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Fragmin
Overview
What is Fragmin?
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.
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 sulphated 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:
What does Fragmin look like?
What are the available doses of Fragmin?
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How should I use Fragmin?
FRAGMIN Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy (as described in ).
FRAGMIN is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):
FRAGMIN 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 patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of FRAGMIN Injection is 120 IU/kg of body weight, but not more than 10,000 IU, subcutaneously (s.c.) 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 13 lists the volume of FRAGMIN, based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.
What interacts with Fragmin?
FRAGMIN Injection is contraindicated in patients with known hypersensitivity to the drug, active major bleeding, or thrombocytopenia associated with positive tests for antiplatelet antibody in the presence of FRAGMIN.
Patients undergoing regional anesthesia should not receive FRAGMIN for unstable angina or non-Q-wave myocardial infarction, and patients with cancer undergoing regional anesthesia should not receive FRAGMIN for extended treatment of symptomatic VTE, due to an increased risk of bleeding associated with the dosage of FRAGMIN recommended for these indications.
Patients with known hypersensitivity to heparin or pork products should not be treated with FRAGMIN.
What are the warnings of Fragmin?
The coadministration of carbamazepine 200 mg BID with nefazodone 200 mg BID, at steady state for both drugs, resulted in almost 95% reductions in AUCs for nefazodone and hydroxynefazodone, likely resulting in insufficient plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant effect for nefazodone. Consequently, it is recommended that nefazodone not be used in combination with carbamazepine (see and ).
FRAGMIN Injection is not intended for intramuscular administration.
FRAGMIN cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular weight heparins.
FRAGMIN should be used with extreme caution in patients with history of heparin-induced thrombocytopenia.
Hemorrhage
FRAGMIN, like other anticoagulants, should be used with extreme caution in patients who have an increased risk of hemorrhage, such as those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal or ophthalmological surgery.
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, which can result in long-term or permanent paralysis. The risk of these events is higher with the use of indwelling epidural catheters or concomitant use of additional drugs affecting hemostasis such as NSAIDs (see and ).
As with other anticoagulants, bleeding can occur at any site during therapy with FRAGMIN. An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site.
Thrombocytopenia
In FRAGMIN clinical trials supporting non-cancer indications, platelet counts of < 100,000/mm and < 50,000/mm occurred in < 1% and < 1% of patients, respectively.
In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the FRAGMIN treatment arm, platelet counts of < 100,000/mm occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the FRAGMIN arm and 8.1% of patients in the OAC arm. FRAGMIN dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm.
Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN. The incidence of this complication is unknown at present. In clinical practice, rare cases of thrombocytopenia with thrombosis have also been observed.
Miscellaneous
Each multiple-dose vial of FRAGMIN 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, FRAGMIN preserved with benzyl alcohol should be used with caution in pregnant women and only if clearly needed. If anticoagulation with FRAGMIN is needed during pregnancy, preservative-free formulations should be used, where possible. (see ).
What are the precautions of Fragmin?
General
FRAGMIN Injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.
FRAGMIN should be used with caution in patients with bleeding diathesis, thrombocytopenia or platelet defects; severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding.
If a thromboembolic event should occur despite dalteparin prophylaxis, FRAGMIN should be discontinued and appropriate therapy initiated.
Drug Interactions
FRAGMIN should be used with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding (see ). Aspirin, unless contraindicated, is recommended in patients treated for unstable angina or non-Q-wave myocardial infarction (see ).
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. No special monitoring of blood clotting times (i.e., APTT) is needed.
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 activity and, therefore, unsuitable for monitoring the anticoagulant effect of FRAGMIN.
Anti-Factor Xa may be used to monitor the anticoagulant effect of FRAGMIN, such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding should occur during FRAGMIN therapy.
Drug/Laboratory Test Interactions
In FRAGMIN 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.
In the FRAGMIN clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with FRAGMIN 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 (NCI-CTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively.
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 Ames Test, mouse lymphoma cell forward mutation test and human lymphocyte chromosomal aberration test and in the mouse micronucleus test. Dalteparin sodium at subcutaneous doses up to 1200 IU/kg (7080 IU/m) did not affect the fertility or reproductive performance of male and female rats.
Pregnancy
Nursing Mothers
Limited data are available for excretion of dalteparin in human milk. One study in 15 lactating women receiving prophylactic doses of dalteparin detected small amounts of anti-Xa activity in breast milk, equivalent to a milk/plasma ratio of <0.025–0.224. As oral absorption of LMWH is extremely low, the clinical implications, if any, of this small amount of anticoagulant activity on the nursing infant are unknown. Caution should be exercised when Fragmin is administered to nursing women.
