ± 0.3 hours.

Following intravenous doses of 40 and 60 IU/kg, mean terminal half-lives were 2.1 ± 0.3 and 2.3 ± 0.4 hours, respectively. Longer apparent terminal half-lives (3 to 5 hours) are observed following subcutaneous dosing, possibly due to delayed absorption. In patients with chronic renal insufficiency requiring hemodialysis, the mean terminal half-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU FRAGMIN (dalteparin) was 5.7 ± 2.0 hours, i.e. considerably longer than values observed in healthy volunteers, therefore, greater accumulation can be expected in these patients.

Clinical Studies

Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

In a double-blind, randomized, placebo-controlled clinical trial, patients who recently experienced unstable angina with EKG changes or non-Q-wave myocardial infarction (MI) were randomized to FRAGMIN (dalteparin) Injection 120 IU/kg or placebo every 12 hours subcutaneously. In this trial, unstable angina was defined to include only angina with EKG changes. All patients, except when contraindicated, were treated concurrently with aspirin (75 mg once daily) and beta blockers. Treatment was initiated within 72 hours of the event (the majority of patients received treatment within 24 hours) and continued for 5 to 8 days. A total of 1506 patients were enrolled and treated; 746 received FRAGMIN (dalteparin) and 760 received placebo. The mean age of the study population was 68 years (range 40 to 90 years) and the majority of patients were white (99.7%) and male (63.9%). The combined incidence of the endpoint of death or myocardial infarction was lower for FRAGMIN (dalteparin) compared with placebo at 6 days after initiation of therapy. These results were observed in an analysis of all-randomized and all-treated patients. The combined incidence of death, MI, need for intravenous heparin or intravenous. nitroglycerin, and revascularization was also lower for FRAGMIN (dalteparin) than for placebo (see Table 10).

Table 10 : Efficacy of FRAGMIN (dalteparin) in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

Indication Dosing Regimen
FRAGMIN (dalteparin) 120 IU/kg/every 12 hr subcutaneous
n (%)
Placebo every12 hr subcutaneous
n (%)
All Treated Unstable Angina and Non-Q-Wave MI Patients 746 760
Primary Endpoints - 6 day timepoint Death, MI 13/741 (1.8)1 36/757 (4.8)
Secondary Endpoints - 6 day timepoint Death, MI, intravenous heparin, i.v. nitroglycerin, Revascularization 59/739 (8.0)1 106/756 (14.0)
1 p-value = 0.001

 In a second randomized, controlled trial designed to evaluate long-term treatment with FRAGMIN (dalteparin) (days 6 to 45), data were also collected comparing 1-week (5 to 8 days) treatment of FRAGMIN (dalteparin) 120 IU/kg every 12 hours subcutaneously with heparin at an APTT-adjusted dosage. All patients, except when contraindicated, were treated concurrently with aspirin (100 to 165 mg per day). Of the 1499 patients enrolled, 1482 patients were treated; 751 received FRAGMIN (dalteparin) and 731 received heparin. The mean age of the study population was 64 years (range 25 to 92 years) and the majority of patients were white (96.0%) and male (64.2%). The incidence of the combined endpoint of death, myocardial infarction, or recurrent angina during this 1-week treatment period (5 to 8 days) was 9.3% for FRAGMIN (dalteparin) and 7.6% for heparin (p=0.323).

Prophylaxis of Deep Vein Thrombosis in Patients Following Hip Replacement Surgery

In an open-label randomized study, FRAGMIN (dalteparin) 5000 IU administered once daily subcutaneously was compared with warfarin sodium, administered orally, in patients undergoing hip replacement surgery. Treatment with FRAGMIN (dalteparin) was initiated with a 2500 IU dose subcutaneously within 2 hours before surgery, followed by a 2500 IU dose subcutaneously the evening of the day of surgery. Then, a dosing regimen of FRAGMIN (dalteparin) 5000 IU subcutaneously once daily was initiated on the first postoperative day. The first dose of warfarin sodium was given the evening before surgery, then continued daily at a dose adjusted for INR 2 to 3. Treatment in both groups was then continued for 5 to 9 days postoperatively. Of the 580 patients enrolled, 553 were treated and 550 underwent surgery. Of those who underwent surgery, 271 received FRAGMIN (dalteparin) and 279 received warfarin sodium. The mean age of the study population was 63 years (range 20 to 92 years) and the majority of patients were white (91.1%) and female (52.9%). The incidence of deep vein thrombosis (DVT), as determined by evaluable venography, was significantly lower for the group treated with FRAGMIN (dalteparin) compared with patients treated with warfarin sodium (see Table 11).