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, 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 between elderly and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised, particularly in geriatric patients with low body weight (< 45 kg) and those predisposed to decreased renal function (see also and and subsections of ).
What are the side effects of Fragmin?
Hemorrhage
The incidence of hemorrhagic complications during treatment with FRAGMIN Injection has been low. The most commonly reported side effect is hematoma at the injection site. The incidence of bleeding may increase with higher doses; however, in abdominal surgery patients with malignancy, no significant increase in bleeding was observed when comparing FRAGMIN 5000 IU to either FRAGMIN 2500 IU or low dose heparin.
In a trial comparing FRAGMIN 5000 IU once daily to FRAGMIN 2500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding events was 4.6% and 3.6%, respectively (n.s.). In a trial comparing FRAGMIN 5000 IU once daily to heparin 5000 U twice daily, the incidence of bleeding events was 3.2% and 2.7%, respectively (n.s.) in the malignancy subgroup.
Unstable Angina and Non-Q-Wave Myocardial Infarction
Table 8 summarizes major bleeding events that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.
| Indication | Dosing Regimen | ||
|---|---|---|---|
| Unstable Angina andNon-Q-Wave MI | |||
| Major Bleeding Events | 15/1497 (1.0) | 7/731 (1.0) | 4/760 (0.5) |
Hip Replacement Surgery
Table 9 summarizes: 1) all major bleeding events and, 2) other bleeding events possibly or probably related to treatment with FRAGMIN (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.
Six of the patients treated with FRAGMIN experienced seven major bleeding events. Two of the events 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 nor died of bleeding complications.
In the third hip replacement surgery clinical trial, the incidence of major bleeding events was similar in all three treatment groups: 3.6% (18/496) for patients who started FRAGMIN before surgery; 2.5% (12/487) for patients who started FRAGMIN after surgery; and 3.1% (15/489) for patients treated with warfarin sodium.
| 2 | ||||
| 4 | ||||
| FRAGMIN vsWarfarin Sodium | FRAGMIN vsHeparin | |||
|---|---|---|---|---|
| Indication | Dosing Regimen | Dosing Regimen | ||
| HipReplacementSurgery | ||||
| Major Bleeding Events | 7/274 (2.6) | 1/279 (0.4) | 0 | 3/69 (4.3) |
| Other Bleeding Events Hematuria | 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) |
Abdominal Surgery
Table 10 summarizes bleeding events that occurred in clinical trials which studied FRAGMIN 2500 and 5000 IU administered once daily to abdominal surgery patients.
| FRAGMIN vs Heparin | FRAGMIN vs Placebo | FRAGMIN vs FRAGMIN | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Indication | Dosing Regimen | Dosing Regimen | Dosing Regimen | ||||||
| FRAGMIN2500 IUonce daily s.c.n(%) | Heparin5000 Utwice daily s.c.n(%) | FRAGMIN5000 IUonce daily s.c.n(%) | Heparin5000 Utwice daily s.c.n(%) | FRAGMIN2500 IUonce daily s.c.n(%) | Placeboonce daily s.c.n(%) | FRAGMIN2500 IUonce daily s.c.n(%) | FRAGMIN5000 IUonce daily s.c.n(%) | ||
| PostoperativeTransfusions | 26/459(5.7) | 36/454(7.9) | 81/508(15.9) | 63/498(12.7) | 14/182(7.7) | 13/182(7.1) | 89/1025(8.7) | 125/1033(12.1) | |
| WoundHematoma | 16/467(3.4) | 18/467(3.9) | 12/508(2.4) | 6/498(1.2) | 2/79(2.5) | 2/77(2.6) | 1/1030(0.1) | 4/1039(0.4) | |
| ReoperationDue to Bleeding | 2/392(0.5) | 3/392(0.8) | 4/508(0.8) | 2/498(0.4) | 1/79(1.3) | 1/78(1.3) | 2/1030(0.2) | 13/1038(1.3) | |
| Injection SiteHematoma | 1/466(0.2) | 5/464(1.1) | 36/506(7.1) | 47/493(9.5) | 8/172(4.7) | 2/174(1.1) | 36/1026(3.5) | 57/1035(5.5) |
Medical Patients with Severely Restricted Mobility During Acute Illness
Table 11 summarizes major bleeding events that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.