Table 11 : Efficacy of FRAGMIN (dalteparin) in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery

Indication Dosing Regimen
FRAGMIN (dalteparin) 5000 IU once daily1 subcutaneous
n (%)
Warfarin Sodium once daily 2 oral
n (%)
All Treated Hip Replacement Surgery Patients 271 279
Treatment Failures in Evaluable Patients DVT, Total 28/192 (14.6)3 49/190 (25.8)
Proximal DVT 10/192 (5.2)4 16/190 (8.4)
PE 2/271 (0.7) 2/279 (0.7)
1 The daily dose on the day of surgery was divided: 2500 IU was given two hours before surgery and again in the evening of the day of surgery.
2 Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of approximately 2.5
3 p-value = 0.006
4 p-value = 0.185

In a second single-center, double-blind study of patients undergoing hip replacement surgery, FRAGMIN (dalteparin) 5000 IU once daily subcutaneously starting the evening before surgery, was compared with heparin 5000 U subcutaneously three times a day, starting the morning of surgery. Treatment in both groups was continued for up to 9 days postoperatively. Of the 140 patients enrolled, 139 were treated and 136 underwent surgery. Of those who underwent surgery, 67 received FRAGMIN (dalteparin) and 69 received heparin. The mean age of the study population was 69 years (range 42 to 87 years) and the majority of patients were female (58.8%). In the intent-to-treat analysis, the incidence of proximal DVT was significantly lower for patients treated with FRAGMIN (dalteparin) compared with patients treated with heparin (6/67 vs 18/69; p=0.012). The incidence of pulmonary embolism detected by lung scan was also significantly lower in the group treated with FRAGMIN (dalteparin) (9/67 vs 19/69; p=0.032).

A third multi-center, double-blind, randomized study evaluated a postoperative dosing regimen of FRAGMIN (dalteparin) for thromboprophylaxis following total hip replacement surgery. Patients received either FRAGMIN (dalteparin) or warfarin sodium, randomized into one of three treatment groups. One group of patients received the first dose of FRAGMIN (dalteparin) 2500 IU subcutaneous within 2 hours before surgery, followed by another dose of FRAGMIN (dalteparin) 2500 IU subcutaneous at least 4 hours (6.6 ± 2.3 hr) after surgery. Another group received the first dose of FRAGMIN (dalteparin) 2500 IU subcutaneous at least 4 hours (6.6 ± 2.4 hr) after surgery. Then, both of these groups began a dosing regimen of FRAGMIN (dalteparin) 5000 IU once daily subcutaneous on postoperative day 1. The third group of patients received warfarin sodium the evening of the day of surgery, then continued daily at a dose adjusted to maintain INR 2 to 3. Treatment for all groups was continued for 4 to 8 days postoperatively, after which time all patients underwent bilateral venography.

In the total enrolled study population of 1501 patients, 1472 patients were treated; 496 received FRAGMIN (dalteparin) (first dose before surgery), 487 received FRAGMIN (dalteparin) (first dose after surgery) and 489 received warfarin sodium. The mean age of the study population was 63 years (range 18 to 91 years) and the majority of patients were white (94.4%) and female (51.8%).

Administration of the first dose of FRAGMIN (dalteparin) after surgery was as effective in reducing the incidence of thromboembolic reactions as administration of the first dose of FRAGMIN (dalteparin) before surgery (44/336 vs 37/338; p=0.448). Both dosing regimens of FRAGMIN (dalteparin) were more effective than warfarin sodium in reducing the incidence of thromboembolic reactions following hip replacement surgery.

Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications

Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes, or who have additional risk factors such as malignancy or a history of deep vein thrombosis or pulmonary embolism.

FRAGMIN (dalteparin) administered once daily subcutaneously beginning prior to surgery and continued for 5 to 10 days after surgery, reduced the risk of DVT in patients at risk for thromboembolic complications in two double-blind, randomized, controlled clinical trials performed in patients undergoing major abdominal surgery. In the first study, a total of 204 patients were enrolled and treated; 102 received FRAGMIN (dalteparin) and 102 received placebo. The mean age of the study population was 64 years (range 40 to 98 years) and the majority of patients were female (54.9%). In the second study, a total of 391 patients were enrolled and treated; 195 received FRAGMIN (dalteparin) and 196 received heparin. The mean age of the study population was 59 years (range 30 to 88 years) and the majority of patients were female (51.9%). FRAGMIN (dalteparin) 2500 IU was superior to placebo and similar to heparin in reducing the risk of DVT (see Tables 12 and 13).

Table 12 : Efficacy of FRAGMIN (dalteparin) in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery

Indication Dosing Regimen
FRAGMIN (dalteparin) 2500 IU once daily subcutaneous
n (%)
Placebo once daily subcutaneous
n (%)
All Treated Abdominal Surgery Patients 102 102
Treatment Failures in Evaluable Patients Total Thromboembolic Reactions 4/91 (4.4)1 16/91 (17.6)
Proximal DVT 0 5/91 (5.5)
Distal DVT 4/91 (4.4) 11/91 (12.1)
PE 0 2/91 (2.2)2
1 p-value = 0.008
2 Both patients also had DVT, 1 proximal and 1 distal

Table 13 : Efficacy of FRAGMIN (dalteparin) in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery

Indication Dosing Regimen
FRAGMIN (dalteparin) 2500 IU once daily subcutaneous
n (%)
Heparin 5000 U twice daily subcutaneous
n (%)
All Treated Abdominal Surgery Patients 195 196
Treatment Failures in Evaluable Patients Total Thromboembolic Reactions 7/178 (3.9)1 7/174 (4.0)
  Proximal DVT 3/178 (1.7) 4/174 (2.3)
  Distal DVT 3/178 (1.7) 3/174 (1.7)
PE 1/178 (0.6) 0
1 p-value = 0.74

In a third double-blind, randomized study performed in patients undergoing major abdominal surgery with malignancy, FRAGMIN (dalteparin) 5000 IU subcutaneous once daily was compared with FRAGMIN (dalteparin) 2500 IU subcutaneous once daily. Treatment was continued for 6 to 8 days. A total of 1375 patients were enrolled and treated; 679 received FRAGMIN (dalteparin) 5000 IU and 696 received 2500 IU. The mean age of the combined groups was 71 years (range 40 to 95 years). The majority of patients were female (51.0%). FRAGMIN (dalteparin) 5000 IU once daily was more effective than FRAGMIN (dalteparin) 2500 IU once daily in reducing the risk of DVT in patients undergoing abdominal surgery with malignancy (see Table 14).

Table 14 : Efficacy of FRAGMIN (dalteparin) in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery

Indication Dosing Regimen
FRAGMIN (dalteparin) 2500 IU once daily subcutaneous
n (%)
FRAGMIN (dalteparin) 5000 IU once daily subcutaneous
n (%)
All Treated Abdominal Surgery Patients1 696 679
Treatment Failures in Evaluable Patients Total Thromboembolic Reactions 99/656 (15.1)2 60/645 (9.3)
  Proximal DVT 18/657 (2.7) 14/646 (2.2)
  Distal DVT 80/657 (12.2) 41/646 (6.3)
PE  
  Fatal 1/674 (0.1) 1/669 (0.1)
  Non-fatal 2 4
1 Major abdominal surgery with malignancy
2 p-value = 0.001

Prophylaxis of Deep Vein Thrombosis in Medical Patients at Risk for Thromboembolic Complications Due to Severely Restricted Mobility During Acute Illness