Three of the major bleeding events that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with FRAGMIN and one in the group receiving placebo). Two deaths occurred after Day 21: one patient in the placebo group died from a subarachnoid hemorrhage that started on Day 55, and one patient died on day 71 (two months after receiving the last dose of FRAGMIN) from a subdural hematoma.
| Indication | Dosing Regimen | |
|---|---|---|
| Medical Patients with SeverelyRestricted Mobility | ||
| Major Bleeding Events at Day 14 | 8/1848 (0.4) | 0/1833 (0) |
| Major Bleeding Events at Day 21 | 9/1848 (0.5) | 3/1833 (0.2) |
Patients with Cancer and Acute Symptomatic Venous Thromboembolism
Table 12 summarizes the number of patients with bleeding events that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding eventwas 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 arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the FRAGMIN arm at Day 71) was fatal.
| Study period | FRAGMIN 200 IU/kg (max. 18,000 IU) sc once daily × 1 month, then 150 IU/kg (max. 18,000 IU) s.c. once daily × 5 months | OACFRAGMIN 200 IU/kg (max 18,000 IU) s.c. once daily × 5–7 days and OAC for 6 months (target INR 2–3) | |||||
|---|---|---|---|---|---|---|---|
| Number at risk | Patients with Major Bleedingn(%) | Patients with Any Bleedingn(%) | Number at risk | Patients with Major Bleedingn(%) | Patients with Any Bleedingn(%) | ||
| Total during study | 338 | 19 (5.6) | 46 (13.6) | 335 | 12 (3.6) | 62 (18.5) | |
| Week 1 | 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) |
Thrombocytopenia
See .
Other
Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bulleous eruption) have occurred rarely. A few cases of anaphylactoid reactions have been reported.
Pain at the injection site, the only non-bleeding event determined to be possibly or probably related to treatment with FRAGMIN and reported at a rate of at least 2% in the group treated with FRAGMIN, was reported in 4.5% of patients treated with FRAGMIN 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 5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day.
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). Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made.
Skin necrosis has occurred rarely. There have been isolated cases of alopecia reported that improved on drug discontinuation.
What should I look out for while using Fragmin?
FRAGMIN Injection is contraindicated in patients with known hypersensitivity to the drug, active major bleeding, or thrombocytopenia associated with positive tests for antiplatelet antibody in the presence of FRAGMIN.
Patients undergoing regional anesthesia should not receive FRAGMIN for unstable angina or non-Q-wave myocardial infarction, and patients with cancer undergoing regional anesthesia should not receive FRAGMIN for extended treatment of symptomatic VTE, due to an increased risk of bleeding associated with the dosage of FRAGMIN recommended for these indications.
Patients with known hypersensitivity to heparin or pork products should not be treated with FRAGMIN.
FRAGMIN Injection is not intended for intramuscular administration.
FRAGMIN cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular weight heparins.
FRAGMIN should be used with extreme caution in patients with history of heparin-induced thrombocytopenia.
What might happen if I take too much Fragmin?
How should I store and handle Fragmin?
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP] .FRAGMIN Injection is available in the following strengths and package sizes:
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Doses of FRAGMIN 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 do not produce a significant change in platelet aggregation, fibrinolysis, or global clotting tests such as prothrombin time (PT), thrombin time (TT) or APTT. Subcutaneous (s.c.) administration of doses of 5000 IU twice daily of FRAGMIN for seven consecutive days to patients undergoing abdominal surgery did not markedly affect APTT, Platelet Factor 4 (PF4), or lipoprotein lipase.
Non-Clinical Toxicology
FRAGMIN Injection is contraindicated in patients with known hypersensitivity to the drug, active major bleeding, or thrombocytopenia associated with positive tests for antiplatelet antibody in the presence of FRAGMIN.Patients undergoing regional anesthesia should not receive FRAGMIN for unstable angina or non-Q-wave myocardial infarction, and patients with cancer undergoing regional anesthesia should not receive FRAGMIN for extended treatment of symptomatic VTE, due to an increased risk of bleeding associated with the dosage of FRAGMIN recommended for these indications.
Patients with known hypersensitivity to heparin or pork products should not be treated with FRAGMIN.
FRAGMIN Injection is not intended for intramuscular administration.
FRAGMIN cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular weight heparins.
FRAGMIN should be used with extreme caution in patients with history of heparin-induced thrombocytopenia.
FRAGMIN should be used with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding (see ). Aspirin, unless contraindicated, is recommended in patients treated for unstable angina or non-Q-wave myocardial infarction (see ).
FRAGMIN Injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.
FRAGMIN should be used with caution in patients with bleeding diathesis, thrombocytopenia or platelet defects; severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding.
If a thromboembolic event should occur despite dalteparin prophylaxis, FRAGMIN should be discontinued and appropriate therapy initiated.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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