In a double-blind, multi-center, randomized, placebo-controlled clinical trial, general medical patients with severely restricted mobility who were at risk of venous thromboembolism were randomized to receive either FRAGMIN (dalteparin) 5000 IU or placebo subcutaneously once daily during Days 1 to 14 of the study. These patients had an acute medical condition requiring a projected hospital stay of at least 4 days, and were confined to bed during waking hours. The study included patients with congestive heart failure (NYHA Class III or IV), acute respiratory failure not requiring ventilatory support, and the following acute conditions with at least one risk factor occurring in > 1% of treated patients: acute infection (excluding septic shock), acute rheumatic disorder, acute lumbar or sciatic pain, vertebral compression, or acute arthritis of the lower extremities. Risk factors include > 75 years of age, cancer, previous DVT/PE, obesity and chronic venous insufficiency. A total of 3681 patients were enrolled and treated: 1848 received FRAGMIN (dalteparin) and 1833 received placebo. The mean age of the study population was 69 years (range 26 to 99 years), 92.1% were white and 51.9% were female. The primary efficacy endpoint was evaluated at Day 21 and was defined as at least one of the following within Days 1 to 21 of the study: asymptomatic DVT (diagnosed by compression ultrasound), a confirmed symptomatic DVT, a confirmed pulmonary embolism or sudden death. The follow-up extended through Day 90

When given at a dose of 5000 IU once a day subcutaneously, FRAGMIN (dalteparin) significantly reduced the incidence of thromboembolic reactions including verified DVT by Day 21 (see Table 15). The prophylactic effect was sustained through Day 90.

Table 15 : Efficacy of FRAGMIN (dalteparin) in the Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility During Acute Illness

Indication Dosing Regimen
FRAGMIN (dalteparin) 5000 IU once daily subcutaneous
n (%)
Placebo once daily subcutaneous
n (%)
All Treated Medical Patients During Acute Illness 1848 1833
Treatment failure in evaluable patients (Day 21)1 DVT, PE, or sudden death 42/1518 (2.8)2 73/1473 (5.0)
Total thromboembolic reactions (Day 21) 37/1513 (2.5) 70/1470 (4.8)
Total DVT 32/1508 (2.1) 64/1464 (4.4)
Proximal DVT 29/1518 (1.9) 60/1474 (4.1)
Symptomatic VTE 10/1759 (0.6) 17/1740 (1.0)
PE 5/1759 (0.3) 6/1740 (0.3)
Sudden Death 5/1829 (0.3) 3/1807 (0.2)
1 Defined as DVT (diagnosed by compression ultrasound at Day 21 + 3), confirmed symptomatic DVT, confirmed PE or sudden death. 22 p-value = 0.0015

Patients with Cancer and Acute Symptomatic Venous Thromboembolism

In a prospective, multi-center, open-label, clinical trial, 676 patients with cancer and newly diagnosed, objectively confirmed acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were studied. Patients were randomized to either FRAGMIN (dalteparin) 200 IU/kg subcutaneous (max 18,000 IU subcutaneous daily for one month) then 150 IU/kg subcutaneous (max 18,000 IU subcutaneous daily for five months (FRAGMIN (dalteparin) arm) or FRAGMIN (dalteparin) 200 IU/kg subcutaneous (max 18,000 IU subcutaneous daily for five to seven days and oral anticoagulant for six months (OAC arm). In the OAC arm, oral anticoagulation was adjusted to maintain an INR of 2 to 3. Patients were evaluated for recurrence of symptomatic venous thromboembolism (VTE) every two weeks for six months.

The median age of patients was 64 years (range: 22 to 89 years); 51.5% of patients were females; 95.3% of patients were Caucasians. Types of tumors were: gastrointestinal tract (23.7%), genito-urinary (21.5%), breast (16%), lung (13.3%), hematological tumors (10.4%) and other tumors (15.1%).

A total of 27 (8.0%) and 53 (15.7%) patients in the FRAGMIN (dalteparin) and OAC arms, respectively, experienced at least one episode of an objectively confirmed, symptomatic DVT and/or PE during the 6-month study period. Most of the difference occurred during the first month of treatment (see Table 16). The benefit was maintained over the 6-month study period.

Table 16 : Recurrent VTE in Patients with Cancer (Intention to treat population)1

Study Period FRAGMIN arm OAC arm
FRAGMIN 200 IU/kg (max. 18,000 IU) subcutaneous once daily x 1 month, then 150 IU/kg (max. 18,000 IU) subcutaneous once daily x 5 months FRAGMIN 200 IU/kg (max 18,000 IU) subcutaneous once daily x 5-7 days and OAC for 6 months (target INR 2-3)
Number at Risk Patients with VTE % Number at Risk Patients with VTE %
Total 338 27 8.0 338 53 15.7
Week 1 338 5 1.5 338 8 2.4
Weeks 2-4 331 6 1.8 327 25 7.6
Weeks 5-28 307 16 5.2 284 20 7.0
1 Three patients in the FRAGMIN arm and 5 patients in the OAC arm experienced more than 1 VTE over the 6-month study period.

In the intent-to-treat population that included all randomized patients, the primary comparison of the cumulative probability of the first VTE recurrence over the 6month study period was statistically significant (p < 0.01) in favor of the FRAGMIN (dalteparin) arm, with most of the treatment difference evident in the first month.

Last reviewed on RxList: 12/2/2010
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, inform the patients to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur the patient should contact his or her physician immediately.

Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Discontinue their use prior to dalteparin therapy whenever possible; if coadministration is essential, the patient's clinical and laboratory status should be closely monitored [see DRUG INTERACTIONS].

Inform patients:

  • of the instructions for injecting FRAGMIN (dalteparin) if their therapy is to continue after discharge from the hospitals.
  • it may take them longer than usual to stop bleeding.
  • they may bruise and/or bleed more easily when they are treated with FRAGMIN (dalteparin) .
  • they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician [see WARNINGS AND PRECAUTIONS ].
  • to tell their physicians and dentists they are taking FRAGMIN (dalteparin) and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken [see WARNINGS AND PRECAUTIONS].
  • to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs [see DRUG INTERACTIONS].

Last reviewed on RxList: 12/2/2010
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, inform the patients to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur the patient should contact his or her physician immediately.

Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Discontinue their use prior to dalteparin therapy whenever possible; if coadministration is essential, the patient's clinical and laboratory status should be closely monitored [see DRUG INTERACTIONS].

Inform patients:

  • of the instructions for injecting FRAGMIN (dalteparin) if their therapy is to continue after discharge from the hospitals.
  • it may take them longer than usual to stop bleeding.
  • they may bruise and/or bleed more easily when they are treated with FRAGMIN (dalteparin) .
  • they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician [see WARNINGS AND PRECAUTIONS ].
  • to tell their physicians and dentists they are taking FRAGMIN (dalteparin) and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken [see WARNINGS AND PRECAUTIONS].
  • to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs [see DRUG INTERACTIONS].

Last reviewed on RxList: 12/2/2010
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Fragmin Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

DALTEPARIN - INJECTION

(DAL-te-PAR-in)

COMMON BRAND NAME(S): Fragmin

WARNING: Tell your doctor you are using dalteparin before having certain spinal procedures (spinal puncture or spinal/epidural anesthesia). Use of this medication before these procedures has rarely caused major bleeding or blood clots in or around the spine. This effect may cause paralysis that may be permanent. Discuss the risks and benefits of treatment with your doctor. Tell your doctor immediately if you have any of these serious side effects: tingling, weakness, numbness, trouble urinating, or pain.

This risk is increased when you use other "blood thinning" medications (e.g., aspirin, clopidogrel, warfarin) or NSAIDs (e.g., ibuprofen, ketorolac, naproxen), or when certain medication delivery devices (indwelling epidural catheters) are used. Do not stop taking any prescribed medication without first talking to your doctor.

You will be monitored closely while you are on this medication.

USES: Dalteparin is used to treat or prevent harmful blood clots. Preventing harmful blood clots helps to reduce the risk of a stroke or heart attack. This medication helps keep your blood flowing smoothly by lowering the activity of clotting proteins in the blood. Dalteparin is a type of heparin, and works as an anticoagulant (commonly called a "blood thinner").

Conditions that increase your risk of developing blood clots include certain types of surgeries (e.g., hip replacement or abdominal), long periods of being in one position (immobile), certain types of heart attack, and a certain type of chest pain called unstable angina. For some medical conditions, dalteparin may be used in combination with other "blood thinners."

HOW TO USE: This medication is injected under the skin (subcutaneously) by a healthcare professional. Follow your doctor's directions for using dalteparin. Do not inject into a muscle (intramuscularly). Dosage and length of treatment are based on your medical condition and response to therapy. Dosage may also be based on your weight for some conditions.

If you are giving yourself injections at home, make sure you learn how to prepare and inject this medication properly. Select a different site for each injection. Ask your doctor, pharmacist, or nurse any questions you may have about how to give yourself dalteparin. Learn how to properly dispose of used syringes, needles, and any unused medication. Never reuse needles or syringes.

If you are uncertain how this medication should be used, ask your doctor or pharmacist to explain it to you.

This medication should not be mixed with or added to any other medication in the same syringe. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time(s) each day.

Take this medication exactly as prescribed by your doctor. Do not skip any doses. It is very important to continue taking this medication even if you feel well. Do not stop taking dalteparin without first talking with your doctor.

Disclaimer

Fragmin Consumer (continued)

SIDE EFFECTS: See also Warning section.

Irritation, bruising, or pain at the injection site may occur. If these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication can cause bleeding if its effect on your blood clotting proteins is too strong. Tell your doctor immediately if any of these unlikely but serious signs of bleeding occur: unusual pain/swelling/discomfort, unusual or prolonged bleeding, unusual or easy bruising.

Tell your doctor immediately if any of these rare but very serious signs of bleeding occur: dark urine, black stools, severe headache, confusion, vision changes, unusual dizziness, fainting, seizures, weakness, numbness.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

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

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Fragmin (dalteparin) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before using dalteparin, tell your doctor or pharmacist if you are allergic to it; or to heparins or pork products; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: serious active bleeding.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: artificial heart valves, bleeding or blood disorders (low platelet counts), certain eye problems (hypertensive or diabetic retinopathy), uncontrolled severe high blood pressure, infection of the heart, kidney disease, liver disease, low platelet counts after previous heparin treatment, certain stomach/intestinal problems (e.g., active or recent ulcers), stroke, recent spinal procedures or puncture, spine problems (such as spinal deformity), recent eye/brain/spinal cord surgery.

Limit alcohol while taking this drug because it may increase the risk of stomach bleeding.

Before having surgery, tell your doctor or dentist that you are using dalteparin.

This medication can infrequently cause heavy bleeding. Be extra careful to avoid injuries (e.g., contact sports). Use an electric razor when shaving and a soft toothbrush when brushing your teeth.

The elderly may be at greater risk for bleeding while using this drug.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor. Pregnant women with artificial heart valves need close monitoring (see Notes).

It is unknown if this medication passes into breast milk. Consult with your doctor before breast-feeding.

Disclaimer

Fragmin Consumer (continued)

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because a very serious interaction may occur: mifepristone.

If you are currently using this medication, tell your doctor or pharmacist before starting dalteparin.

Before using dalteparin, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

This medication is sometimes used together with other drugs that have "blood thinning" or anti-platelet effects such as aspirin, clopidogrel, or warfarin. When these combinations are prescribed by your doctor, you will require closer monitoring to minimize your risk of bleeding. Keep all medical and laboratory appointments.

Check all prescription and nonprescription medicine labels carefully since many contain pain relievers/fever reducers (NSAIDs such as ibuprofen, naproxen, or aspirin) which can increase the risk of bleeding/anti-platelet effect when used with dalteparin. Low-dose aspirin, as prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention or to prevent clotting of artificial heart valves (usually these dosages are 81-325 milligrams per day), should be continued. Consult your doctor or pharmacist for more details.

This product may affect the results of certain lab tests. Make sure laboratory personnel and your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include excessive bleeding and bruising.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood counts including hemoglobin, hematocrit and platelets, checking stool for blood) should be performed periodically to monitor your progress or check for side effects. Additional lab tests (anti-factor Xa blood levels) should be performed in certain cases, especially if you have severe kidney disease, are pregnant with artificial heart valves, or if the dalteparin does not appear to be working properly. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store the US product at room temperature between 68-77 degrees F (20-25 degrees C).

Store the Canadian product at room temperature between 59-86 degrees F (15-30 degrees C).

Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507 (Canada).

Information last revised July 2010. Copyright(c) 2010 First Databank, Inc.

Fragmin Patient Information Including Side Effects

Brand Names: Fragmin

Generic Name: dalteparin (Pronunciation: DAL te PAR in)

What is dalteparin (Fragmin)?

Dalteparin is an anticoagulant (blood thinner) that prevents the formation of blood clots.

Dalteparin is used together with aspirin to prevent blood vessel complications in people with certain types of angina (chest pain) or heart attack.

Dalteparin is also used to prevent a type of blood clot called deep vein thrombosis (DVT), which can lead to blood clots in the lungs (pulmonary embolism). A DVT can occur after certain types of surgery, or in people who are bed-ridden due to a prolonged illness.

Dalteparin is also used long-term to treat a type of blood clot called venous thromboembolism (VTE) in people with cancer.

Dalteparin may also be used for other purposes not listed in this medication guide.

What are the possible side effects of dalteparin (Fragmin)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using dalteparin and call your doctor at once if you have a serious side effect such as:

  • unusual bleeding (nose, mouth, vagina, or rectum), bleeding from wounds or needle injections, any bleeding that will not stop;
  • easy bruising, purple or red pinpoint spots under your skin;
  • pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;
  • black or bloody stools, coughing up blood or vomit that looks like coffee grounds;
  • numbness, tingling, or muscle weakness (especially in your legs and feet);
  • loss of movement in any part of your body;
  • sudden weakness, severe headache, confusion, or problems with speech, vision, or balance; or
  • trouble breathing.

Less serious side effects include pain, redness, or swelling where the medicine was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Fragmin (dalteparin) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about dalteparin (Fragmin)?

You should not use this medication if you are allergic to dalteparin, heparin, or pork products, or if you have active bleeding, or a low level of platelets in your blood after testing positive for a certain antibody while using dalteparin.

If you need anesthesia for a medical procedure or surgery, tell the doctor ahead of time that you are using dalteparin. You may need to stop using the medicine for a short time.

Dalteparin may cause you to bleed more easily, especially if you have: a bleeding disorder, hemorrhagic stroke, an infection in the lining of your heart, uncontrolled high blood pressure, stomach or intestinal bleeding or ulcer, or if you have had recent brain, spine, or eye surgery.

Many other drugs (including some over-the-counter medicines) can increase your risk of bleeding or life-threatening blood clots, and it is very important to tell your doctor about all medicines you have recently used.

Blood clots around the brain or spinal cord may occur if you use dalteparin with other drugs that can affect blood clotting, including aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) such as Advil or Motrin, and any other medications to treat or prevent blood clots.

Avoid taking aspirin unless your doctor recommends it as part of your treatment. Aspirin can increase your risk of bleeding.

Tell your caregivers at once if you have signs of bleeding such as black or bloody stools, coughing up blood, confusion, feeling like you might pass out, or any bleeding that will not stop.

Side Effects Centers

Fragmin Patient Information including How Should I Take

What should I discuss with my healthcare provider before using dalteparin (Fragmin)?

You should not use this medication if you are allergic to dalteparin, heparin, or pork products, or if you have:

  • active or uncontrolled bleeding; or
  • or a low level of platelets in your blood after testing positive for a certain antibody while using dalteparin.

Dalteparin may cause you to bleed more easily, especially if you have:

  • a bleeding disorder that is inherited or caused by disease;
  • hemorrhagic stroke;
  • an infection of the lining of your heart (also called bacterial endocarditis);
  • uncontrolled high blood pressure;
  • stomach or intestinal bleeding or ulcer; or
  • recent brain, spine, or eye surgery.
  • a genetic spinal defect;
  • a history of spinal surgery or repeated spinal taps; or
  • if you are using other medications to treat or prevent blood clots.

If you have any of these other conditions, you may need a dalteparin dose adjustment or special tests:

  • eye problems caused by diabetes or high blood pressure;
  • severe liver or kidney disease;
  • recent stomach bleeding; or
  • low levels of platelets in your blood.

FDA pregnancy category B. Dalteparin is not expected to harm an unborn baby. However, some forms of this medication contain a preservative that may be harmful to a newborn. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether dalteparin passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use dalteparin (Fragmin)?

Dalteparin is injected under the skin. You may be shown how to use injections at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles and syringes.

You should be sitting or lying down during the injection. Do not inject dalteparin into a muscle.

Use a different place on your stomach each time you give the injection. Your care provider will show you the best places on your body to inject the medication. Do not inject into the same place two times in a row.

Prepare your dose in a syringe only when you are ready to give yourself an injection. Do not use the medication if it has changed colors or has particles in it. Call your doctor for a new prescription.

Do not mix dalteparin with other medications in the same syringe unless your doctor tells you to.

If you use a single-dose prefilled syringe, follow the injection instructions closely. Single-dose syringes come in two different types and the directions for use are not the same for each type.

Use a disposable needle only once. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.

When used for DVT or blood vessel complications, dalteparin is usually given every day until your bleeding condition improves. When used for VTE, dalteparin is often used for several months. Follow your doctor's instructions.

To be sure this medication is not causing harmful effects, your blood and your stool (bowel movement) may need to be tested often. Your nerve and muscle function may also need to be tested. Visit your doctor regularly.

Tell any doctor who treats you that you are using dalteparin. If you need surgery or dental work, tell the surgeon or dentist ahead of time that you are using this medication. If you need anesthesia for a medical procedure or surgery, you may need to stop using dalteparin for a short time.

Store dalteparin vials (bottles) at room temperature away from moisture and heat. Once you have used a vial for the first time, the medicine will keep at room temperature for up to 2 weeks. Throw away the vial after 2 weeks have passed since you first used the vial, even if there is still medicine left in it.

Side Effects Centers

Fragmin Patient Information including If I Miss a Dose

What happens if I miss a dose (Fragmin)?

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose (Fragmin)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose may cause excessive bleeding.

What should I avoid while using dalteparin (Fragmin)?

Avoid taking aspirin unless your doctor recommends it as part of your treatment. Aspirin can increase your risk of bleeding.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

What other drugs will affect dalteparin (Fragmin)?

Many other drugs (including some over-the-counter medicines) can increase your risk of bleeding, and it is very important to tell your doctor about all medicines you have recently used. Bleeding or blood clots around the brain or spinal cord may occur if you use dalteparin with other drugs that can affect blood clotting, such as:

  • dextran (Gentran, Hyskon);
  • heparin, warfarin (Coumadin);
  • abciximab (ReoPro), eptifibatide (Integrelin), tirofiban (Aggrastat);
  • cilostazol (Pletal), clopidogrel (Plavix), dipyridamole (Persantine, Aggrenox), prasugrel (Effient), ticlopidine (Ticlid);
  • enoxaparin (Lovenox), fondaparinux (Arixtra), tinzaparin (Innohep);
  • argatroban (Acova), bivalirudin (Angiomax), lepirudin (Refludan);
  • alteplase (Activase), tenecteplase (TNKase), urokinase (Abbokinase);
  • an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Motrin, Advil), diclofenac (Cataflam, Voltaren), etodolac (Lodine), indomethacin (Indocin), ketoprofen (Orudis), ketorolac (Toradol), meloxicam (Mobic), nabumetone (Relafen), naproxen (Aleve, Naprosyn), piroxicam (Feldene), and others; or
  • salicylates such as Backache Relief Extra Strength, Novasal, Nuprin Backache Caplet, Doan's Pills Extra Strength, Pepto-Bismol, Tricosal, and others.

This list is not complete and other drugs may interact with dalteparin. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about dalteparin.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 6.02. Revision date: 12/15/2010.

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